Biological Bases of Behavior - EPPP Fundamentals, Step One

1 Biological Bases of Behavior Ashley Gorman, Daniel DaSilva, and Brenda Stepak Broad Content Areas Biological and neural bases of behavior Psychopharmacology Methodologies supporting this body of knowledge Introduction Biological processes are responsible, whether in isolation or concert with other processes, for all human and animal behavior. The biological system consists of highly complex, delicate, and integrated structures and mechanisms that are not fully understood by science. However, our knowledge in this area is growing at a rapid pace. We present the core components involved in the critical role biophysi- ological processes play in human and animal behavior, with a focus on structures, functions, interventions, and methodologies. Central Nervous System It is important to understand that the brain forms only one part of what is known as the central nervous system (CNS), which, as a unit, comprises the brain and spinal cord. Elegant in design but complex in function, the brain and spinal cord make up the biological core of the human experience. To understand this system in terms of its functions and dysfunctions requires an understanding of these major structures and their role in the integration of our internal and external experiences. Spinal Cord The human spinal cord is a segmented cord linked with the organs and muscles of specific body regions. The spinal cord has four major divisions with 30 total segments, from the neck to the sacrum. The segments are identified according to their location in one of the three regions: cervical (C1–C8), thoracic (T1–T12), lumbar (L1–L5), and sacral (S1–S5). Fibers entering the dorsal portion of the spinal cord carry sensory information from the body to the brain. Descending fibers exit- ing the ventral portion of the spinal cord carry motor information to the muscles. 2 EPPP FUNDAMENTALS, STEP ONE When the spinal cord is damaged, a person loses the ability to feel and/or move the corresponding portion of his or her body at and below the site of the damage. For example, damage to the upper cervical regions of the spinal cord results in quadriplegia (inability to move the arms and legs), whereas damage to lower cervi- cal regions results in paraplegia (inability to move the legs). Incomplete damage to the spinal cord may result in muscle weakness (paresis) as opposed to total immobility (paralysis). In addition to mediating voluntary movement, the spinal cord is also involved in involuntary movements such as reflexes (e.g., the with- drawal reflex from pain). Brain Skull and Cranial Meninges The CNS, and the brain in particular, is guarded by several layers of protec- tion. The most obvious is the skull, which is the bone structure forming the cra- nial vault. Just inside and, in various places, closely attached to the skull is the dura mater. This fibrous membrane also forms the falx cerebri, which extends down into the longitudinal fissure separating the two hemispheres of the brain. The arachnoid mater is a thinner and more delicate membrane separated from the dura by the subdural space, through which passes a series of veins. Finally, the pia mater is the most delicate and highly vascular membrane, which closely follows the contours of the brain. The pia is separated from the dura by the sub- arachnoid space, which contains a network of arteries, veins, and connective tis- sue known as trabeculae. Ventricles Providing both protection and structural support, the internally located ventricu- lar system comprises open chambers and channels filled with cerebral spinal fluid (CSF). This colorless fluid circulates through the two large lateral ventricles, located internally in each cerebral hemisphere, to the centrally located third ven- tricle, through the cerebral aqueduct, and into the fourth ventricle in the dorsal brain stem. From there, the fluid flows in the subarachnoid space around the brain and spinal cord. The fluid is formed predominantly in the linings of the lateral ventricles known as the choroid plexus, and then reabsorbed after its cir- culation. The CSF maintains the brain’s neutral buoyancy in the cranial vault and plays an important role in protection from infection and regulation of cerebral blood flow. Cerebrum Gross examination of the human brain reveals that the surface comprises convo- lutions of fissures (the inward folds) and gyri (the smoothly curved hills), both serving to increase the surface area of the cortex. Comprising six layers of cell bodies and interconnections, the cortex forms the outer and most visible layer of the brain, also known as the gray matter. Although functionally significant, the fissures and gyri also form the definitions and boundaries of the major structures of the telencephalon, or cerebrum, which includes the four major lobes (frontal, temporal, parietal, and occipital). Each lobe is represented bilaterally in the right and left hemispheres. 1. Biological Bases of Behavior 3 Frontal Lobe Located anterior of the central sulcus, the frontal lobe is the largest of the four lobes, governs output, and is considered the seat of higher cortical and cognitive function- ing. Major anatomical subdivisions include the primary motor cortex, premotor cortex, orbitofrontal cortex, and prefrontal cortex. These regions are particularly devoted to attention, cognition, reasoning, problem solving, and voluntary movement. Directly anterior to the central sulcus is the primary motor cortex. This gyrus, which runs laterally from superior to inferior, is crucial in the initiation of motor movements, and isolated muscle groups are specifically represented along this gyrus. Moreover, the relative representation in this region corresponds directly to the req- uisite accuracy of motor control. For example, hands, fingers, lips, and tongue are heavily represented, whereas other regions, such as the trunk and torso, are less so. Damage to this region will produce deficits in motor learning, and more severe forms of lateralized damage will produce hemiparesis. Directly anterior to the primary motor cortex is the premotor cortex, a region dedicated to the initiation and execution of limb movements in conjunction with input from other cortical regions. Mirror neurons located here have been associ- ated with imitation and empathy, and have been the focus of some autism studies (Acharya & Shukla, 2012; Schulte-Ruther, Markowitsch, Fink, & Piefke, 2007; Williams, Whiten, Suddendorf, & Perrett, 2001). Prefrontal and orbitofrontal regions, located anterior to the primary motor cortex, are most often associated with the higher-level cognitive functions also known as the executive functions, which include reasoning, planning, and judg- ment. Dysfunction in this region has been associated with many disorders, includ- ing attention deficit hyperactivity disorder (ADHD) and schizophrenia. Inhibitory control is also most often associated with this region. The frontal lobe injury sus- tained in the mid-1800s by Phineas Gage, a railroad construction worker, is often considered an illustrative example of classic frontal lobe impairment. For the majority of individuals, the inferior lateral region of the left frontal lobe is known as Broca’s area. This area is particularly dedicated to the fluent production of oral and written speech, as well as grammar and comprehension of syntax. The dysfunction associated with a lesion here is most often recognized as Broca’s (or expressive) aphasia (an acquired disorder of language). Temporal Lobes Located inferior to the lateral sulcus, the temporal lobes are divided into the supe- rior, middle, and inferior temporal gyri. Located in the superior temporal gyrus is the site of primary auditory processing, where conscious perception of sound takes place. This region, typically found in the infolded region of superior temporal gyrus, is also known as Heschl’s convolutions. Reception of stimuli in this region is considered “tonotopic,” which corresponds to individual frequencies detected at the level of the cochlea located in the inner ear. Stimuli arrive here by way of the vestibulocochlear nerves and the medial geniculate nuclei of the thalamus, and undergo only partial “decussation,” by which incoming stimuli are transmit- ted to the contralateral hemisphere for processing. Because of partial decussation, or crossing of fibers, sound stimuli critical for auditory language comprehension will still arrive at the language-dominant hemisphere. Immediately adjacent and posterior to the primary auditory cortex is the auditory association cortex, where sound is further processed. In the language-dominant hemisphere, this region is known as Wernicke’s area, which is dedicated to the comprehension of language. 4 EPPP FUNDAMENTALS, STEP ONE Lesions in this region will disrupt not only the ability to comprehend language but also the meaningful expression of language, a deficit known as Wernicke’s (or receptive) aphasia. Parietal Lobes The parietal lobes are located posterior to the central sulcus and include the site of primary somatosensory processing on the postcentral gyrus. Major neuroana- tomical structures also include the inferior and superior parietal lobules. Within the parietal lobes are large regions of the heteromodal cortex, where different sen- sory modalities are integrated to construct a complete picture. The parietal lobes process visual information along dorsal and ventral pathways from the occipital lobes to help coordinate movements and behaviors with the environment. Damage to posterior regions of the parietal lobe can result in neglect syndromes such as hemispatial neglect, which is characterized by an inability to attend to features of the environment in the space contralateral to the lesion site. As noted, primary somatosensory processing occurs on the postcentral gyrus, where “somatotopic” detection of touch, pressure, pain, and temperature takes place. As on the primary motor cortex, regions of the sensory cortex proportion- ally represent body regions depending on their relative sensitivity; for example, there is heavy representation of the finger tips, face, and lips. Lateralized lesions here will result in hemisensory loss (loss of sensation on one side of the body). Occipital Lobes Located posterior to the temporal and parietal lobes, the occipital lobes are geo- graphically defined by the parieto-occipital sulcus visible on the medial surface of the hemisphere. Primarily dedicated to visual processing, primary visual process- ing is located in the region of the occipital pole, posterior to the calcarine sulcus. Primary visual processing is photopic in nature, receiving its stimuli from the retina and optic nerve by way of the lateral geniculate nucleus of the thalamus. Properties such as color and movement are processed at the primary visual, or striate, cortex. They are then sent for further processing and integration along the dorsal stream to parietal regions for processing of object location and along the ventral stream to temporal regions for object identification. These areas adjacent to primary processing, also known as peristriatal regions, are considered visual asso- ciation areas, which further process and integrate visual stimuli. Lesions in primary visual processing regions result in cortical blindness. Other lesions can result in disturbances in color perception and inability to detect orientation or movement. Teuber, Battersby, and Bender (1960) performed groundbreaking studies in visual processing and perception, finding that lesions of secondary processing regions result in deficits in such basic percepitual abilities as judgment of relative size, shape, and orientation. Deficits in the naming and recognition of objects presented visually may be specifically associated with lesions of the temporal lobes, a region of tertiary visual processing. Subcortical Brain Regions Hippocampus The inferior temporal lobe curls in toward the midline and forms a region known as the hippocampus. As part of the limbic system, the hippocampus is critical for 1. Biological Bases of Behavior 5 memory formation, such as the transfer of memories to longer-term stores. The classic cases of a patient initially known as H.M., whose hippocampi were sur- gically removed to control seizures, and Clive Wearing, a British musician who contracted encephalitis, illustrate the debilitating memory impairments associated with bilateral hippocampal lesions. Amygdala Also part of the limbic system, the amygdala is located anterior of the hippocam- pus and is involved in processing olfactory stimuli. However, the amygdala is most often associated with processing emotions. Its connections to midbrain structures make the amygdala an essential component of the “fight or flight” response. Thalamus Located superior to and contiguous with the brain stem is the thalamus. This struc- ture performs the critical relay functions between the cortex and the brain stem. Specific nuclei, or collections of nerve cells, form the specific transmission sites in the thalamus to and from specific cortical regions. Because of these very rich intercon- nections, the thalamus also performs important attention and perceptual functions. Basal Ganglia The basal ganglia is an important subcortical structure comprising a network of complex loops involved in motor output (i.e., descending motor pathways), emo- tions, cognition, and eye movements. The main components of the basal ganglia include the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra. The cerebral cortex provides most of the input to the basal gan- glia, and the primary outputs of the basal ganglia are sent to the thalamus. Motor abnormalities due to basal ganglia do not involve paresis or paralysis, but rather the coordination and rhythm of movement. These syndromes are referred to as “extrapyramidal syndromes.” For example, slow movements (i.e., bradykinesia) or excessive muscle rigidity result from basal ganglia dysfunction. Movement disor- ders such as Parkinson’s disease (PD) and Huntington’s disease result from abnor- mal activity in the basal ganglia. Brain Stem Comprising the medulla (also referred to as the medulla oblongata), pons, and midbrain, the brain stem forms the core of the brain. The midbrain and its compo- nent structures are surrounded by the cerebral hemispheres. Located caudally, or toward the tail, is the pons (or bridge), followed by the medulla, which is essen- tially contiguous with the spinal cord. Functionally, the brain stem, as a unit, is involved in the control and regulation of autonomic functions and maintaining the body’s homeostasis, including breathing, heart rate, temperature regulation, and blood pressure. The reticular formation, including the reticular activating system, plays important roles in alertness, consciousness, and pain. It also plays important roles in regulating the respiratory and cardiovascular systems. Ascending sensory pathways from the spinal cord rise through dorsal regions, whereas descending motor fibers pass through anterior regions of the brain stem. Cerebellum Attached to the posterior brain stem is the cerebellum. Rich in neurons, the cer- ebellum is structurally divided into the superior, middle, and inferior cerebellar 6 EPPP FUNDAMENTALS, STEP ONE peduncles. The middle cerebellar peduncle is the only structure visible on surface examination of the brain. The cerebellum comprises a gray matter cortex and subcortical white matter with rich interconnections to cortical regions of the other hemispheres of the brain. Functionally, the cerebellum is most often associated with the regulation of movement, including automatic and rhythmic movements, coordination of the limbs, and postural control. Studies have also associated the cerebellum with cognitive functions such as learning and attention (Helmuth, Ivry, & Shimizu, 1997). The cerebellum is particularly vulnerable in multiple sclerosis, which can result in disruption of ocular movements such as nystagmus (a rapid rhythmic eye movement that is particularly enhanced when the gaze is in the same direction of the lesion site). Lesions of the cerebellum can also produce motor incoordination and a characteristic wide-based stance and gait. Neurons The neuron is the building block of the nervous system. Neurons vary in size and shape and are highly specialized to a specific function. A typical neuron consists of a cell body (containing the nucleus), dendrites (short processes emerging from the cell body that receive inputs from other neurons), and axons (long processes that carry output away from the cell body). Most neurons in the human brain are “multipolar,” that is, they have multiple dendrites and axons. A myelin sheath, which is an insulating fatty layer, surrounds the axon and speeds up transmission. Axons can range in length from 1 millimeter to 1 meter. The synapse is the space between two neurons in which chemical and/or electrical communication occurs. In most cases, the axon from one neuron communicates with the dendrites of another neuron. Chemicals known as neurotransmitters are released “presynaptically” by the axon terminal of one neuron and bind to neurotransmitter receptors on the “post- synaptic” neuron, which may then cause postsynaptic excitation or inhibition. When postsynaptic excitation reaches a minimum threshold, that neuron then fires an action potential, causing that neuron to send the neural signal down its axon. The firing of a neuron is an “all-or-nothing” phenomenon–that is, the strength of neu- ronal firing does not vary in response to the strength of the input. In other words, a neuron either fires or it does not. After a neuron fires, there is a refractory period during which it is unable to fire again until it reestablishes an electrochemically based resting potential state. Different neurotransmitters have different effects on cells (excitatory or inhibitory), and the amount of a neurotransmitter that is avail- able for binding to the postsynaptic neuron can be affected by various medications. Neurotransmitters Neurotransmitters are chemicals that transmit signals from one neuron to another and are classified according to their molecular size. Biogenic amines (e.g., acetyl- choline [ACh] and serotonin), catecholamines (e.g., dopamine [DA], norepineph- rine [NE], and epinephrine), and amino acids (e.g., gamma-aminobutyric acid [GABA] and glutamate) are smaller molecular messengers, whereas neuropeptides (e.g., vasopressin, oxytocin, and substance P) are larger molecules. Neurotransmitters 1. Biological Bases of Behavior 7 fit into a receptor site like a lock and key, although a variety of neurotransmitters may fit into a single type of receptor (Zillmer & Spiers, 2001). The most significant neurotransmitters to psychopharmacology include NE, serotonin, DA, GABA, ACh, and glutamate (Wegman, 2012). Norepinephrine or “noradrenalin” is a catecholamine and functions as a hor- mone and a neurotransmitter. It is formed in the brain stem at a site called the “locus coeruleus” and is found in the sympathetic nervous system and CNS. It regulates mood, memory, alertness, hormones, and the ability to feel pleasure. Elevated levels may lead to anxiety, whereas low levels may cause depression (Wegman, 2012). NE also underlies the “fight or flight” response and is released into the blood as a hormone by the adrenal gland in response to stress or arousal. It is primarily considered an excitatory neurotransmitter, but may result in inhibi- tion in some areas. DA is also a catecholamine and can be both excitatory and inhibitory. The majority of DA neurons are in the substantia nigra. DA pathways extend to the frontal lobes, basal ganglia, and hypothalamus. Overactivity of DA in the pathway to the frontal lobes has been implicated in schizophrenia, and the loss of DA- producing neurons in the basal ganglia pathway is the underlying cause of PD. Underactivity of DA has also been implicated in ADHD (Wegman, 2012). DA plays a role in emotions, movement, and endocrine functioning, as well as attention, sociability, motivation, desire, pleasure, and reward-driven learning. Serotonin (5-HT) is a biogenic amine and is primarily inhibitory. It is widely distributed throughout the brain and originates in the raphe nuclei in the brain stem. Pathways extend to the limbic system, and serotonin levels are associated with the regulation of mood, anger, aggression, anxiety, appetite, learning, sleep, sexual functioning, level of consciousness, and pain. Low levels of serotonin are associated with depression, obsessive-compulsive disorder, and anxiety disorders (Wegman, 2012). Acetylcholine is also a biogenic amine and plays a major role in the parasym- pathetic nervous system and autonomic nervous system (Zillmer & Spiers, 2001). It is the primary neurotransmitter at the neuromuscular junction (the synapse between neuron and muscle cells) and is involved in movement. Degeneration of ACh in the striatum of the brain is associated with the movement disorder called Huntington’s disease. ACh also plays a major role in activating the brain through the reticular activating system and regulates alertness and attention. Another cho- linergic system involving the hippocampus influences attention, learning, and memory (Zillmer & Spiers, 2001). Gamma-aminobutyric acid is an amino acid and is the major inhibitory neuro- transmitter of the CNS. It is widely distributed throughout the CNS but is most con- centrated in the striatum, hypothalamus, spinal cord, and temporal lobes. GABA is associated with emotion, balance, and sleep patterns. Low levels of GABA are associated with high anxiety and agitation, and higher levels are associated with a reduction in anxiety (Wegman, 2012). GABA deficiencies are also implicated in epilepsy, and many antiepileptic drugs increase GABA activity. Glutamate is also an amino acid and is the brain’s primary excitatory neuro- transmitter. It is widely distributed throughout the CNS. It is a basic building block of proteins and plays an important role in learning and memory (Wegman, 2012). Excessive glutamate causes excitotoxicity (cell death due to excessive stimulation and excitation), and is implicated in cell death following traumatic brain injury and stroke. 8 EPPP FUNDAMENTALS, STEP ONE Psychopharmacology Psychologists may or may not have prescription privileges, depending on whether they have specialized training and whether this training is recognized by the state in which they practice or if they work for the federal government. It is impera- tive for even nonprescribing psychologists to possess a general understanding of psychotropic agents and whether they may be indicated. Often the psychologist will act as the intermediary between the patient and a prescribing clinician. It is necessary to be able to recognize when an evaluation for psychotropic medication (or for termination of medication) may be beneficial to the patient. Each patient is unique and will have different requirements based on age, sensitivities to medica- tions, and other characteristics. Pharmacokinetics and Pharmacodynamics Psychotropic medications cross the blood–brain barrier and cause physiological and biochemical changes. The mechanism of action for these medications is com- plex. To put it simply, these medications alter the activity of neurotransmitter com- munication between neurons by doing one or more of the following: disrupting the action of the neurotransmitter at the synapse (thus blocking the action of the neurotransmitter), inhibiting the enzymes that break down neurotransmitters in the synaptic cleft (thus boosting the overall transmission of that neurotransmitter), changing the sensitivity of postsynaptic neurons to neurotransmitters, or increas- ing the amount of neurotransmitter produced and available at the synapse. Psychoactive drugs are able to cause downstream biochemical and physiologi- cal changes by binding to receptor sites on neurons and either boosting the action of a particular neurotransmitter system or blocking the action of a neurotransmit- ter system. An agonist is a chemical that binds to a receptor site and mimics the activity of a neurotransmitter, thus causing the same downstream effects as that neurotransmitter and boosting the overall system. A partial agonist also binds to a receptor site and mimics the activity of a neurotransmitter, but cannot produce 100% of the effect of a full agonist, even at very high doses. An inverse agonist binds to the same receptor site as an agonist, but has the opposite effect of full agonists by causing a reduction in the overall efficacy of a neurotransmitter system. An antagonist also blocks or reverses the effect of agonists or inverse agonists, but when an agonist is not present, it has no effect of its own (Stringer, 2011). Pharmacodynamics describes the biochemical and physiological effects of drugs on the body. Pharmacokinetics describes how the body handles the drug through absorption, distribution, metabolism, and elimination. Absorption is the process through which drugs reach the bloodstream. This process occurs mainly in the small intestine and results in the drug’s onset and degree of action. A poorly absorbed drug may not reach the minimal effective concentration required in the blood for clinical efficacy. The bloodstream transporting a drug to its site of action serves as the distribution. The speed of distribution varies depending on how the drug is administered. For example, drugs taken orally must first travel through the digestive system, whereas drugs injected intramuscularly have a faster response. When a drug enters the bloodstream, metabolism begins. The body recognizes the drug as a foreign substance and attempts to eliminate it via chemical transfor- mation. Metabolism occurs primarily in the liver and kidney. People metabolize 1. Biological Bases of Behavior 9 psychotropic agents differently, and the sensitivities and preferences of each indi- vidual patient must be considered to get optimum risk–benefit ratios. For example, children and the elderly may metabolize drugs differently than young adults, and therefore dosage or scheduling adjustments may be required to achieve the best risk–benefit ratios. Once a drug is in circulation, elimination is a function of renal and hepatic processes. The elimination half-life of the drug is the time it takes for drug concentration to decrease by half due to excretion and metabolic change. In the steady state, the rate of elimination is equal to the rate of administration of the drug. A therapeutic window is defined by the range of a drug dose that can result in desired clinical efficacy without resulting in unsafe side effects. For example, if a drug has a narrow therapeutic window, then there is only a small range of dosages that can result in the desired benefit before it becomes unsafe. A therapeutic index is the ratio of the amount of drug that causes the desired benefit to the amount of the drug that produces dangerous side effects. It is more desirable for a drug to have a high therapeutic index, as it is a measure of drug safety. Psychoactive drugs can be classified according to the clinical disorders that they treat (e.g., anxiolytics, antidepressants, antipsychotics, mood stabilizers, stim- ulants, and pain medications). Psychoactive drug classes have unique mechanisms of action, even those that treat similar clinical disorders, and all have notable side effects and possible drug interactions that must be considered. The following sec- tion summarizes the primary psychoactive drug classifications, their mechanism of action, side effects, and drug interactions. Anxiolytics Anxiolytics refer to the psychotropic medications that may be used to treat anxiety disorders and can be classified into benzodiazepines and nonbenzodiazepines. Examples of anxiolytics that are benzodiazepines are alprazolam (Xanax), clonaz- epam (Klonapin), diazepam, (Valium), and lorazepam (Ativan). Anxiety disorders that may be treated with benzodiazepines include gen- eralized anxiety disorder, panic disorder, phobic disorders, adjustment disorder with anxiety, anxiety disorder due to a general medical condition, and substance- induced anxiety disorder (Pies, 2005; Wegman, 2012). Additionally, some benzo- diazepines are used as sleep agents and others may treat seizure disorders and alcohol withdrawal as well as other psychiatric disorders (Pies, 2005). Benzodiazepines act through the CNS and cause muscle relaxation as well as sedative, anxiolytic, and anticonvulsant effects. They enhance the action of GABA (which is an inhibitory neurotransmitter) and block the rapid release of stress hormones associated with anxiety and panic. These medications are rapidly and completely absorbed after oral administration and distributed throughout the body. Some are short acting and some are long acting (Stahl, 2011). The most significant side effects of benzodiazepines include drowsiness, confusion or feelings of detachment, dizziness, imbalance, and high potential for dependence. When discontinued, they must be tapered slowly to prevent with- drawal symptoms. In regard to drug interactions, benzodiazepines increase the effects of alcohol and other CNS depressants. They should be used cautiously in patients with liver disease and avoided in patients with a history of substance abuse (Stahl, 2011). Medications other than benzodiazepines are used to treat anxiety, how- ever, they do not provide the immediate relief that the benzodiazepines provide. 10 EPPP FUNDAMENTALS, STEP ONE Buspirone (BuSpar) is an example of a nonbenzodiazepine anxiolytic. Compared to benzodiazepines, BuSpar does not induce tolerance, causes less fatigue, and lacks hypnotic, anticonvulsant, and muscle-relaxant properties (Ingersoll & Rak, 2016). Gabapentin (Neurontin), an anticonvulsant, frequently prescribed for neuro- pathic pain, is also often prescribed off-label for anxiety. It is generally tolerated well and abuse/dependence are not concerns (Heldt, 2017). Pregabalin (Lyrica) is another anticonvulsant prescribed for anxiety (Stahl, 2011). Hydroxyzine (Vistaril, Atarax) is an antihistamine that reduces anxiety more than other medications in its class. It is very sedating so it is not that effective for daytime use. Abuse and dependence are not concerns with this medication (Heldt, 2017). Since the 1990s benzodiazepines have been increasingly replaced by selective serotonin reuptake inhibitors (SSRIs) and other antidepressants as clinicians’ first choice for the treatment of anxiety disorders, due to their increased safety, lower side-effect profile, and decreased likelihood of dependence (Asho & Sheehan, 2004). Barbiturates are medications that were formerly used for sedation and to induce sleep, but have now been essentially replaced by benzodiazepines. The side effects of barbiturates are extreme, including tolerance, physical dependency, and very severe withdrawal symptoms. They also enhance the function of GABA in the CNS (Stringer, 2011). Antidepressants Antidepressants are a diverse group of medications. Each class has different mecha- nisms of action. The primary classifications of antidepressants include monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), SSRIs, norepinephrine– dopamine reuptake inhibitors (NDRIs), and serotonin–norepinephrine reuptake inhibitors (SNRIs). In general, antidepressants do not cause dependence, toler- ance, or addiction. These medications are used to treat disorders such as unipolar major depression, dysthymic disorder, adjustment disorders, and mood disorder due to general medical condition. These medications are also used in the treat- ment of many anxiety disorders (Pies, 2005), ADHD, and eating disorders. The use of antidepressants is relatively contraindicated in patients with bipolar disorder, as they may induce mania unless the patient is currently being treated with a mood stabilizer (Stahl, 2011; Stein, Lerer, & Stahl, 2012). They are also used in the treat- ment of OCD (Ingersoll & Rak, 2016). The medications listed earlier target a class of neurotransmitters called the monoamines, which include NE, serotonin, and DA. The “monoamine hypothesis” of depression dates back to the 1960s and postulates that depression is caused by abnormal functioning of these neurotransmitters. Based on this hypothesis, antidepressant medications are thought to increase the availability of these neu- rotransmitters at the synaptic level. However, a simple deficiency of monoamines at the synaptic level is no longer thought to explain the mechanisms of action of these medications in full (Patterson, McCahill, & Edwards, 2010), and antidepres- sants likely affect many biological systems in addition to neurotransmitter uptake (Mycek, Harvey, & Champe, 1997). TCAs These drugs, as indicated in their name, are categorized on the basis of their chemical three-ring structure (Pies, 2005). Examples of TCAs include ami- triptyline (Elavil), nortriptyline (Pamelor and Aventyl), imipramine (Tofranil), and 1. Biological Bases of Behavior 11 desipramine (Norpramin). Absorption of the tricyclic drugs occurs in the small intestine, and peak levels occur within 2 to 8 hours following ingestion (Golan, Tashjian, Armstrong, & Armstrong, 2008). Tricyclics block the reuptake of sero- tonin and NE (thus increasing the activity of these neurotransmitter systems by making them more available for binding to postsynaptic neurons); however, the precise mechanism of action of the TCAs is unknown (Stringer, 2011). Unfortunately, this class of medications has side effects that make them unattrac- tive. Side effects of TCAs fall into three categories: cardiac/autonomic, anticholinergic, and neurobehavioral. Orthostatic hypotension (a drop in standing blood pressure) is one of the most common reasons for discontinuation of this medication (Pies, 2005). MAOIs MAOIs are rarely used today because of serious drug–drug and drug– food interactions. They block the reuptake of monoamine neurotransmitters (sero- tonin, NE, and DA) by blocking their respective monoamine transporters, thus increasing the levels of these neurotransmitters in the synaptic cleft (Keltner & Folks, 2005). Examples of MAOIs include phenelzine (Nardil) and tranylcypromine (Parnate). The most dangerous side effect of MAOIs is hypertensive crisis, which can occur when an MAOI is taken with tyramine (Stahl, 2011). SSRIs These medications, which block the reuptake of serotonin by selective binding, are especially effective for the treatment of depression with agitation and/ or comorbid anxiety. The term “selective” is used because they have weaker affinity for blocking the action of other monoamines. Examples of SSRIs include fluoxetine (Prozac), paroxetine (Paxil), fluvoxamine (Luvox), setraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). SSRIs are less likely to cause anticholinergic and cardiac/autonomic side effects than the TCAs; however, side effects do include gastrointestinal side effects, headache, sexual dysfunction, insomnia, psychomotor agitation, and occasional extrapyramidal reactions (Wegman, 2012). Serotonin syn- drome, a dangerous side effect, can occur when two serotonergic drugs are taken at the same time or when excessively high amounts of a single serotonergic agent is ingested. Symptoms include a change in mental status, shivering, confusion, rest- lessness, flushing, diaphoresis (sweating), diarrhea, lethargy, myoclonus (muscle twitching and jerks), and tremors. In its extreme form it can be lethal (Heldt, 2017). Atypical antidepressants do not fall into the earlier categories. They include the following. NDRI: These antidepressants work by blocking the reuptake of NE and DA. An example of an NDRI is bupropion (Wellbutrin or Zyban). Zyban is for smoking cessation. SNRI: These medications block the reuptake of serotonin and NE. An example of an SNRI is venlafaxine (Effexor). Desvenlafaxine (Pristiq) was designed from a metabolite of Effexor. Levomilnacipran (Fetzima) is a newer SNRI (released in 2013). Mirtazapine/Remeron: A serotonin-norepinephrine antagonist. This atypical antidepressant medication increases both serotonin and norepinephrine release by blocking the appropriate autoreceptors. Trintellix/Vortioxetine: The mechanism of action of this atypical antidepres- sant is unclear. It has even been described as a new class of medication. It differs from SSRIs in its multimodal effect of serotonin transport and reuptake. It also improves cognitive symptoms, which distinguishes it from other antidepressants (Bass & Iliades 2014). 12 EPPP FUNDAMENTALS, STEP ONE Trazodone: This atypical antidepressant is often used to treat insomnia, rather than as an antidepressant (Adams, Holland, & Urban 2017). Priapism (an intractable erection) is a rare side effect (Stahl, 2011), but can occur. Over-the-counter products: St. John’s wort, S-adenosyl methionine (SAMe), 5-HTP, omega-3 fatty acids, and folic acid have all been shown to have some efficacy in treating depression. Omega-3 fatty acids and folic acid are typically used in conjunction with antidepressants (Preston & John- son, 2014). However, it is important to note that these alternative reme- dies can also have negative side effects and adverse drug interactions. For example, St. John’s wort can reduce the effectiveness of oral contracep- tives and omega-3 fatty acids can increase the risk of bruising and bleed- ing, especially when combined with blood thinners (Wegman, 2012). Ketamine: A possible future agent for depression, Ketamine is an anesthetic agent and a drug of abuse. Known as Special K, it must be given by IV and its effects only last a few days. It may be best used as a model to develop other drugs that are similar but have fewer side effects (Ingersall & Rak 2016). Antipsychotics Antipsychotics are primarily used to treat schizophrenia, schizophreniform disor- der, schizoaffective disorder, brief psychotic disorder, bipolar disorder, and agitation (Pies, 2005). Several neurochemical abnormalities are associated with schizophrenia but the DA system is the most studied (Patterson et al., 2010). All traditional (or first- generation) antipsychotic medications block DA receptors, whereas atypicals (or second generation) also block serotonin receptors (Patterson et al., 2010). Conventional antipsychotics (“typical” or “first generation”) First devel- oped in the 1950s, all of the drugs in this group seem to have equal efficacy but differ in potency and side effects. Examples of conventional antipsychotics include haloperidol (Haldol), thioridazine (Mellaril), molinidine (Moban), thiothix- ene (Navane), fluphenazine (Prolixin), trifluoperazine (Stelazine), chlorpromazine (Thorazine), Loxipine (Loxitane), and Pimozide (Orap) (Preston & Johnson, 2014). Conventional antipsychotics may cause extrapyramidal symptoms (EPSs), including parkinsonism, acute dystonia, akathisia, and tardive dyskinesia. The first three EPSs are early drug reactions. The fourth, tardive dyskinesia, results from long-term use. Parkinsonism includes bradykinesia (slowed movements), tremor, and rigidity. Acute dystonia includes muscle spasms in the tongue, face, neck, and back. Akathisia is characterized by restless movements and symptoms of anxiety and agitation. Tardive dyskinesia is characterized by abnormal involuntary, stereo- typed movements of the face, tongue, trunk, and extremities. Unfortunately, this syndrome may be irreversible, even when antipsychotic medications are discontin- ued (Lehne, 2013). A 2017 Food and Drug Administration (FDA)-approved medica- tion, valbenazine (Ingrezza), improves tardive dyskinesia symptoms. Another potential side effect is neuroleptic malignant syndrome (NMS), a rare but life-threatening reaction characterized by catatonia, stupor, fever, and auto- nomic instability. Additional side effects of the antipsychotics may include ortho- static hypotension, sexual dysfunction, and sedation, as well as anticholinergic effects such as dry mouth, constipation, and difficulty with urination (Lehne, 2013). Atypical antipsychotics (second generation) Atypical antipsychotics became available in the 1990s. In addition to blocking DA receptors in the CNS, the 1. Biological Bases of Behavior 13 atypicals also block serotonin receptors (Patterson et al., 2010). Initially, the atypical antipsychotic medications were thought to be more effective than the typical or first-generation antipsychotics; however, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a National Institutes of Health (NIH)-funded nationwide clinical trial, revealed that the typical or first-generation antipsychotics may indeed be just as effective as some of the newer atypical antipsychotic medi- cations (Lieberman et al., 2005). The newer atypical produce less EPSs than the typical antipsychotics; however, they may cause dangerous metabolic effects such as weight gain, diabetes, and dyslipidemia (Lehne, 2013). Atypical antipsychotics include olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), paliperidone (Invega), iloperidone (Fanapt), asenapine (Saphris), clozapine (Clozaril), risperidone (Risperdal), and cariprazine (Vraylar), which was FDA approved in 2015 for schizophrenia and bipolar disorder. Abilify is unique as it does not block DA completely but rather is a partial agonist at the DA receptor. Clozapine is actually one of the more effective atypical antipsychotics although it is also the most dangerous. Fatal agranulocy- tosis (dangerously low white blood cell count causing decreased ability to fight infection) is a potential side effect. Therefore, testing of white blood counts is done on a regular basis (before treatment, weekly for 6 months, then biweekly for 6–12 months, and every 4 weeks after that). Risperdal (risperidone) is a first-line medication for new onset schizophrenia and is also well accepted for treatment of agitation and aggression in dementia and in bipolar disorders. It is noted that an unfortunate side effect of Risperdal is hyperprolactinemia leading to gyneco- mastia (enlargement of breast tissue in males; Heldt, 2017). Risperdal is also FDA approved for minimizing self-harm in autism and disruptive behavior disorders in children and adolescents (FDA News Release, 2015; Stahl, 2011; Stringer, 2011). There is a high result of noncompliance with psychotic disorders as the ill- ness precludes insight. Therefore, other methods of dosing antipsychotics were developed. Several have rapidly dissolving tablets or long-acting injectables. Long- acting antipsychotics include Fluphenazine, Olanzapine, Paliperidone, Risperi- done, Aripiprazole, and Haloperidol (Heldt, 2017). Mood Stabilizers Lithium was the first mood-stabilizing medication approved by the FDA for the treatment of acute mania and hypomania. It has well-documented efficacy in pre- venting relapse in bipolar disorder. Lithium’s mechanism of action is complex and simply a theory. It is suspected to involve NE and serotonin (Wegman, 2012). Unfortunately, lithium has a slow onset of action and a narrow therapeutic index (i.e., the therapeutic dose is close to toxic). Common side effects of lithium include nausea, diarrhea, vomiting, thirst, excessive urination, weight gain, and hand tremor. A reversible increase in white blood cell count frequently occurs with lithium use. Chronic use side effects include hypothyroidism, goiter, and rarely kidney damage. Toxicity may result in lethargy, ataxia, slurred speech, shock, delirium, coma, or even death (Wegman, 2012). Drug interactions with diuretics can increase plasma lithium concentration, and those with nonsteroidal anti-inflammatory agents can increase serum lithium levels (Stahl, 2011). Antipsychotics and anticonvulsant medications may also be used as mood stabilizers and are considered first-line treatments for bipolar disorder (Wegman, 2012). For example, the antipsychotic aripiprazole (Abilify) is FDA approved 14 EPPP FUNDAMENTALS, STEP ONE for acute and maintenance treatment of bipolar mania, and another, Symbyax (a fluoxetine/olanzapine combination), is FDA approved for treatment of refrac- tory depression associated with bipolar disorder (Wegman, 2012). Examples of anticonvulsants used as mood stabilizers include divalproex (Depakote), lamitrogine (Lamictal), carbamezepine (Tegretol), and topiramate (Topamax). Anticonvulsants work by enhancing the actions of GABA, the brain’s major inhibitory neurotransmitter (Wegman, 2012). One example of a serious side effect of an anticonvulsant medication (Lamictal) is Stevens–Johnson syndrome, a potentially fatal skin rash. Opiates (Narcotic Analgesics) Opiates refer to natural or synthetic compounds obtained from the juice of the opium poppy that are used as drugs. Natural opiates include opium, morphine, and codeine. Semisynthetic derivatives of opiates include morphine, heroin, Per- codan (oxycodone hydrochloride and aspirin), and Dilaudid (hydromorphone hydrochloride). Drugs with opium like mechanism of action are called opioids. The brain produces its own version of opiates called endogenous opiates (Mycek et al., 1997), and there are naturally occurring binding sites in the brain called opiate receptors. Opiates are used to relieve intense pain and the anxiety that goes along with it. They also induce sleep. Some opiates are prescribed for severe diarrhea or coughs (Stringer, 2011). Opiates are often manufactured in combination with non- opiate analgesics, such as aspirin and acetaminophen (e.g., Percodan or oxyco- done hydrochloride and aspirin). The two work well in combination because these different classes of drugs affect pain pathways via different mechanisms of action (Stringer, 2011). Long-term opiate use changes the way nerve cells work in the brain, which can lead to withdrawal symptoms when they are suddenly discontinued. These withdrawal symptoms may include diarrhea, vomiting, chills, fever, tearing and runny nose, tremor, abdominal cramps, and pain (Stringer, 2011). Opiates may be abused for their euphoric effects. Regarding drug interaction, the depressant actions of morphine are enhanced by MAOIs and TCAs (Mycek et al., 1997). Opioid replacement therapy is the first-line treatment for addiction. A less- addictive opioid replaces the opioid of abuse. For example, Methadone, used for opioid detox, is a high-potency opioid (about five times stronger than morphine). Its long half-life is what causes it to be less addictive than other opioids. Buprenor- phine (Subutex), also used for opioid replacement therapy, is a partial opioid agonist. While it binds to the opioid receptor strongly, it does not activate it and blocks other opioids from binding. A benefit of this drug is that a 30-day supply may be prescribed (Heldt, 2017). Psychostimulants Psychostimulants increase prefrontal cortex levels of NE and DA (Pies, 2005) and are primarily used to treat ADHD. Some examples of psychostimulants include amphetamine (Adderall), methylphenidate (Concerta, Ritalin, and Metadate), lis- dexamfetamine (Vyvanse), dexmethylphenidate (Focalin and Dexadrine), armoda- fanil (Nuvigil), and modafinil (Provigil), which are prescribed more for sleep disorders such as narcolepsy. Some antidepressants can be used in treating ADHD because they also enhance the actions of NE and DA in the prefrontal cortex (Preston & Johnson, 2014; Wegman, 2012). 1. Biological Bases of Behavior 15 Side effects of the psychostimulants may include insomnia, headache, tics exacerbation, nervousness, irritability, overstimulation, tremor and dizziness, weight loss, abdominal pain or nausea, possibly slow normal growth in children, and blurred vision (Stahl, 2011). There are numerous potential drug interactions. For example, they should not be used with MAOIs as they may cause a hyperten- sive crisis (Stahl, 2011). Some nonstimulant medications are also used to treat ADHD; however, they are generally less effective with a response rate of about 40% compared to 70% for stimulants. Atomoxetine (Strattera) is a norepinephrine reuptake inhibitor with a minor effect on serotonin and almost no effect on DA. There is very little potential for abuse. Guanfacine (Tenex, Intuniv) and clonidine (Catapres, Kapvay) reduce the hyperactivity and impulsivity associated with ADHD rather than increase focus. These medications can be sedating rather than stimulating (Heldt, 2017). Combined Treatments: Psychopharmacology and Beyond It is important to note that the psychoactive medications described earlier often complement other nonmedication approaches to treatment for many psychiatric and neurological illnesses. For example, in the treatment of mild depression, cog- nitive behavioral therapy (CBT), antidepressants, and their combination have been shown to result in equal benefit (Otto, Smits, & Reese, 2005). For the treatment of severe depression, antidepressants used in combination with CBT have been shown to be better than either CBT or medication alone (Keller et al., 2000). Bright light therapy, proper diet, and exercise are also beneficial when treating depression. Electroconvulsive therapy, transcranial magnetic stimulation, vagal nerve stimulation, and deep brain stimulation (DBS) are strategies for intractable depression (Wegman, 2012). For PTSD, psychotherapy is the first-line treatment although some symp- toms such as panic and depression may be treated with psychotropic medication (Preston & Johnson, 2014). For insomnia, cognitive behavioral therapy for insomnia (CBT-I) is shown to be equally effective and have longer lasting effects than psychotropic medication when active treatment is discontinued (Perlis, 2011). Psychoactive medications are almost always used in the treatment of psychotic disorders. Unfortunately, schizophrenia and other forms of psychoses continue to be very difficult to treat. Psychotherapy, family therapy, skills training, psych- oeducation, and vocational training often complement medication management (Patterson et al., 2010). Antipsychotics and anticonvulsant medications are also commonly used as first-line treatments for bipolar disorder, although they are commonly used in combination with psychotherapy (Wegman, 2012). Psychostimulants, which are primarily used to treat ADHD, are commonly used as part of a treatment plan involving multiple therapy modalities, includ- ing behavioral modification, parent and social skills training, and school-based interventions. Finally, environmental, social, and psychological interventions are crucial when managing patients with dementia. In the future, pharmacogenomics and pharmacogenetics may increasingly play a part in how medications are selected. As people metabolize drugs at different 16 EPPP FUNDAMENTALS, STEP ONE rates, researchers are learning how to individualize diagnosis through genetic test- ing to avoid adverse drug reactions. There are limitations to the testing as they are not available for all medications and can be costly. Neuroimaging The types of brain imaging techniques that can be used to visualize neuroanatomy and assess for neurological disorders are usually divided into “structural” and “functional” imaging techniques. Structural Imaging CT CT uses x-rays to look at slices of the brain, providing information on the density of brain tissue. There are two primary features that distinguish CT scans from tra- ditional x-rays. First, rather than taking one view, the x-ray beam in CT is rotated around the patient to take many different views from different angles. Then, x-ray data are reconstructed by a computer to obtain detailed images of soft tissues, liquid, air, and bone. The appearance of brain tissue on a CT scan depends on the tissue density. Very dense tissue, such as bone, appears white. Less dense tissue, such as air, appears black. The term hyperdense refers to brighter areas and hypodense refers to darker areas. Areas of intermediate density are referred to as isodense. Brain tis- sue that is rich in cells has a different density than areas rich in axons. White mat- ter is slightly darker than gray matter due to its high myelin content. CSF is denser than air and is usually dark gray in color. In some instances, intravenous contrast material containing iodine is injected into the patient prior to obtaining the CT scan for better visualization of certain tissues. This contrast material is denser than brain tissue and will therefore appear hyperdense (white) in areas of increased vascularity or breakdown of the blood–brain barrier. CT images are often obtained with and without contrast for comparison. An enhancing lesion refers to areas that are absorbing this contrast material and may be indicative of brain neoplasms, abscess, infarct (area of dead tissue resulting from obstructed blood flow), demy- elinating disease, resolving hematoma, or vascular malformation. Clinically, CT is often used in the emergency room to detect acute hemor- rhage or skull fracture following trauma. Fresh intracranial hemorrhage coagulates almost immediately and shows up as hyperdense (white) areas. Acute cerebral infarcts often cannot be seen with CT, although areas of abnormality resulting from cell death after a cerebral infarct are later visible. CT scans are also useful in the detection of neoplasms (tumor), mass effect, or ventricular enlargement, for example, in the context of hydrocephalus. Magnetic Resonance Imaging MRI was developed in the 1980s and uses powerful magnetic fields that cause pro- tons to align themselves in response to the magnetic field’s line of force. Unlike CT scans, MRI scans are not described in terms of density, rather they are described in terms of intensity, or brightness, of the signal. The term “hyperintense” refers to a brighter area, and the term “hypointense” refers to a darker area. 1. Biological Bases of Behavior 17 Clinically, MRI provides high-contrast, high-resolution imaging with good ana- tomical detail. MRI is the preferred method for detecting small lesions such as plaques found in patients with multiple sclerosis, subtle tumor, or chronic hem- orrhage. CT is not as sensitive in detection of white matter or neurodegenerative disorders. However, MRI costs more and takes longer. CT is preferred in urgent assessment of head trauma with suspected intracranial hemorrhage, and it is better at visualizing bony structures (e.g., skull fracture). CT is also preferred for patients who have metallic implanted devices, such as a pacemaker. MRI is preferred in nonurgent situations in which a higher-resolution imaging method is required for better anatomical detail (Blumenfeld, 2010). Neuroangiography Neuroangiography is used to visualize lesions of blood vessels through the use of radiographs and injection of contrast material into the vasculature. It is the gold standard for evaluating vascular diseases in head, neck, and spine, such as atherosclerotic plaques and other vessel narrowings, aneurysms, and arteriove- neous malformation (AVM). Angiography is often invasive and requires general anesthesia. Wada Test The Wada test is an example of neuroangiography that is helpful in localizing language function and aiding in presurgical planning, particularly in patients with epilepsy who are undergoing brain resection. For this procedure, amobarbital is selectively infused into each carotid artery while the patient is awake, essentially “putting to sleep” the contralateral hemisphere, so that various cognitive functions (e.g., memory and language) can be assessed in that hemisphere. Functional Neuroimaging Electroencephalography EEG is considered the original method for measuring brain activity. To measure brain activity using an EEG, a small metal disk that records the electrical activity of the neurons in the underlying brain area is attached to the scalp. These small elec- trical impulses are amplified and displayed on paper using a chart recorder called an electroencephalograph. EEG is useful in detecting widespread abnormality in brain function in a variety of contexts (e.g., sleep, anesthesia, coma, traumatic brain injury, and epilepsy), but its sensitivity and spatial resolution for detecting brain lesions are poor. Positron Emission Tomography PET uses small amounts of injected radioactive material to measure regional cere- bral blood flow via glucose metabolism or oxygen consumption. The idea is that areas of the brain that are more active will use more glucose (and hence become radioactive) than less active areas. However, the brain is always active, so the brain’s normal background activity is usually measured first to establish a baseline, which is then “subtracted” from the activity measured during the test. PET scans are useful for mapping the distribution of neurotransmitters and identifying brain dysfunction due to stroke, epilepsy, tumor, dementia, and other brain-impairing conditions. 18 EPPP FUNDAMENTALS, STEP ONE Functional MRI Functional MRI (fMRI) was developed directly from MRI and can detect function- ally induced changes from blood oxygenation. The basic idea is that oxygen distri- bution varies with brain activity and the amount of oxygen in the blood changes the magnetic properties of the blood without having to inject any radioactive materials, such as with PET or CT. Like MRI, fMRI has excellent resolution and provides a detailed structural map, while also providing functional information. fMRI can be used to measure the brain’s real-time response to motor activities or neuropsychological tests. Disorders Aphasia Aphasia refers to an acquired disorder of language (as opposed to a developmen- tal language disorder) and can affect expressive speech, receptive speech, reading (alexia), and/or writing (agraphia). Aphasia syndromes can be subdivided into three major classifications: fluent aphasia (in which speech is fluent but there are difficulties with comprehension and/or repetition of words or phrases spoken by others), nonfluent aphasia (in which expressive speech is notable for poor articulation or poor grammar, but comprehension is relatively preserved), and pure aphasia (in which select aspects of language are affected, such as reading or writing). Under the category of fluent aphasia is Wernicke’s aphasia (also known as sensory aphasia or receptive aphasia), in which the primary deficit is the inability to understand language. Speech is usually fluent (with normal rate and articula- tion) but the content of the speech is often nonsensical and meaningless, often containing neologisms (nonwords) or incorrect combinations of words (“word salad”). People with Wernicke’s aphasia often have poor insight into their deficit and may expect others to understand what they are saying. The ability to repeat what others say is also impaired. The lesion typically associated with Wernicke’s aphasia is in the left temporal lobe. Transcortical sensory aphasia is similar to Wernicke’s aphasia in that it is also a fluent aphasia in which comprehension is poor, but the individual can repeat what others say (unlike Wernicke’s). The lesion is usually in the border zones between the parietal and temporal lobes. Broca’s aphasia (also known as motor or expressive aphasia) is a nonfluent aphasia in which the person speaks in a slow, halting manner, with poor gram- mar and limited prosody. Only keywords are used, and use of verbs or connect- ing words is limited. Damage is usually in the left frontal lobe around Brodmann areas 44 and 45, also known as “Broca’s area.” Writing is usually slow and effortful. Repetition is also impaired. Auditory comprehension and reading comprehension are relatively preserved. Transcortical motor aphasia is similar to Broca’s aphasia (and is sometimes referred to as “little Broca’s”) in that it is also a nonfluent aphasia, but the person is able to repeat what others say (unlike Broca’s aphasia). Damage usually occurs in the left frontal areas surrounding Broca’s area, leaving Broca’s area and its con- nections to Wernicke’s area intact. 1. Biological Bases of Behavior 19 Conduction aphasia is a specific disorder in which people can speak normally (therefore, it is considered a fluent aphasia), name objects, and understand speech, but the sole deficit is in the repetition of what others say. Conduction is considered a “disconnection syndrome” in which the expressive speech center of the brain and the receptive speech center are disconnected. Damage is thought to affect the arcuate fasciculus, which is the large white matter tract connecting Broca’s area and Wernicke’s area. Anomic aphasia consists of a focal deficit in naming objects, although the per- son can adequately produce meaningful speech, comprehend speech, and repeat speech. The angular gyrus is thought to be affected in this type of aphasia, although some degree of anomia, or problems with word finding, is present in most types of aphasias and is not consistently localized to a particular brain region. In global aphasia, all aspects of language are impaired, including expressive speech, comprehension, repetition, reading, and writing. Alexia Alexia is the acquired inability to read (as opposed to dyslexia, which refers to a developmental disorder of reading starting in childhood). Pure alexia refers to impairments with reading, whereas the ability to write is relatively preserved. The pathology is usually a stroke in the posterior region of the left hemisphere, affect- ing the posterior region of the corpus callosum, disconnecting the visual centers of the brain from the language centers of the brain. Agraphia Agraphia refers to an acquired disorder of writing (as opposed to a develop- mentally based writing disorder beginning in childhood). Agraphia may affect a variety of components of writing, including spelling, grammar, letter forma- tion, or visuospatial errors (e.g., poor spacing or orientation of letters). Differ- ent types of agraphia are usually classified based on accompanying symptoms such as alexia, apraxia, or visuospatial disorders. The site and extent of damage can range from parietal lobe, frontal lobe, corpus callosum, and subcortical structures. Apraxia Apraxia is an acquired disorder of skilled, purposeful movement that is not due to a primary motor or sensory impairment such as paresis or paralysis. For example, a person may not be able to demonstrate how to brush his or her hair or wave goodbye on command. There are many types of apraxia. In some cases, the action may be carried out accurately but in a clumsy manner, and in other forms of apraxia, the person may commit errors such as performing sequenced actions in the wrong order (such as sealing an envelope before placing the letter inside). The lesion site may vary depending on the type of apraxia but is usually in the left hemisphere. 20 EPPP FUNDAMENTALS, STEP ONE Dementia Dementia is an umbrella term that refers to a decline in two or more areas of cog- nitive functioning resulting in significant impairments in activities of daily living. The term dementia does not imply a specific cause and could be due to progres- sive, static, or reversible etiologies (National Institute of Neurological Disorders and Stroke [NINDS]—National Institutes of Health, n.d.). Although cognitive functions do decline with age, dementia is not a normal part of the aging process. Dementia is also distinct from delirium, which is an acute and potentially reversible form of cognitive decline. The term “dementia” has recently been replaced by the term “neurocognitive disorder” in the DSM-5 (American Psychiatric Association, 2013). Alzheimer’s disease (AD) is the most common cause of dementia in those aged 65 and older. Approximately 10% of people over the age of 65 are living with AD in the United States, and nearly half of those older than 85 have the disease (www. ninds.nih.gov/disorders/dementias/dementia.htm). A neurocognitive disorder due to AD is defined by the DSM-5 as a decline in memory and at least one other cog- nitive domain and a progressive, steady decline in cognition, and no evidence of mixed etiology. The onset must be insidious with gradual progression over time. These features should not be better accounted for by an Axis I disorder, medical disorder, or delirium. AD is considered a “cortical dementia” because it primarily results in neuronal loss and atrophy of the cerebral cortex, namely, the medial temporal areas, includ- ing the amygdala, hippocampal formation, and entorhinal cortex. In later stages of the disease, the following brain areas may also be affected: basal temporal cortex, parietal–occipital cortex, posterior cingulate gyrus, and frontal lobes. The primary motor, somatosensory, visual, and auditory cortices are relatively spared. The primary pathological changes in AD are beta-amyloid plaques (insoluble pro- tein cores) and neurofibrillary tangles (intracellular protein tangles) which can be found throughout the cortex, although primarily in the limbic cortex region (e.g., the hippocampus), which is involved in memory. Neurotransmitter changes are also present, with primary dysfunction in the cholinergic neurons, which are involved in learning and memory. Current medications used to treat AD, such as cholinesterase inhibitors, pre- vent the breakdown of ACh. These medications include galantamine (Razadyne), rivastigmine (Exelon), and donepezil (Aricept). Weight gain, sedation, and rarely, seizures, are some of the side effects. These drugs should not be combined with other cholinesterase inhibitors (Stahl, 2011). Another medication known as memantine (Namenda) works by regulating glutamate, which, in excess, can lead to cell death. These medications typically slow the progression of AD, rather than restore previously lost cognitive functions. Side effects include dizziness, headache, and constipation (Stahl, 2011). The diagnosis of AD is based on clinical presentation, obtained through a detailed clinical history and evaluation of cognitive abilities (McKhann et al., 2011). Sophisticated imaging and biomarker techniques, such as PET and CSF assays, are also being developed to identify the pathological hallmarks of the disease, which develop years before the clinical signs of memory loss appear (Sperling et al., 2011). Not everyone who has these pathological changes in their brain will go on to develop AD. In the early stage of the disease (1–3 years), mild impairments may be seen in memory, particularly new learning and retention of new memories over time, with 1. Biological Bases of Behavior 21 remote memory being relatively spared. Other cognitive areas affected include visuospatial functioning (e.g., topographic disorientation and difficulty with con- struction) and language (e.g., word finding and naming). Increased frustration and irritability may also be present. In the intermediate stage (2–10 years), increased impairments in memory, visuospatial skills, and language are present, with the emergence of apraxia, acalculia, aphasia, or agnosia. In the later stages (8–12 years), intellectual functions may be severely impaired, verbal output may be mini- mal, and the patient may develop problems with his or her gait and motor control. The greatest risk factor for developing AD is age. Most cases of AD are spo- radic, although several risk genes have been implicated. The risk gene with the strongest influence is called apolipoprotein E-e4 (APOE-e4). Scientists estimate that APOE-e4 may be a factor in 20% to 25% of Alzheimer’s cases. There is also a rare form of “familial” AD, which is caused by an autosomal dominant gene and often onsets before age 60. Biomarkers (short for “biological markers”) are substances which can reliably be measured in an organism in order to diagnose a disease, infection, or other medical state. Biomarkers are now being used in conjunction with neuroimaging techniques to assist in earlier and more accurate detection of AD. A 4-year study was announced in 2015 by the Alzheimer’s Association in conjunction with the American College of Radiology aimed at using PET scans to detect the presence of amyloid plaques in the brain (Alzheimer’s Association, 2015). This study is called the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS). The amy- loid PET imaging makes amyloid plaques visible on brain PET scans, enabling the detection of the hallmark pathology of AD in living patients. Amyloid PET imaging alone does not establish a diagnosis of AD. The results of this imaging must be correlated with clinical findings such as neurobehavioral status and cog- nitive testing. Preliminary results from the IDEAS study (Rabinovici et al., 2017) showed that the rates of amyloid PET positivity were 54.3% in mild cognitive impairment (MCI) and 70.5% in dementia. Changes in the clinical care of these patients were present in the majority of these patients (e.g., counseling, medica- tion changes). These early findings indicate that amyloid PET may have a con- siderable positive effect on patient care. Pick’s disease is a rare form of cortical dementia that is caused by degeneration of the frontal and temporal lobes of the brain. Pick’s disease is one specific cause of a heterogenous group of dementias referred to as frontotemporal dementia (FTD). Pathologically, Pick’s disease is distinguishable on autopsy by characteristic Pick inclusion bodies usually found in cortical and hippocampal neurons in the frontal and anterior temporal lobes (as opposed to the amyloid plagues and neurofibrillary tangles, which are the hallmark of AD; Heilman & Valenstein, 2003). Dementia due to Pick’s disease, as well as other types of FTDs, are characterized by personality changes such as behavioral disinhibition, which often occur early in the course of the disease, as well as executive dysfunction and language abnormalities. Memory problems are also present, but tend to become more obvious later in the disease (as opposed to AD where memory loss is typically the primary presenting problem). Onset is typically younger than that of AD, occurring between ages 50 and 60. There is no treatment for Pick’s disease. Cerebrovascular disease is the second leading cause of acquired dementia following AD and is caused by multiple infarcts, or strokes, in either large ves- sels or smaller vessels which penetrate deeper in the brain. Dementia due to cer- ebrovascular disease tends to begin earlier than AD and is more common in men 22 EPPP FUNDAMENTALS, STEP ONE than women. Alternative terminology includes multi-infarct dementia, vascular dementia, or vascular cognitive impairment. The onset is typically abrupt with a stepwise or fluctuating course. Risk factors include hypertension, abnormal lipid levels, smoking, diabetes, obesity, cardiovascular disease, or previous stroke or transient ischemic attacks. Cerebrovascular disease may coexist with other causes of dementia, including AD (O’Brien et al., 2003). The types of deficits present in vascular dementia are variable and depend on the nature, type, and extent of the cerebrovascular lesions. Focal deficits may be present, as well as gait distur- bance or psychomotor retardation. Depression or mood changes are also common. Cognitive deficits common in vascular dementia include psychomotor processing speed, complex attention, and executive functioning. Diagnostic criteria are similar to that of AD but differ in the onset and course of the disease, and focal neuro- logical signs (e.g., gait abnormalities or weakness of an extremity) or evidence of cerebrovascular disease on neuroimaging is required (American Psychiatric Asso- ciation, 2013). Treatments are often preventive, focusing on the underlying risk factors (e.g., smoking cessation, exercise, and dietary modifications) as well as aspirin, anticoagulants, or antihypertensive medications. PD is a progressive neurodegenerative condition that is characterized clini- cally by tremor, rigidity, bradykinesia (slowed movement), and postural instability. PD is considered a movement disorder and is caused by the degeneration of the substantia nigra, which is a nucleus in the basal ganglia, and the loss of DA, which is produced by this nucleus. The basal ganglia is a subcortical structure involved in regulating voluntary movement. Lewy bodies are often present in the substantia nigra on autopsy. Dementia occurs in 20% to 60% of patients (American Psychiatric Association, 2013). Parkinson’s dementia is considered a “subcortical” dementia and may be characterized by deficits in executive functioning, learning and recall aspects of memory, slowed psychomotor speed, and bradyphrenia (slowed thinking). There are typically no cortical disturbances such as aphasia or apraxia. Depression is relatively common and affects approximately 30% of patients with PD. The major motoric symptoms of PD can be broken down into positive and negative symptoms. The positive symptoms (actions that are not seen in “nor- mals”) include a resting tremor that often has a pill rolling quality, muscular rigidity, or increased muscle tone, and involuntary movements, or akathisia. The negative symptoms (the inability to engage in behaviors that normals can do) include difficulty with positioning, difficulty standing from a sitting position, shuf- fling gait, bradykinesia or slowed movement, and blankness in facial expression (e.g., masked facies). Treatment includes medications that boost the DA system in the brain, such as levodopa (L-DOPA), a precursor to DA. These medications may become less effec- tive over time as the disease progresses, and there is less and less DA available. DA agonists such as L-DOPA primarily help with the motor symptoms of the disease, but the cognitive symptoms are not improved. Neurosurgery such as DBS uses a surgically implanted device called a neurostimulator to deliver electrical stimula- tion to block the abnormal electrical signals within the basal ganglia. This type of treatment treats the motor symptoms of the disease and is used with patients whose symptoms are not adequately controlled with medication (NINDS, n.d.). Huntington’s disease or Huntington’s chorea is also a movement disorder and is caused by a degenerative loss of neurons in the basal ganglia, particularly the caudate nucleus. Neurotransmitters such as GABA and NE, which normally inhibit 1. Biological Bases of Behavior 23 the DA pathways, die during the course of the disease, thus creating a hyperactive DA system. It is an autosomal dominant genetic disorder affecting approximately 5/100,000. The defect causes a part of DNA, called a cytosine, adenine, guanine repeat, to occur many more times than normal. Offspring have a 50% chance of developing this disorder. The disorder typi- cally appears in the third or fourth decade of life. Dementia almost always occurs and is characterized by a decline in memory retrieval and executive functioning, with more severe deficits in memory and global intellectual functioning later in the disease. Behavioral disturbances occur in up to 50% of cases and are often the initial feature of the disease. These behavioral changes may include depres- sion, personality changes, anxiety, irritability, restlessness, or psychosis (NINDS, n.d.). The abnormal movements associated with this disease include “choreiform movements” (frequent, brisk jerks of the pelvis, trunk, and limbs), athetosis (slow uncontrolled movements), and unusual posturing. These motor symptoms often present months to a year after the disease onsets. Subtle changes in personality, memory, and coordination are often the first symptoms of the disease. There is no treatment for Huntington’s disease. Genetic counseling plays an important role for those with a family history of Huntington’s disease. Dementia due to HIV disease is primarily a subcortical dementia caused by direct pathophysiological changes in the brain due to HIV. Alternative terminol- ogy includes AIDS dementia complex (ADC) or HIV/AIDS encephalopathy. Neu- ropathological findings include diffuse, multifocal destruction of white matter and subcortical structures, resulting in cognitive, behavioral, and motor symptoms. Cognitive symptoms include forgetfulness, slowness, concentration problems, and problem-solving difficulties. Behavioral manifestations include apathy and social withdrawal as the primary features, although some individuals may experience visual hallucinations, delusions, or delirium. Motor symptoms include tremors, bal- ance problems, impaired repetitive movements, ataxia, and hypertonia. CD4 counts are an important biomarker of HIV disease, and dementia due to HIV disease is more likely to occur as CD4+ count levels fall below 200 cells per microliter. With the advent of highly active antiretroviral therapy (HAART), the fre- quency of dementia due to HIV disease has declined from 30% to 60% of people infected with HIV to less than 20%. Chronic traumatic encephalopathy (CTE) is a recently defined progressive neurodegenerative disorder linked to a history of head trauma. Dr. Bennet Omalu first documented the presence of CTE upon autopsy in an NFL football player in 2002 (Omalu et al., 2005). As of now, CTE can only be diagnosed with postmortem examination of the brain. The neuropathology of CTE is characterized primarily by hyperphosphorylated-tau protein (p-tau). This p-tau protein is usually distrib- uted in an irregular, focal distribution around the periventricular regions (Hay, Johnson, Smith, & Stewart, 2016). The neuropathology of p-tau is not unique to CTE, although a recent consensus panel funded by the NINDS/NIBIB (McKee et al., 2016) found acceptable interrater reliability amongst neuropathologists in discriminating between 25 cases of various tauopathies, including CTE, AD, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degen- eration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The clinical manifestations of CTE include a broad range of psychiatric, behav- ioral, and cognitive changes. It remains unclear whether the neuropathological 24 EPPP FUNDAMENTALS, STEP ONE changes associated with CTE result in a specific set of behavioral, cognitive, or emotional symptoms. Current limitations in the study of CTE include the reliance on retrospective reporting of family members to gather associated clinical informa- tion postmortem, the lack of prospective studies, and similarities in neuropsychi- atric symptoms between CTE and other neurodegenerative and neuropsychiatric disorders (Hanlon, McGrew, & Mayer, 2017). Pseudodementia The term pseudodementia has been used in the past to describe a dementia-type presentation in a variety of psychiatric illnesses, although depression tends to be the most common cause. This type of dementia may occur in a subset of patients with mood disorders and these features may resemble other neurological etiolo- gies of dementia. Individuals with depression may report various cognitive prob- lems in their daily lives, including slowed processing speed, memory problems, and attention problems. The onset of these cognitive symptoms can sometimes be linked to a precise date of onset (perhaps associated with onset of a life stressor or emotional upset), and the course tends to progress more rapidly than in dementia. Subjective cognitive complaints in depression are typically greater in severity than the actual impairment on testing. Conversely, patients with AD may underestimate their impairments due to the poor insight that is often a hallmark of the later stages of the disease. Several presenting features can distinguish organic dementia from dementia due to depression. First, cortical signs such as aphasia, apraxia, and agnosia are typically absent in depression. Second, depressed patients may exhibit psychomo- tor slowing and inconsistent effort or attention during neuropsychological testing, rather than primary problems with retentive memory or visuospatial function- ing. Cognitive impairments occurring during the acute stages of depression are typically reversible with treatment for the depressive symptoms. However, it is important to note that depression may also co-occur in the early stages of demen- tia, and cognitive symptoms in this context would be less likely to improve with antidepressant treatments. Mild Cognitive Impairment The term MCI has been coined to capture the transitional time period between normal aging and dementia. MCI is defined as the state in which at least a single cognitive domain, usually memory, is impaired to a greater extent anticipated for someone’s age, although the patient does not meet criteria for dementia and does not exhibit significant changes in their everyday, functional abilities (Peterson, 1995). These individuals are at an increased risk for developing dementia in subse- quent years. Since the conception of MCI, four clinical subtypes of MCI have been defined: amnestic MCI-single domain, amnestic MCI-multiple domains, nonam- nestic MCI-single domain, and nonamnestic MCI-multiple domain (Busse, Hensel, Gühne, Angermeyer, & Riedel-Heller, 2006). The course of MCI can last for up to 5 years (Peterson et al., 1997). When followed longitudinally, individuals with MCI have a significantly increased rate of developing dementia, with conversion rates ranging from 8% to 15% per year, 1. Biological Bases of Behavior 25 compared to a rate of 1% to 2% per year for the “normal” aging population (Devanand et al., 2008; Peterson et al., 1997). Individuals with amnestic MCI have the highest risk of progressing to AD (Busse et al., 2006). Delirium Delirium, or acute confusional state, is defined as a disturbance in consciousness accompanied by a change in cognition that cannot be better accounted for by a dementia process. Delirium differs from dementia in that its onset is typically abrupt (developing over the course of hours or days), the course is often fluctuat- ing, and it is oftentimes reversible. A delirium state can be caused by a general medical condition (e.g., infection or metabolic disturbance), substance intoxica- tion, or withdrawal, medication, toxin exposure, or a combination of factors. Delir- ium is common in inpatient hospital settings, affecting up to 30% of medically hospitalized patients. It is more common in the elderly. The hallmark feature of delirium is impairment in the ability to focus or sustain attention. A patient with delirium may have difficulty focusing on a conversation or may be easily distracted. In addition to this attention disturbance, the patient may demonstrate a change in memory, orientation, language, or perception. Concussion Concussion, which is a form of mild traumatic brain injury, is the result of a direct or indirect trauma to the head. Although a loss of consciousness may occur, it is not necessary for diagnosis. Although many diagnostic frameworks have been developed, all require an identified trauma to the head, as well as at least some alteration of consciousness, posttraumatic amnesia (or amnesia for the event), or some focal neurological deficit. Most of the literature suggests the presence of concussion-related symptoms for a few hours to several days after the injury. However, a more enduring syn- drome of symptoms can occur and is known as postconcussion syndrome (PCS). For most, this syndrome will also resolve usually within the first 3 months. How- ever, there is a smaller group of individuals who can remain symptomatic for over 3 months and, sometimes, up to several years following the injury. Post- concussion syndrome can be associated with a triad of somatic, cognitive, and behavioral symptoms. Somatic symptoms can include disordered sleep, fatigue, headaches, sensitivity to light and/or noise, vertigo or dizziness, and/or nausea. Personality/emotional changes can include anxiety, depressed affect, irritability, and/or apathy. Residual cognitive disturbances can include impaired attention and concentration, diminished short-term memory, slowed learning, decreased processing speed, lack of initiation, and poor planning, organization, and prob- lem solving. Seizure Disorders A seizure is an episode of abnormal electrical firing of neurons resulting in abnor- mal behavior or experience of the individual (NINDS, 2004; Zillmer, Spiers, & 26 EPPP FUNDAMENTALS, STEP ONE Culbertson, 2008). The abnormal neuronal firing that occurs during a seizure may result in strange sensations, emotions, behavior, or sometimes convulsions or loss of consciousness. Epilepsy is a condition in which an individual experi- ences two or more unprovoked seizures. An unprovoked seizure means there is no identifiable cause or trigger. Having a seizure is not the same as being diag- nosed with epilepsy. For example, someone may experience an isolated seizure without going on to develop epilepsy. Some children experience febrile seizures, in which a seizure occurs in the context of a high fever. However, most children with febrile seizures do not go on to develop epilepsy. Approximately 1% of the U.S. population has experienced an unprovoked seizure or has been diagnosed with epilepsy (NINDS, 2004). There are many causes of epilepsy. Anything that disrupts the normal pattern of neuronal activity may cause a seizure, for exam- ple, brain damage, abnormal development, illness, infection, toxins, drugs, or trauma. In about half of the cases of epilepsy, the exact cause is idiopathic, or unknown (NINDS, 2004). There are several classifications of seizures. The first main classification is generalized versus partial or focal. In a generalized seizure, both sides of the brain are affected, resulting in loss of consciousness (or altered con- sciousness), falls, or muscle spasms. There are several types of generalized seizures. In a tonic–clonic generalized seizure, formally known as a grand mal seizure, the individual typically loses consciousness and exhibits stiffen- ing of the body and repetitive jerking of the arms and/or legs. In an absence seizure, formally known as a petit-mal seizure, the person may appear to be staring into space. Focal seizures, also called partial seizures, affect only one part of the brain. In a simple partial seizure, the individual does not lose consciousness. A person with a simple partial seizure may experience sudden and unexplained joy or anger or may hear, smell, or see things that are not real. In a complex partial seizure, the person experiences an alteration or loss of consciousness. A person having a com- plex partial seizure may display repetitive movements or behaviors, such as blinks, twitches, mouth movements, or more complicated actions. Temporal lobe epilepsy is the most common type of recurring focal seizures and may be associated with memory problems due to involvement of the hippocampus. Some people with partial or focal seizures experience an aura, or unusual sensation that warns a seizure is about to happen. Not all seizures are distinctly partial or generalized. Some seizures may begin as a partial seizure and then spread to the entire brain. In addition, some people may appear to have a seizure, but there is no evidence of seizure activity in their brain. These events are referred to as nonepileptic seizures, formally referred to as pseudoseizures. The cause of these nonepileptic seizures may be psychogenic in origin, and sometimes people with epilepsy also have psychogenic seizures. It can be difficult to distinguish between epileptic and nonepileptic seizures, and careful evaluation and monitoring are required. Epilepsy is usually diagnosed with EEG monitoring, brain scans, blood tests, neurological or behavioral tests, and a thorough check of medical history. Epilepsy is usually treated with antiseizure medication, although not all individuals with epilepsy respond well to these medications. When medications are not effective in controlling seizures, surgery to remove the affected brain tissue may be consid- ered, depending on the nature and type of seizures. 1. Biological Bases of Behavior 27 References Acharya, S., & Shukla, S. (2012). Mirror neurons: Enigma of the metaphysical mod- ular brain. Journal of Natural Science, Biology, and Medicine, 3(2), 118–124. doi:10.4103/0976-9668.101878 Adams, M., Holland, N., & Urban, C. (2017). Pharmacology for nurses: A patho- physiologic approach (5th ed.). New York, NY: Pearson. American Psychiatric Association. (2013). 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