Chopter 15 / Diagnoss of Anxiety and Amiaty-Related Disorders 43 Neurobiologic Mechanisms of Anxiety Research in the last two decades postu- lies several neurobiologic mechanisms focused on functional neuroanatomical pathways, neurochemisiry, and the neu roendocrinology of anxiety.** Although most preclinical and neuroimaging stud ies have explored anxiety in younger pa- tients, newer diagnostic techniques shed light on neurobiologic mechanisms, di nosis, and possible treatment of latesife anxiety as well. This section summarizes this literature and discusses its relevance to older patients in light of normal age- related changes in various neurorransmit ter systems. Functional Neuroanatomic Pathways. Several theoretic models involving. fimne= tional neuroanatomic pathways have been implicated in the neurobiology of anxiety states.®" One complex schema concerns the central role of a “behavioral tion system” in manifestations of anxiety that involve neuroanatomic structures of the septohippocampal system and nora- renergic, serotonergic, and GABAergic neurotransmitter systems.” A second mode!” proposes a neuroanatomic hy- pothesis for panic disorder, locating the seute panic attack in the brain stem, ane ticipatory anxiety in the limbic system, and phobic avoidance in the prefrontal In a third and most recent model the amygdala (an almond-shaped struc- ture in the medial temporal lobe) me- diates fear and anxiety responses with ex: tensive afferent and efferent connections ‘tomany other fearrelated neuronal struc tures including hippocampus, locus cert Jeus, thalamus, hypothalamus, and orbito- frontal cortex. At their core, these functional pathways may best be concep- tualized as 2 central fearresponse system, with the amygdala as a critical hub Efferent pathways of the central nucleus of the amygdala (CnA) project to several target areas in the brainstem and hypo- thalamus to mediate cognitive, physiologi- cal, emotional, and behavioral character- istics of anxicty." Under normal ci cumstances, reciprocal connections of medial prefrontal cortex with amygdala exert an “executive inhibitory contro!” over affect and modulate autonomic and neuroendocrine function." However, under threatening circumstances, an ine stinctive, quicker, and more primitive “fight, flight, or freeze” response with input from the thalamus is executed, by- passing the more cognitive cortical re- sponse. Although favoring survival during cons of evolution, an amygdalacemered response has insufficient inhibitory corti cal influences. This unbalanced response appears tobe the hallmark of pathological anxiety disorders, particularly panic disor- der; itis also present in PTSD and, toa lesser extent, in obsessive-compulsive dis order (OCD) and generalized anxiety dis order (GAD). Nourochemistry of Anxiety Several neurotransmitter systems have been implicated in anxiety disorders, These include the amino acid neurotrans- mitters gamma aminobutyric acid (GABA) and glutamate, as well as the monoamine transmitters norepinephrine and serotonin. GABA, an inhibitory neu- rotransmitter, plays a central role in anxi- ery. Circulating GABA binds to its recep» tor (the GABA, receptor) that changes the electrochemical gradient across the cell surface membrane, resulting in de creased neuronal firing. Benzodiazepine receptors are present in many of these GABA, receptors and facilitate the binding of GABA to its recep- tor (all benzodiazepine receptors are asso- ciated with GABA but notall GABA recep- lors are associated with benzodiazepine receptors). Benzodiazepines may de- crease anxiety, therefore, by enlancing, GABA binding to the GABA, receptor. In- hibitory GABA input that occurs at many synapses throughout the cortex and sub- cortical areas serves to balance the ubiqui-444 Port V J Ansioty and Related Disorders (Panic, OCD, Phobias) tous stimulatory neurotransmitter gluta mate. The role of glutamate in anxiety has not yet been clarified, but the numerous interactions of glutamate with other neu= rotransmitters, including the catechola- ines, suggest that it plays a major role. Monoamine neurotransmitter also play a role in anxiery, both directly and indirecdly, by modulating GABA and gh tamate; for example, serotonin modulates both GABA and glutamate. Norepi- nephrine, a catecholamine neurotrans milter arising from the locus ceruleus in the midbrain, may play a central role in the development of panic attacks as well in heightening anxiety. Yohimbine, for example, which increases _norepineph- rine via antagonism of as presynaptic autoreceptors, can induce panic in indi- viduals prone to panic disorders?" In addition to increased levels of mono- amine oxidase B, decreased noradrener™ gic function in old age includes decreased. numbers of locus ceruleus neurons and decreased norepinephrine content in many brain areas.®° This decline in nora- drenergie function may also explain a Neuroendocrinology of Anxioty ‘The hypothalamicpituitar-adrenal (HPA) axis also plays a central role in anxiety states, particularly posttraumatic. stress and panic disorders." Although the HPA axis can be activated acutely, in the stress of chronic anxiety states, such 2s PTSD (and depression), a chronic dysreg- Ulation of this axis seems to occur." Acute stress induces activation of HPA axis, causing increased levels of cortico- tropinereleasing hormone (CRF), which then stimulates production of adrenocor ticotropic hormone, resulting in ine creased cortisol production. Increased levels of cortisol bring the system back to homeostasis via a negative feedback mech- anism. Long-term stress tends to dysregu- late this mechanism, potentially resulting in high levels of resting cortisol. Antide- pressant treatment can potentially nor malize such HPA dysregulation. Despite the role of the HPA axis in anx- iety, a single neurobio sgeriatic anxiety is unlikely. Whether the aging brain per se may be associated with increased predisposition to develop anxi- ety symptoms, as itis for depressive symp- toms, is also unclear. ic substrate for Panic Anxiety, Obsessive- Compulsive Disorders, Phobias Extreme states of anxiety are sometimes associated with panic, OCD, and phobias. These spectrum disorders are less com- on in old than in younger aduli, but when they do occur they may prevent the elderly person from participating in the normal activities of daily life. Panic Disorder (with and without Agoraphobia) Individuals who experi tack, regardless of age state of extreme autonomic hyperarousal and are usually convinced that they will die, “go crazy,” or lose control of their behavior. Because panic attacks inevitably arise without warning, patients become continually anxious, anticipating the next panic attack (“anticipatory anxiety”) One coping mechanism is to avoid loca tions or activities associated with past panic auacks, which leads to secondary phobic avoidance behavior (agorapho- bia). Lateonset agoraphobic fears may also arise from an episode of physical ill- Panic attacks rarely develop for the first time in late life. When they do appear, particularly in conjunction with agora phobia, they are often associated with a serious depressive or physical illness. The prevalence of spontaneous panic attacks, with or without secondary agoraphobia, in older people is extremely low. Panicand agoraphobic symptoms in older ce a panic at