Question

5. Discuss the evidence for a biological basis of anxiety disorders (Be sure to provide at least 3 separate pieces of evidence). Does Generalized Anxiety disorder differ from any of the other anxiety disorders in terms of its biological features, if so in what ways?

Answer 1

INTRODUCTION TO EMOTIONAL PROCESSING

• Mood and anxiety disorders are characterized by a variety of neuroendocrine, neurotransmitter, and neuroanatomical disruptions. Identifying the most functionally relevant differences is complicated by the high degree of interconnectivity between neurotransmitter- and neuropeptide-containing circuits in limbic, brain stem, and higher cortical brain areas. Furthermore, a primary alteration in brain structure or function or in neurotransmitter signaling may result from environmental experiences and underlying genetic predisposition; such alterations can increase the risk for psychopathology.

Functional Anatomy

• Symptoms of mood and anxiety disorders are thought to result in part from disruption in the balance of activity in the emotional centers of the brain rather than in the higher cognitive centers. The higher cognitive centers of the brain reside in the frontal lobe, the most phylogenetically recent brain region. The prefrontal frontal cortex (PFC) is responsible for executive functions such as planning, decision making, predicting consequences for potential behaviors, and understanding and moderating social behavior.
• The orbitofrontal cortex (OFC) codes information, controls impulses, and regulates mood. The ventromedial PFC is involved in reward processing1 and in the visceral response to emotions.2 In the healthy brain, these frontal cortical regions regulate impulses, emotions, and behavior via inhibitory top-down control of emotional-processing structures.
• The emotional-processing brain structures historically are referred to as the “limbic system” (Fig. 1). The limbic cortex is part of the phylogenetically ancient cortex. It includes the insular cortex and cingulate cortex. The limbic cortex integrates the sensory, affective, and cognitive components of pain and processes information regarding the internal bodily state.4,5 The hippocampus is another limbic system structure; it has tonic inhibitory control over the hypothalamic stress-response system and plays a role in negative feedback for the hypothalamic–pituitary–adrenal (HPA) axis.
• Hippocampal volume and neurogenesis (growth of new cells) in this structure have been implicated in stress sensitivity and resiliency in relationship to mood and anxiety disorders. An evolutionarily ancient limbic system structure, the amygdala, processes emotionally salient external stimuli and initiates the appropriate behavioral response. The amygdala is responsible for the expression of fear and aggression as well as species-specific defensive behavior, and it plays a role in the formation and retrieval of emotional and fear-related memories. (Fig. 2 depicts the amygdala’s involvement in fear circuitry). The central nucleus of the amygdala (CeA) is heavily interconnected with cortical regions including the limbic cortex. It also receives input from the hippocampus, thalamus, and hypothalamus.

hypothalamus.

Fig. 1

The limbic system. (A) Lateral view of cortex. (B) Sagittal view of slice through midline. NAc, nucleus accumbens; OFC, orbital frontal cortex; PAG, periaqueductal gray, VTA, ventral tegmental area.

Fig. 2

The fear response is a hardwired process involving the amygdala. (Adapted fromDavis M. The role of the amygdala in fear and anxiety. Ann Rev Neurosci 1992;15:356; with permission.)

Neuroendocrine and Neurotransmitter Pathways

In addition to the activity of each brain region, it also is important to consider the neurotransmitters providing communication between these regions. Increased activity in emotion-processing brain regions in patients who have an anxiety disorder could result from decreased inhibitory signaling by γ-amino-butyric-acid (GABA) or increased excitatory neurotransmission by glutamate.

Well-documented anxiolytic and antidepressant properties of drugs that act primarily on monoaminergic systems have implicated serotonin (5-hydroxytryptamine, 5-HT), norepinephrine (NE), and dopamine (DA) in the pathogenesis of mood and anxiety disorders. Genes whose products regulate monoaminergic signaling have become a prime area of research in the pathophysiology of mood and anxiety disorders, and they are thought to be critical for the mechanism of action of antidepressant drugs.

Monoaminergic regulators include transmitter receptors; vesicular monoamine transporter (vMAT), which packages these neurotransmitters into vesicles; the vasopressin (AVP), oxytocin, and vasopressin (AVP), oxytocin, and transmitter-specific reuptake transporters serotonin transporter (SERT), neurotonin transporter, and dopamine transporter; the enzyme monoamine oxidase, which degrades 5-HT, DA, and NE; and the enzyme catecholamine-O-methyltransferase (COMT), which degrades DA and NE.

In the central nervous system, classic neurotransmitters often are packaged and co-released with neuropeptides, many of which are expressed in limbic regions where they can influence stress and emotion circuitry (Table 1). The functional implications of these limbic co-localizations have been addressed in numerous reviews.

Neuropeptides with particularly strong links to psychopathology include cholecystokinin (CCK), galanin, neuropeptide Y (NPY), vasopressin (AVP), oxytocin, and corticotropin-releasing factor (CRF), among others. CCK is found in the gastrointestinal system and vagus nerve and is located centrally in numerous limbic regions.

Galanin is co-localized with monoamines in brainstem nuclei. It influences pain processing and feeding behavior and also regulates neuroendocrine and cardiovascular systems.

NPY is known for its orexigenic effects and is expressed abundantly in the central nervous system, where it is co-localized with NE in the hypothalamus, hippocampus, and amygdala. Centrally, oxytocin regulates reproductive, maternal, and affiliative behavior.

Central AVP regulates fluid homeostasis but also can co-localize with oxytocin to influence affiliative behavior19 or with CRF to regulate the HPA axis.

Table 1

Neuropeptides in stress and psychopathology

CRF in parvocellular neurons of the hypothalamic paraventricular nucleus is the primary secretagogue for the HPA axis in response to a threatening stimulus. AVP synergizes with CRF in HPA axis activation. In the HPA axis, CRF is released from the paraventricular nucleus and acts on receptors in the anterior pituitary to elicit production and release of adrenocorticotropic hormone (ACTH), which is released systemi-cally and activates production and release of glucocorticoids from the adrenal cortex.

In humans, the main stress steroid is cortisol; in rats it is corticosterone. HPA axis activity is regulated by numerous other limbic system structures, including the amygdala, which enhances HPA axis activity, and the hippocampus, which suppresses HPA axis activation (Fig. 3).

Fig. 3

The HPA axis. Black line- Suppression connection; dotted line- Facilitory connection; dots and dashes line- Suppression connection indirect pathway (via BNST and other limbic regions); and dashed lines- Facilitory connection indirect pathway (via BNST...

Standardized endocrine challenge tests to assess HPA axis activity include the dexamethasone suppression test and the CRF stimulation test. In the dexamethasone suppression test, systemic administration of dexamethasone, a synthetic glucocorticoid, decreases (ie, suppresses) plasma ACTH and cortisol concentrations via negative feedback at the level of the pituitary gland. In the CRF stimulation test, intravenously administered CRF (which does not enter the central nervous system) elevates plasma ACTH and cortisol concentrations by stimulating CRF1 receptors in the anterior pituitary. A combination of the dexamethasone suppression test and the CRF stimulation test, the Dex/CRF test, developed by Holsboer and colleagues, generally is considered to be the most sensitive measure of HPA axis activity.

Genetic Contribution to Emotionality

Each anxiety disorder, as well as major depressive disorder (MDD), has both genetic and environmental contributions to vulnerability. In attempts to identify the genetic contribution for psychopathology, the candidate genes have largely been the same across diagnoses. Researchers have tended to concentrate on the genes whose products regulate the HPA axis and monoaminergic signaling. Ongoing research supports the hypothesis that a genetic predisposition may be shared among mood and anxiety disorders, with the individual clinical manifestation being a product of both genetic and environmental influences. In particular, epigenetic factors may permit a remarkably complex range of gene–environment interactions.

Among the limited longitudinal studies available, there is much support for a “developmental dynamic pattern” regarding the influence of genetic factors on individual differences in symptoms of depression and anxiety. In this model, the impact of genes on psychopathology changes so that different developmental stages are associated with a unique pattern of risk factors. This model is in sharp contrast to a “developmental stable model” in which the genetic contribution to psychopathology is mediated by one set of risk factors that do not change with the age of the subject.

Another approach for assessing the impact of genes on risk for psychopathology focuses not on diagnostic class but on more circumscribed phenotypic characteristics. A recent study assessed anxious behavioral characteristics in children between 7 and 9 years of age. They found shared and specific genetic effects on anxiety-related behavior but no single underlying factor, supporting the hypothesis that genes are involved in the general predisposition for anxiety-related behavior and also for specific symptom subtypes.

PANIC DISORDER

Anatomical and Neuroimaging Findings in Panic Disorder

Neuroimaging in patients who have panic disorder (PD) under resting conditions and under anxiety- or panic-provoking conditions has identified neuroanatomical alterations associated with symptom severity or treatment response.

Single-photon emission computed tomography (SPECT) identified lower metabolism in the left inferior parietal lobe and overall decreased bilateral cerebral blood flow (CBF) in patients who had PD as compared with control subjects, and this decrease corresponded with symptom severity.

Other studies, however, have demonstrated elevated glucose uptake in the amygdala, hippocampus, thalamus, midbrain, caudal pons, medulla, and cerebellum as measured by positron emission tomography (PET).

These elevations normalize after successful pharmacological or behavioral therapy, suggesting that the increased glucose uptake in these regions is state dependent. Patients who had PD had decreased frontal activity bilaterally but increased activity in the right medial and superior frontal lobe in SPECT studies. Interestingly, the CBF asymmetry and shift to the right hemisphere correlated with disorder severity in individual patients.

After administration of the respiratory stimulant doxapram, patients who had PD exhibited a greater decrease in PFC activity but a larger increase in cingulate gyrus and amygdala activity while experiencing panic than control subjects. In patients who had PD who were administered sodium lactate to provoke a panic attack, functional MRI (fMRI) demonstrated elevated CBF in the right OFC and left occipital cortex but decreased CBF in the hippocampus and amygdala. Other studies have shown that patients who do not experience a panic attack after sodium lactate infusion show no differences in CBF compared with control subjects. Interestingly, when a spontaneous panic attack was observed in an fMRI study, the panic was associated with significantly increased activity in the right amygdala.

Imaging analyses of patients who have PD who are in an anxious (but not panicked) state also have provided important data. Upon presentation of threatening words in fMRI studies, the left posterior cingulate and left medial frontal cortex were activated in these patients.25 Others have shown that presentation of negative emotional words elicits activations in the right amygdala and right hippocampus in patients who have PD.

When patients who have PD are presented with anxiety-provoking visual stimuli, they exhibit increased activity in the inferior frontal cortex, hippocampus, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and OFC.

Compared with healthy control subjects, patients who had PD exhibited less activation in the ACC and amygdala when shown pictures of angry faces. These latter results were interpreted as a blunted response caused by chronic hyperactivity in these circuits in patients who had PD.