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In order to understand the mechanisms involved in anxiety, and hence its treatment, the underlying neuronal circuitry must first be understood. Three important concepts underlie the functional anatomy of anxiety: a defence system, which makes immediate responses to a situation by using fight, flight or freezing behaviour; a behavioural inhibition system, which is involved in information gathering and suppressing behaviours that might endanger the individual; and, an avoidance system,

to escape or avoid situations that an individual recognises as dangerous prior to the event. These three systems work together as one, causing fight or flight, so preventing any behaviour that might lead to danger (Sandford et al. 2000). Evidence for these concepts is from years of animal and human studies (Gray & McNaughton, 2003; Blanchard, Blanchard, Griebel & Nutt, 2008).

The brain structures and pathways underlying these three systems are complex and involve many neural circuits at different levels depending on the type of anxiety and, in the case of pathological anxiety, the type of disorder (Kim & Gorman, 2005). What is known of the neuroanatomy of anxiety from animal, immnuocytochemistry and imaging studies can be simplified to three different levels (Carrasco & Van de Kar 2003). The brainstem is responsible for autonomic responses. The limbic system is responsible for the affective states of anxiety, emotions, mood changes and neuroendocrine changes in stress hormones, such as cortisol and other glucocorticoids. Finally, the higher limbic system and neocortex are responsible for conscious or cognitive responses to anxiogenic stimuli. There is bi-directional feedback between these pathways causing an enhanced response, leading to anxiety or a damping down of the response in normal individuals who do not suffer from anxiety (Carrasco & Van de Kar 2003). In sufferers of anxiety disorders, the control of these neural circuits might be impaired (Kim & Gorman, 2005). The next sections describe the involvement of these regions of the brain in the aetiology of anxiety in more detail.

Brainstem

In the brain stem, noradrenaline (NA) -releasing neurons in the locus coeruleus (LC) are involved in producing the immediate FFFS response to anxiogenic stimuli in co- ordination with the periaqueductal grey (PAG), the grey matter located around the cerebral aqueduct located in the midbrain (Singewald, Salchner & Sharp, 2003). In extreme danger when an organism is under immediate threat, the PAG is the region of the brain that is most likely to be activated, causing undirected escape, attack or catastrophic panic. In panic disorder, it is this region that is likely to be at fault (Grey & McNaughton, 2003; Blanchard, et al., 2008). The release of NA from the LC is responsible for arousal, drive and appetite (Smith & Nutt, 1996; Sullivan, Coplan, Kent & Gorman, 1999). Normally, during stress responses projections from the LC to

the amygdala, the hippocampus, the hypothalamus, the nucleus tractus solitarius, the periaqueductal grey, the prefrontal cortex and the thalamus are activated. The projections to these cortical and subcortical regions are responsible for mediating fear and anxiety. Most of these regions also innervate the LC. Thus, the NA neurons in the LC are in a position to integrate both external and internal data and activate structures that have roles in stress and anxiety responses (Kent, Mathew & Gorman, 2002). This neuronal activity focuses attention and promotes scanning behaviour (Jenck, Moreau & Martin, 1995; Singewald et al., 2003; Mansour et al., 2003). Additionally, noradrenergic projections from the LC activate the autonomic nervous system, including the cardiovascular and pulmonary systems, readying them for a FFFS response while suppressing systems which are not needed at this stage, such as the digestive and urinogenital systems.

Alongside the NA system, the raphé nuclei in the brain stem, which consist of many different subsets of serotonergic neurons including the median (MRN) and dorsal (DRN) raphé nuclei, are involved in the control of these anxiety responses (Abrams et al., 2005; Kim & Gorman, 2005). These neurons are thought to mediate a complex of differential responses to anxiogenesis, projecting to forebrain circuits involved in the regulation of anxiety responses and to the LC where they regulate NA release (Abrams et al., 2005). All of these regions communicate widely with the limbic system including the hypothalamus.

Additionally, the brainstem and limbic system send signals to the prefrontal lobes and paralimbic cortex, which include the orbitofrontal cortex, the bed nucleus of the stria- terminalis (BNST), the insula, the anterior-temporal and the anterior cingulate. This information is processed and a response co-ordinated (Liotti et al., 2000). Thus, all of these systems in the brain stem coordinate with other CNS structures and the external and internal environment to elicit a response.

Limbic system

The limbic system consists of many brain structures and pathways, the main ones being: the amygdala, the anterior thalamic nucleus, the fornix, the hippocampus, the septal nuclei, the hypothalamus, the mammillary bodies, the BNST, the medial forebrain bundle, and the prefrontal lobes. Phylogenetically the limbic system is the

oldest part of the brain and has a key role in the creation and processing of emotions (Chorpita & Barlow 1998; Phan, Wager, Taylor, & Liberzon, 2002).

The PAG is connected to the dorsal hypothalamus, which mediates the more sophisticated escape mechanisms that are likely to be employed when the threat is not as immediate and so panic does not ensue. In Gray and McNaughton’s model (2003) the hypothalamus is responsible for simple active avoidance, for example, phobia. The hypothalamus also has a key role in coordinating neuroendocrine responses to anxiety via the Hypothalamic-Pituitary-Adrenal (HPA) axis, the slow stress response (see Figure 1.1), and the symapthoadrenomedullary system (SAM). The SAM is the immediate response to environmental stressors, mediated by cells in the adrenal medulla and different areas of the brain depending on the type of stress causing an increase in adrenaline and NA. Examples of the SAM include activity by nuclei in the brainstem in response to low oxygen, or the frontal lobes in response to a cognitive or psychological stressor (Mravec, 2005). The LC and the hypothalamus detect these hormone rises and activate the CNS (Mravec, 2005). The HPA axis causes the release of glucocorticoids, such as cortisol, which are involved in stress and the FFFS response (Carrasco & Van de Kar, 2003; Sandford et al., 2000). Interestingly, most of the hypothalamic nuclei are larger in males than females (Swaab, 1997). The hypothalamus is, in turn, connected to the amygdala.

Figure 1-1The HPA axis.

The amygdala, is made up of many nuclei and is generally divided into the central, lateral and basolateral nuclei. The amygdala has been likened to a switchboard, controlling, co-ordinating and directing anxiety responses (Kim & Gorman, 2005). The central nuclei send projections to the hypothalamus, LC, and PAG, to activate the HPA axis and thus, cortisol secretion from the adrenals and NA release from the LC, to increase sympathetic arousal. Additionally, the lateral nucleus processes signals from the higher brain regions involved in the anxiety response, such as the prefrontal cortex, the cingulate gyrus, the hippocampus and the thalamus.

More specifically, studies have shown that the amygdalae co-ordinate simple avoidance and so co-ordinate with the hypothalamus in mediating avoidance during phobic states, as well as having a role in mediating the arousal components of GAD (Gray & McNaughton, 2003). Studies on animals and humans with damaged or removed amygdala, provide evidence for this role of the amygdala in the expression, memory conditioning of, and release, of fear and anxiety (Davies, 1992). Thus, the amygdalae are where memories of fearful events are created, which explains their

role in causing avoidance/aversion to situations (Singewald, Salchner, & Sharp 2003; Davis 1998).

There are hemispheric differences between the size and function of the amygdalae (Kim & Gorman, 2005). The size of the left amygdala is often diminished in anxiety sufferers and is thought to be linked to the control of anxiety responses. The right amygdala is thought to be more active in pathological states (Kim & Gorman, 2005).

In summary, the amygdala communicates with the neocortex where conscious thoughts are generated and processed. They also communicate with the thalamus, which co-ordinates sensory signals prior to sending them to the cortex (Davidson, 2002). The amygdala finally communicate back with the brain stem.

The bed nucleus of the stria-terminalis (BNST), a part of the extended amygdala, receives input from all three of the amygdaloid nuclei and has multiple connections to all of the limbic and cortical regions involved in the fear and anxiety response. It is involved in mediating anxiety responses, rather than the fear responses for which the amygdaloid nuclei are responsible, and for the longer-term regulation of the anxiety response (Bangasser, Santollo, & Shors, 2005). It is also thought to modulate the cortisol releasing factor (CRF)-cortisol pathway, rather than the immediate sympathetic pathways, which are co-ordinated by the hypothalamus (Carrasco & Van de Kar, 2003). Interestingly, the BNST is highly sexually dimorphic and densely expresses gonadal steroid receptors, and differs in size between males and females (Toufexis, Myers & Davis, 2006).

The septo-hippocampal formation, consisting of the hippocampus, the dentate gyrus, the entorhinal cortex, the subicular area, and the posterior cingulate cortex, acts as a comparator, comparing known information about a situation with the actual situation (Gray & McNaughton, 2003). One of its roles is in approach-avoidance conflicts (Degroot & Treit, 2003; Graeff, 1994). According to Gray and Mc Naughton (2003) the septo-hippocampal loop responds to threat by interrupting ongoing behaviour (behavioural inhibition) via the psychological BIS. This allows information gathering, known as risk-assessment behaviour (Blanchard et al., 2008). The BIS is active in situations where there is a conflict, for example, where information held is incongruous with information about the current situation, or proceeding with one goal

might involve entering a threatening situation thus creating an approach-avoidance conflict. The LC in the brain stem stimulates this hypervigilant, information- gathering, attentional output. Information gathering also involves the recall of memories stored elsewhere, for example in the temporal lobes (Rokers, Mercardo, Allen, Myers & Gluck, 2002; McNaughton & Corr, 2004). In recalling memories relevant to a potentially threatening situation, the septo-hippocampal system has the capacity to increase the valence of affectively negative stimuli. Gray and McNaughton (2003) suggest that this increasing of perceived threat and subsequent storage of these increasingly negative memories are what lead to the rumination and excessive anxiety seen in general anxiety disorder. Interestingly, lesions to the septo- hippocampal system closely resemble the effects of anxiolytic drugs (Gray & McNaughton, 2003); also, anxiolytic drugs and lesions to the hippocampus have very mild effects on mnemonic memory function (Gray & McNaughton, 2003). Finally, if the septohippocampal system determines that there is a threat, it sends information to the lateral nucleus of the amygdala, which mediates the appropriate avoidance reaction and the arousal components of GAD. Additionally, the BIS is able to interrupt ongoing motor behaviour and increase attention to the perceptual world (sensory vigilance) via connections from the subiculum, which is part of the septo- hippocampal loop system, to the nucleus accumbens (Gray & McNaughton, 2003). This is because the nucleus accumbens sends signals via the substantia nigra to the motor control areas of the basal ganglia and the entire thalamocortical sensory processing system. In extreme stress, there is often a degeneration of hippocampal volume, which might lead to extreme anxiety (Douglas Bremner et al., 1995).

Paralimbic system and prefrontal cortex

The orbitofrontal cortex, the insular, the anterior temporal and the anterior cingulate receive information from the limbic system and the brainstem (Liotti, Mayberg, Brannan, McGinnis, Jerabek, & Fox 2000). The cingulate cortex is a bridge in communication between the prefrontal lobes, the limbic system and the brainstem (Milad et al., 2007). Lesions to this region lead to a disinhibition of emotion and an inability to modify behaviour according to environmental circumstances (Milad et al., 2007). Damage to the orbitofrontal cortex and the cingulate gyrus cause decreased anxiety. Surgery in these regions has been used as a way of relieving suffering from extreme anxiety that is resistant to treatment by standard pharmacotherapy; often this

includes people who suffer from OCD (Ballantine, Bouckoms, Thomas, & Giriunas 1987). In PET studies, the orbitofrontal cortex is also implicated in worry (Wu, Buchsbaum, Hershey, Hazlett, Sicotte, & Chad Johnson 1991).

Anxiety can begin at any one of the levels discussed above, brainstem, limbic regions, paralimbic and prefrontal cortices (see Figure 1.2 below). These systems respond to stimuli and feed back to the other levels in order to co-ordinate a response, or create anxiety in the individual (Gray & McNaughton, 2003). The neurotransmitter systems involved in co-ordinating these responses at different structural levels are very complex. The following section continues the discussion looking at the neurotransmitters known to have a role in the aetiology of anxiety.