Stress or cytokine-induced release of glucocorticoids normally produce immunosuppressive and anti-inflammatory changes but may have other effects in the brain (Sorrells et al., 2009). Chronic elevated levels of cortisol impair synaptic plasticity, diminish neurogenesis and spinal density, and may result in dendritic atrophy (McEwen and Magarinos, 2001) and dysregulate glutamate neurotransmission (Iyo et al., 2010). Such changes may contribute to alterations in brain regions such as the hippocampus that may manifest as syndromes associated with migraine, such as depression (Musazzi et al., 2011). Data supporting increases

in stress hormones including noradrenaline and cortisol in response to stress in migraineurs have been reported (Leistad learn more et al., 2007), thus providing a basis for specific brain-induced changes in migraine. Migraine BIBW2992 mw is considered to be a hyperexcitable state, and increases in excitatory neurotransmitters during the interictal period may reflect such a state (Prescot et al., 2009). Of the brain regions studied, the hippocampus, amygdala, hypothalamus, and prefrontal cortex seem to play an important role in this process. Some regions such as the hippocampus and prefrontal cortex are responsive to the repeated action of glucocorticoids, together with excitatory amino acids and other mediators, on the

brain region that affect hippocampal function and structure (McEwen, 2007). The before hippocampus has been a model for understanding the effects of stress on neuronal plasticity and allostatic load (McEwen, 2001). In stressful conditions, neurogenesis and apoptosis in hippocampus are suppressed (Kubera et al., 2011). Such a situation could be operating every time an individual has a migraine attack. The process may involve other brain regions that have connections with the hippocampus,

including the hypothalamus and the amygdala. For example, with unpredictable stress, inhibitory input to neurons involved in the hypothalamus are reportedly suppressed, leading to dysregulation of the axis and potentially overexposure of the brain to glucocorticoids (Joëls et al., 2004) In addition, a putative role for the amygdala in allostatic load, related to anticipatory anxiety, has been suggested (Schulkin et al., 1994). The involvement of the amygdala in migraine has been supported by a number of other reports, including changes related to cortical spreading depression (Dehbandi et al., 2008); chronic migraineurs show decreased amygdala volume (Valfrè et al., 2008). Its role in this may relate to the high levels of anxiety or fear in patients with migraine (Casucci et al., 2010), particularly in those suffering from chronic daily migraine (Dodick, 2009). Given the role of the hypothalamus in autonomic control (viz.