Common sites of action for citalopram and cognitive-behavioral treatment of social anxiety were observed in the amygdala, hippocampus, and neighboring cortical areas, ie, brain regions subserving bodily defense reactions to threat.

An rCBF pattern of relatively increased cortical rather than subcortical perfusion was observed in the nonphobic subjects, indicating that cortical evaluative processes were taxed by public performance. In contrast, the social phobia symptom profile was associated with increased subcortical activity. Thus, the functional neuroanatomy of social phobia involves the activation of a phylogenetically older danger-recognition system.

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

Patients with combat-related posttraumatic stress disorder (PTSD) show altered cognitive and affective processing and symptomatic responding following exposure to trauma reminders. Previous symptom provocation studies using brain imaging have involved Vietnam veterans. In this study neural correlates were investigated in patients with PTSD resulting from trauma in more recent war zones. (15)Oxygen water and positron emission tomography were used to measure regional cerebral blood flow (rCBF) in patients with war- and combat-related chronic PTSD during exposure to combat and neutral sounds. Self-reports and heart rate confirmed symptomatic responding during traumatic stimulation. The war-related condition, as compared to the neutral, increased rCBF in the right sensorimotor areas (Brodmann areas 4/6), extending into the primary sensory cortex (areas 1/2/3), and the cerebellar vermis. RCBF also increased in the right amygdala and in the periaqueductal gray matter adjacent to the pons. During provocation rCBF was lowered in the right retrosplenial cortex (areas 26/29/30 extending into area 23). Symptom provocation in PTSD promote sensorimotor, amygdaloid and midbrain activation. We conclude that perceptually induced symptom activation in PTSD is associated with an emotionally determined motor preparation and propose that subcortically initiated rather than cortically controlled memory mechanisms determine this pattern.

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