Neuroimaging studies to date have primarily focused on basal ganglia or striatal pathology and have shown preliminary evidence of impaired dopaminergic functioning in these regions. The interest in these specific brain regions followed accumulating clinically based evidence of dopaminergic deficits in social anxiety disorder (Appendix 1). Neuroanatomically, of the four major dopamine pathways in the CNS, dysfunctions of the mesocortical and mesolimbic (ventral striatal, including the nucleus accumbens) pathways appear most relevant to social anxiety, with a presumed lesser importance of tuberoinfundibular and nigrostriatal (dorsostriatal) pathways, although published imaging studies do not provide sufficient spatial resolution to make this determination.
A study by Tiihonen et al. (82) reported a decrease in striatal dopamine reuptake sites on SPECT in patients with social anxiety disorder compared to normal volunteers, which suggests a deficit of dopaminergic innervation into the striatum. The authors suggested that the lowered dopamine reuptake site density reflects an overall smaller number of dopaminergic synapses and neurons in the striatum of patients with social anxiety disorder. The recent [123I]iodobenzamide ([123I]IBZM) SPECT study of Schneier et al. (5), which showed reduced mean D2 receptor binding in the striatum, implicated dopaminergic hypofunction in the striatum. However, the interpretation of this report is difficult to reconcile with the report by Tiihonen et al. of decreased dopamine transporter binding, in that decreased binding potentials of the SPECT radiotracer [123I]IBZM could also reflect increased levels of free dopamine in the vicinity of D2 receptors, altered affinity of D2 receptors for dopamine, or some combination of these factors. It was recently argued that SPECT or PET studies measuring dopamine binding after changes in synaptic dopamine levels are probably more complex than accounted for by simple binding occupancy models and might involve changes in the subcellular distribution of receptors (83). Indeed, most of the variance in D2 receptor binding appears to be due to alterations in receptor expression, whereas endogenous dopamine levels contribute to only about 10%–20% of the variance (personal communication, Marc Laruelle, M.D., 2001).
Most neuroimaging studies not specifically focusing on dopamine systems have detected basal ganglia and cortical abnormalities, and one study suggested amygdala involvement. Using magnetic resonance spectroscopy (MRS), Davidson et al. (84) reported a decrease in choline and creatine signal-to-noise ratios in the subcortical, thalamic, and caudate areas, as well as lowered N-acetylaspartate signal-to-noise ratios in cortical and subcortical regions, which was interpreted as possible neuronal atrophy and degeneration. The use of signal-to-noise ratios and limited spatial resolution were notable limitations of this study, as more recent MRS studies have analyzed the ratios of metabolites (85). Potts et al. (86) showed in another MRS study that patients with social anxiety disorder had a greater decrease in putaminal volumes during aging than normal comparison subjects. In studies of cerebral blood flow (CBF), Stein and Leslie (87) found no basal metabolic cerebral differences between patients and comparison subjects on SPECT, which indicated that any posited subcortical abnormality might not affect resting metabolism. Bell et al. (88), in a symptom-provocation study measured by means of H215O-labeled PET, reported an array of anxiety-related changes but stated that the changes specific to social anxiety disorder included increased regional CSF in the right dorsolateral prefrontal cortex and left parietal cortex. Finally, a recent fMRI study (89) implicated the amygdala in the pathophysiology of social anxiety, suggesting the generation of a hypersensitive amygdala when patients are exposed to potentially fear-relevant stimuli. In this study, neutral face stimuli elicited greater amygdala activity bilaterally in patients versus comparison subjects, despite knowledge that the neutral faces were not harmful, as shown by subjective ratings of anxiety. The causal relationship between fear elicitation and amygdaloid activation is unclear; however, this preliminary study is the first direct evidence for a role of the amygdala in social anxiety disorder.
In summary, there are few replicated neuroimaging studies to date regarding social anxiety disorder, but the convergence of data thus far implicates basal ganglia structures, the amygdala, and varied cortical regions. SPECT studies of the dopamine transporter and D2 receptor in the striatum thus far are inconclusive in confirming a hypothesis of low dopamine innervation. Recent initiatives, such as the development of a PET D2 receptor agonist ligand (90), which allows for direct determinations of neurotransmitter-D2 receptor interactions, will potentially provide valuable information on the role of this receptor in social anxiety disorder.