Y of situations, while imbalances in regulation of the basal ganglia and amygdala are hypothesized to result in excessive reward-seeking or avoidance behavior, impacting both normal development and propensity for psychiatric illness. It should be noted that most studies included in the meta-analysis used a region of interest approach, although whole brain data were included when available; thus the meta-analysis is inherently limited by the available data and tasks used. Similarly, GingerALE models observed findings to identify common regions of group differences; however, this approach does not include null findings. The studies included come from three different laboratories (Schwartz, Fox, and Blackford) and some of these studies represent overlapping samples of subjects (Bar-Haim et al., 2009; Guyer et al., 2006; Helfinstein et al., 2011; Jarcho et al., 2014, 2013; P ez-Edgar et al., 2007) and (Blackford et al., 2013, 2011; Clauss et al., 2011); however, each study used a different task, thus findings represent common brain activation across cognitive processes, subjects, laboratories, and ages. Finally, there was heterogeneity in psychopathology/psychotropic medication use across samples; thus, the findings may represent both inhibited individuals with psychopathology and resilient individuals. In future studies, separating out these two groups will be critical to understanding how inhibited temperament leads to risk for psychopathology.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptProg Neurobiol. Author manuscript; available in PMC 2016 April 01.Clauss et al.Page2.3. Human Studies of Brain StructureAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript2.3.1. Amygdala–Inhibited temperament is characterized by an avoidance of novelty, which fMRI studies have shown is primarily subserved by POR-8 biological activity LY-2523355 dose increased amygdala activation. However, the underlying cause of increased amygdala activity is unknown. For example, increased amygdala activity may result from more neurons, more synapses, or alterations in neuron function. To determine whether inhibited individuals had differences in amygdala volume, we used three measures (manual tracing, voxel-based morphometry, and surface mapping) to measure amygdala volume in inhibited and uninhibited individual (Clauss et al., 2014b). Inhibited individuals had larger amygdala volume across all three measures, and the volume differences were most prominent in the basolateral subnucleus. Importantly, larger amygdala volume correlated with stronger activation to faces, providing an initial link between structure and function. In rodent models, chronic immobilization stress increases the number of spines on the basolateral subregion (Mitra et al., 2005; Vyas et al., 2002); inhibited adults may be particularly vulnerable to stress or may experience more stress as a result of their social inhibition, suggesting a possible mechanism for increased basolateral amygdala volume in inhibited adults. In a second study investigating amygdala volume, larger amygdala volumes were found in adolescents who spent more time close to their mother at age 5 during a peer-play task (Hill et al., 2010). Larger amygdala volume has also been associated with traits similar to inhibited temperament, including fearfulness (van der Plas et al., 2010), sensitivity to punishment (Barros-Loscertales et al., 2006), and harm avoidance (Iidaka et al., 2006). Several recent studies suggest that amygda.Y of situations, while imbalances in regulation of the basal ganglia and amygdala are hypothesized to result in excessive reward-seeking or avoidance behavior, impacting both normal development and propensity for psychiatric illness. It should be noted that most studies included in the meta-analysis used a region of interest approach, although whole brain data were included when available; thus the meta-analysis is inherently limited by the available data and tasks used. Similarly, GingerALE models observed findings to identify common regions of group differences; however, this approach does not include null findings. The studies included come from three different laboratories (Schwartz, Fox, and Blackford) and some of these studies represent overlapping samples of subjects (Bar-Haim et al., 2009; Guyer et al., 2006; Helfinstein et al., 2011; Jarcho et al., 2014, 2013; P ez-Edgar et al., 2007) and (Blackford et al., 2013, 2011; Clauss et al., 2011); however, each study used a different task, thus findings represent common brain activation across cognitive processes, subjects, laboratories, and ages. Finally, there was heterogeneity in psychopathology/psychotropic medication use across samples; thus, the findings may represent both inhibited individuals with psychopathology and resilient individuals. In future studies, separating out these two groups will be critical to understanding how inhibited temperament leads to risk for psychopathology.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptProg Neurobiol. Author manuscript; available in PMC 2016 April 01.Clauss et al.Page2.3. Human Studies of Brain StructureAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript2.3.1. Amygdala–Inhibited temperament is characterized by an avoidance of novelty, which fMRI studies have shown is primarily subserved by increased amygdala activation. However, the underlying cause of increased amygdala activity is unknown. For example, increased amygdala activity may result from more neurons, more synapses, or alterations in neuron function. To determine whether inhibited individuals had differences in amygdala volume, we used three measures (manual tracing, voxel-based morphometry, and surface mapping) to measure amygdala volume in inhibited and uninhibited individual (Clauss et al., 2014b). Inhibited individuals had larger amygdala volume across all three measures, and the volume differences were most prominent in the basolateral subnucleus. Importantly, larger amygdala volume correlated with stronger activation to faces, providing an initial link between structure and function. In rodent models, chronic immobilization stress increases the number of spines on the basolateral subregion (Mitra et al., 2005; Vyas et al., 2002); inhibited adults may be particularly vulnerable to stress or may experience more stress as a result of their social inhibition, suggesting a possible mechanism for increased basolateral amygdala volume in inhibited adults. In a second study investigating amygdala volume, larger amygdala volumes were found in adolescents who spent more time close to their mother at age 5 during a peer-play task (Hill et al., 2010). Larger amygdala volume has also been associated with traits similar to inhibited temperament, including fearfulness (van der Plas et al., 2010), sensitivity to punishment (Barros-Loscertales et al., 2006), and harm avoidance (Iidaka et al., 2006). Several recent studies suggest that amygda.