Challenges in developing novel treatments for childhood disorders: lessons from research on anxiety

Abstract

Alterations in brain development may contribute to chronic mental disorders. Novel treatments targeted toward the early-childhood manifestations of such chronic disorders may provide unique therapeutic opportunities. However, attempts to develop and deliver novel treatments face many challenges. Work on pediatric anxiety disorders illustrates both the inherent challenges as well as the unusual opportunities for therapeutic advances. The present review summarizes three aspects of translational research on pediatric anxiety disorders as the work informs efforts to develop novel interventions. First, the review summarizes data on developmental conceptualizations of anxiety from both basic neuroscience and clinical perspectives. This summary is integrated with a discussion of the two best-established treatments, cognitive behavioral therapy and selective serotonin reuptake inhibitors. Second, the review summarizes work on attention bias to threat, considering implications for both novel treatments and translational research on neural circuitry functional development. This illustrates the manner in which clinical findings inform basic systems neuroscience research. Finally, the review summarizes work in basic science on fear learning, as studied in fear conditioning, consolidation, and extinction paradigms. This summary ends by describing potential novel treatments, illustrating the manner in which basic neuroscience informs therapeutics.

Figure 1

The dot-probe paradigm. (a) The structure of the dot-probe paradigm. Trials begin with fixation and end with an asterisk probe. These events are separated by a face pair, which can vary across experimental trials in terms of depicted emotions and the timing. Hence, faces can include an angry and neutral picture, or different emotions, each presented for varying times, including 500ms as shown, or other times, such as brief exposures (eg, 17ms with a mask). (b) The design used in a dot-probe training experiment with children, as described in more detail in Eldar et al (2008). This experiment involved an initial pretraining assessment, a training session designed to induce attention bias, a posttraining reassessment, and a stress induction paradigm. (c) Summary of results from Eldar et al (2008). Bias training successfully induced greater attention bias and anxiety responses to stress than a control training regimen.

Figure 2

Two fMRI studies of amygdala-prefrontal cortex (PFC) engagement in adolescent generalized anxiety disorder (GAD). (a) Stimulus event timing parameters in the two studies. For both, stimuli began with a 500 ms fixation symbol and ended with an 1100ms asterisk dot-probe target. However, for facial stimuli, one study utilized brief 17ms faces, followed by an 83ms backward mask; the other study utilized 500 ms faces with no mask. (b) Results. The top of Panel b shows the location of a between-group right amygdala difference where GAD showed greater activation than healthy adolescents in a masked 17ms threat-vs-neutral-face contrast. The figure also shows a positive correlation between anxiety severity in GAD and amygdala engagement. The bottom of Panel b shows the location of a between-group difference in right PFC activation where GAD showed greater activation than healthy adolescents in an unmasked 500 ms threat-vs-neutral contrast. The figure also shows a negative correlation between anxiety severity in GAD and PFC engagement. More details of methods and results from these studies appear in Monk et al (2006, 2008).

Figure 3

Procedures for monitoring eye tracking in adolescent rhesus monkeys. These procedures involve displaying photographs while monkeys’ gaze fixations are monitored with an infrared camera. (a) Data in four monkeys during the viewing of human threat-neutral faces. Panel a shows an example of utilized stimuli, as also employed in dot-probe studies with human adolescents. The adjacent graph depicts the mean percentage of gazes to human faces in neutral–fearful pairs (left) and neutral–angry pairs (right). A paired t-test of fixation percentages to neutral vs angry expressions revealed a significant difference in orientating toward angry expressions, paired t = 2.3, p < 0.05. Thus, monkeys spend significantly more time viewing threat relative to neutral faces as depicted during the dot-probe task. (b) A schematic representation of the apparatus, where a monkey is seated in a primate chair while pairs of photographs are presented on a computer. Although pilot work used human faces, ongoing work is using monkey faces, as shown in the figure, to increase ecological validity. An example of gaze fixation patterns from one monkey to a typical face pairing is displayed on the left.

Figure 4

Emerging research implicates conditioning in social phobia. (a) A schematic representation of the experiment in Lissek et al (2008b). This experiment demonstrated perturbed conditioning in social phobia, when neutral conditioned-stimulus (CS) photographs of an individual were paired with unconditioned stimuli (UCS) consisting of angry expressions from the same individual and angry comments. Although the original experiment was conducted using adult photographs and adult patients, Figure 4 relies on adolescent photographs, given relevance for studies in adolescence, a time by which precursors of adult social phobia appear readily apparent. (b) Schematic depiction of neural architecture presumably engaged on presentation of CS paired with the depicted UCS during conditioning. (c) Schematic depiction of neural architecture presumably engaged during CS extinction.