Both SSRIs and CBT are thought to induce clinically meaningful change by balancing perturbed neural and cognitive processes associated with threat perception and interpretation. Such therapies may target specific biases in threat processing, such as hypervigilance toward threats, emerging in specific social evaluative contexts, or they may target more general processes, such as those that engender rumination on threats associated with excessive worrying. Insights on novel therapeutics might emerge by focusing specifically on the manner in which CBT and SSRIs alter specific processes, such as attention bias toward threat.
Increased attention to threat serves an adaptive function by facilitating the detection of danger (LeDoux, 2000
). Advantaged allocation of processing resources to overt threats is adaptive, in that it facilitates responses to dangerous situations. However, biased threat processing has been implicated in the etiology and maintenance of anxiety disorders (Bar-Haim et al, 2007
; Beck, 1976
; MacLeod et al, 2002
; Williams et al, 1996
). Indeed, considerable research demonstrates that the attention system of anxious individuals is distinctively sensitive to threats (Bar-Haim et al, 2007
; Mogg and Bradley, 1998
). Thus, allocating attention toward extreme threat represents a normative response; however, a reduced threshold for eliciting threat-related attention allocation to mild threats represents a core feature of clinically significant anxiety.
Various paradigms quantify threat-related attention biases, each showing replicable effects. Nevertheless, a focused review on specific attention-related behaviors may clarify key aspects of complex relations among attention, threat-processing, and anxiety, manifest across development and even across species. When considering a focused perspective, the dot-probe paradigm probably represents the single best task affording a developmental perspective (MacLeod et al, 1986
; Pine, 2007
). This task assesses individual differences in attention-orienting behavior to one or another spatial location, which occurs in the context of a target-probe identification paradigm. On each trial (), a central fixation cross is displayed, followed by presentation in opposite hemifields of two stimuli, one threat related (eg, angry face) and one neutral (eg, neutral face). Upon offset, a target probe appears at the location occupied by one face, which participants detect as quickly and accurately as possible. Response latencies provide a ‘snapshot’ of attention allocation with fast responses occurring to probes at attended locations. Manipulating timing of face-probe offset–onset presentations shifts the ‘snapshot’ timing. Thus, chronometry of threat–attention interactions is examined by measuring bias across various timing parameters.
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 (more ...)
Meta analysis (Bar-Haim et al, 2007
; Williams et al, 1996
) documents a moderate effect size of attention bias across diverse anxious groups. As such, attention bias represents a general feature of between-group differences in anxiety, and the bias is not observed typically in nonanxious individuals. Threat bias represents an instance where attention prioritization of low-level threat-related material occurs only in specific, anxious subgroups but not in most healthy individuals. Quantitative review also suggests that relatively slow-developing, elaborative processing contributes to threat biases. However, on the dot-probe task, a significant bias is also observed with brief (eg, 17 ms) threats, stimuli that are difficult, if not impossible, to consciously perceive. Moreover, subliminal exposure to threat-neutral displays in anxious, relative to nonanxious individuals, yields an effect size almost twice as large as for supraliminal exposures (Bar-Haim et al, 2007
). This implicates early, rapidly and implicitly deployed, attention processes in individual differences.
Work has begun to examine the threat bias/anxiety association from a developmental perspective. This is important, given the strength of findings in adults, coupled with other data on developmental aspects of clinical anxiety (Pine, 2007
). The extant literature establishes that children as young as 7 reliably perform the dot-probe task.
In terms of attention bias’s role in early anxiety, three positions have been advanced. One suggests that threat-related attention biases and individual differences in anxiety go hand in hand from early in development (Martin et al, 1992
). That is, an association between threat bias and individual differences in anxiety might emerge even in preschoolers, considering individual differences in anxiety manifest either as clinical pathology or as associated potential precursors, such as behavioral inhibition (Pine, 2007
). A second position (Kindt et al, 1997
) suggests that the association between threat bias and between-group differences in anxiety only manifests relatively late in development. That is, both anxious and nonanxious children are presumed to enter early development with an equally strong bias toward threat, a bias not found in nonanxious adults. With increasing age, nonanxious children selectively learn to inhibit this bias, whereas anxious children fail to do so. Finally, a third position (Fox et al, 2007
) suggests that attention bias is shaped by interactions between temperament and caregiver behaviors. Certain children, predisposed to fear novelty, may be raised in ways that heightens attention to threats, thereby contributing to eventual onset of clinically significant anxiety. Of note, all three theories may be compatible with observations associating ventral prefrontal cortex (vPFC) maturation with increased modulation of subcortical structures in which fear reactions are represented.
For the first position, individual differences are expected early, such that only anxious infants and young children demonstrate attention biases. Individual differences in vPFC maturation might ultimately account for the fact that many of these anxious children mature to become nonanxious adolescents and adults. As such, processes whereby vPFC exerts increasing control over amygdala engagement may be analogous to extinction of fears, but played out over the extended time course of development as opposed to relatively narrow window of fear-conditioning experiments (Quirk and Gehlert, 2003
). For the second position, attention bias is expected in both anxious and nonanxious infants and young children (Kindt et al, 1997
). Here, prefrontal cortex (PFC) maturation might reduce these biases only in those individuals who remain nonanxious. This position receives partial support from work finding threat bias in both anxious and nonanxious children. By contrast, other studies find a significant bias only in anxious children (Waters et al, 2008
). For the third position, attention biases are expected to emerge early in the unique subset of children born with an underlying anxiety predisposition and exposed to particular rearing environments. Here, interactions between predispositions and rearing are expected to sculpt behavior through their evolving effects on vPFC-amygdala circuitry development.
Thus, the first and the third positions predict threat bias in particular subsets of at-risk or affected children, whereas the second position predicts threat bias in most, if not all children. These discrepancies might be resolved through studies that rely on longitudinal designs measuring threat bias very early in life in at-risk youths. For example, a study following at-risk offspring of anxious parents might clarify the degree to which individual differences in threat bias predate or reflect later anxiety. Moreover, by examining the influence of both genetic predisposition and caregiver behavior, such a study might clarify the degree to which environmental influences interact with early-manifesting risk to shape both attention bias and clinical anxiety.
Attention bias probably represents the single most frequently noted correlate of individual differences in anxiety. Nevertheless, scant empirical evidence clarifies the degree to which attention bias represents a downstream effect, as opposed to a causal factor. Experimental manipulations provide one method for evaluating causality, whereby training procedures induce attention bias, followed by an assessment of stress reactivity. In two studies, MacLeod and colleagues (MacLeod et al, 2002
) were the first to causally implicate training-induced attention biases in stress reactivity. Specifically, in these studies, nonanxious adults were randomly assigned to training conditions. One condition induced bias toward threat, by repeatedly pairing target probes with the spatial location of threat cues. The other induced avoidance by pairing probes to the location of the neutral stimuli. Experimentally induced bias did not affect anxiety following training but it did cause congruent changes in state anxiety following a stress induction task.
A growing number of experiments document reliable effects of training on attention bias (Clarke, 2008
; Dandeneau et al, 2007
; Eldar et al, 2008
; Wilson et al, 2006
). Of note, none of these studies utilizes very brief threat exposures, so effects only pertain to stimuli that can be readily perceived. Regardless, by reliably demonstrating robust training effects, the work shows that attention bias is not strongly trait-like. Of particular relevance for the present review, one such study trained children to have a bias (see ; Eldar et al, 2008
). This study showed that attention bias influenced children’s response to an acute laboratory stressor. Thus, attention biases can be reliably manipulated in the laboratory. This work sets the stage for the first set of future studies that eventually will evaluate the clinical relevance of these training effects.
A particularly important next step will be to explore the role of computer-based attention training in anxiety disorder treatment. No published studies consider this issue. Evidence of clinically relevant effects in patients could directly link research on therapeutics and attention bias. For example, for some children, computer-based training of attention may be more acceptable than traditional in-person therapy formats, and it may offer advantages by delivering exposure where attention can be controlled in a systemized manner. Perhaps most importantly, such computer-based approaches may augment the approach to attention retraining that forms a core feature of CBT. With CBT, patients attempt to use cognitive control strategies to willfully alter their attention focus. With computer training, subjects are taught implicitly to control attention, through repetitive training procedures, in the absence of explicit instructions. Thus, combining CBT with computerized retraining may simultaneously target explicit and implicit processes. As such, computer-based interventions have potential for improving outcomes in research on child anxiety disorder therapeutics.
Consistent observations linking anxiety to threat bias suggest the importance of examining associated neural circuitry. Demonstrating parallel developmental relations across species among threat bias, anxiety, and neural architecture would increase the clinical relevance of research in animals and possibly inform therapeutics. Such parallels are expected, given other evidence of cross-species conservation in the neural architecture of fear.
Research on the rodent threat response precisely delineates the topography and chronometry of distributed neural circuitry engagement during threat-orienting behavior. Engagement of the amygdala, immediately following threat exposure, represents a key early-occurring process initiated for visual threats when information passes from the retina to the thalamus and immediately to the amygdala (LeDoux, 2000
). This process is thought to provide very quick but relatively crude signals to the organism, associated with engagement of attention in the service of early threat detection and stimulus reinforcement learning (Blair et al, 2005
). As such, this early process reflects the central role of the amygdala in immediate, rapid, implicit modulation of attention orienting to threats (Davis and Whalen, 2001
). Data in humans demonstrate comparable effects (Phelps and LeDoux, 2005
). Accordingly, from the clinical perspective, this view suggests that hypersensitivity in the amygdala may be involved in anxiety-related perturbations manifest in the immediate response to threats.
Following quick amygdala engagement, research in rodents demonstrates more gradual cortical engagement, providing more detailed representation of threat features (LeDoux, 2000
). Such detailed representation facilitates engagement of architecturally more complex cortically based processes, which also allow flexible modulation of amygdala-based processes. Other work implicates vPFC afferents specifically in modulation of amygdala engagement (Quirk and Mueller, 2008
). From the clinical perspective, this suggests that healthy vPFC engagement, when encountering threats, represents an adaptive phenomenon. This might counteract a diathesis, manifest in amygdala hypersensitivity, which allows pediatric anxiety to remit. Conversely, clinical expression may reflect failure of vPFC maturation to counteract an underlying diathesis.
Available imaging data using variants of the dot-probe task in youths (Monk et al, 2006
; Monk et al, 2008
) demonstrate the relevance of data on topography and chronometry of fear circuitry function in rodents (). Thus, exposure to very brief threats in the context of a dot-probe experiment produces amygdala engagement in anxious but not healthy adolescents (Monk et al, 2008
). The magnitude of this engagement positively correlates with both anxiety severity and attention bias, consistent with the view of early amygdala engagement as representing anxiety and associated threat bias. Activity in vPFC, in contrast, correlates negatively with activity in the amygdala during brief threat exposure, with stronger correlations in healthy than anxious adolescents. This suggests that perturbed interactions between vPFC and the amygdala support attention bias and the clinical state. Data from a second dot-probe experiment, using longer threat exposures, also support this view (Monk et al, 2006
). Here, data demonstrate increased vPFC engagement in anxious relative to healthy adolescents, with no between-group differences in the amygdala. This suggests that vPFC engagement during longer threat exposure reflects the influences of cortically based regulatory processes over underlying hypersensitivity, presumably involving the amygdala and associated subcortical structures. Consistent with this view and in contrast to data during brief threat exposure, vPFC engagement with longer exposures predicts lower levels of anxiety among anxious youths. Thus, data in rodents and humans implicate the amygdala in initial threat reactions and PFC-amygdala connectivity in later regulatory responses. Of note, however, key questions emerge. For example, imaging studies most consistently implicate lateral vPFC in threat–attention interactions, where data on extinction most consistently implicate medial PFC (mPFC). This raises questions addressable through research on animals about the nature of developmental relations among amygdala and specific PFC-based functions.
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 (more ...)
Research in nonhuman primates could facilitate work on therapeutics. As a first step, working with Jim Winslow, we have begun to examine the effects of threat on orienting in juvenile nonhuman primates, through an examination of eye-scanning patterns exhibited in a variant of the dot-probe task. This work fits within a broader context relating human and nonhuman primate development to diverse indicators of anxious behavior, including facial expressivity and vocalization (Nelson et al, 2002
). As with research on cognition, a narrow focus may provide traction when attempting to bridge data across development and across species. Thus, work focused narrowly on the dot-probe task models specific, highly salient behavior, to facilitate a mechanistic understanding of specific cross-species parallels. This narrow focus, however, serves to bridge broader research demonstrating the manner in which anxious behavior exhibits parallel changes across development in a range of mammalian species.
As shown in , juvenile nonhuman primates exhibit a tendency to orient selectively to threat stimuli. As a second step, in ongoing work, we have begun to examine the relationship between individual differences in anxious behavior and threat orienting. The demonstration of distinct threat-orienting behavior in anxious relative to nonanxious monkeys would further suggest the suitability of modeling threat-orienting behavior in young monkeys to facilitate understanding of pediatric anxiety. Third, demonstrating a parallel affect of SSRIs on threat-orienting behavior in monkeys and children would further solidify the suitability of research on threat-orienting behavior in nonhuman primates as a model for threat biases in pediatric anxiety disorders. Establishing primate attention training paradigms might also facilitate research on the degree to which attention-related plasticity extends across contexts. Thus, imaging studies relate individual difference in brain function to individual difference in attention bias, supporting the contention that individual differences in anxiety relate to difference in brain development. However, attention bias can be trained rapidly, showing an influence operating on very brief timescales. Studies in nonhuman primates might reveal the manner in which these brief training effects interact with brain development to shape behavior.
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 (more ...)
Following demonstration of such parallels, research on nonhuman primates could stimulate research on therapeutics. Such an approach could involve procedures, such as invasive imaging methods, reversible lesions, or intracellular recordings, which precisely elucidate the role of amygdala-vPFC circuitry in threat-orienting behavior. Moreover, novel therapies could be evaluated based on their capacity to alter threat-orienting behavior through direct effects on circuitry. Demonstrating robust effects on behavior would provide further justification for developing suitable procedures for safely altering threat-orienting behavior in humans.