HEIGHTENED ANXIETY IS associated with reduced recruitment of control mechanisms for emotional cues that are emotionally arousing, potentially aversive, and threat-related. It has also been shown that increased anxiety in healthy subjects induces a reduced involvement of prefrontal control structures (prefrontal cortex, PFC). Models of the processing of anxiety and related behavior have suggested a network of interconnected neuronatomical regions including the amygdala, hippocampus, thalamus, and PFC.[3, 4] The PFC could be crucial in mechanisms underlying the regulation of emotion, such as inhibition.[5, 6] In the case of a pathological level of anxiety in the clinical and pre-clinical field the ability to suppress this automatic processing would be impaired in subjects with anxiety disorder, inducing a sort of attentive bias toward the potentially aversive cues.
A promising and alternative theory called the ‘valence model’, however, explained the relationship between anxiety and emotional information processing by suggesting that withdrawal-related emotions such as anxiety are located in the right hemisphere, whereas approach-related emotions are biased to the left hemisphere.[8-10] Thus, an increased level of anxiety might be associated with dysfunctional right hemispheric activity, with increased activation when aversive conditions are processed.[7, 11] This second model furnished clear evidence of the different behavior induced by positive versus negative emotional stimuli with regard to hemispheric lateralization, suggesting that high anxiety subjects had more right frontal hyperactivation in comparison with the left side. This may induce unbalanced processing of the two stimulus categories, with a consistent bias toward the negative one, meaning that the negative stimuli were selected and processed more quickly than the positive stimuli.
The aim of the present study was therefore to investigate the effect of anxiety on information processing by performing a memory task in which familiar versus novel emotional information was recognized. Specifically, memory retrieval of emotional stimuli was used to verify the effect of anxiety levels in healthy low- or high-anxiety subjects on short-term memory performance.[13, 14] With regards to the brain area contribution to the memory task, it was previously shown that the dorsolateral prefrontal cortex (DLPFC) was implicated in the retrieval of knowledge in both normal and pathological processes. Moreover, some evidence suggests that multiple regions of the PFC have the capacity to perform multiple types of executive control functions (i.e. evaluate, maintain, inhibit, or select). In particular, evidence indicates that the orbitofrontal cortex (OFC) participates in the executive control of information processing and behavioral expression by inhibiting neural activity associated with uncomfortable (e.g. painful) information. Bias effects of anxiety on performance and efficiency have been demonstrated to be greater on tasks imposing demands on the retrieval of more relevant information, that is, potentially threatening information.
Moreover, it has been found that anxiety subjects had a more significantly impaired ability to discard cues that are semantically related to the target stimuli, with specific attentional bias induced by an increased influence of the stimulus-driven attentional system and a decreased influence of the goal-directed attentional system. Thus anxiety could affect the ability to correctly recognize and discard incorrect and irrelevant information, necessary for correct retrieval behavior.
In the present study, anxiety level in healthy subjects was used as an independent group variable to test its effect on the retrieval process in the case of emotional positive and negative cues. Transcranial magnetic stimulation (TMS) was then used to induce increased activation of the left DLPFC. TMS, thought to be the creation of a perturbation, offers a unique opportunity to interact directly with the functioning of a cortical area during the execution of the memory task.[17, 18] Previously it was thought that low-frequency TMS could be effective in anxiety disorder, which might be associated with brain hyperexcitability and related cognitive activation. Also recently, studies in healthy subjects tested the valence hypothesis based on the assumption of increased right hemispheric activity in anxiety disorder. In line with this hypothesis, recent evidence showed that low-frequency TMS of the right DLPFC produced a decreased anxiety-related behavior. Moreover, TMS significantly reduced vigilant attention for fearful faces.
In the present study we took into account the underlying interhemispheric competition by adopting the valence hypothesis. An activation TMS paradigm may be used to increase the cortical excitability of the left hemisphere in order to enhance the response to positive emotional cues. To the best of our knowledge, no previous study has analyzed the effect of the potentiation of the contralateral left hemisphere, which might counterbalance the abnormal hyperactivation of the right hemisphere in anxiety disorder for a retrieval memory task. The main expected effect was a more symmetrical vigilant attention toward both positive and negative memories (unbiased performance).
Moreover, we hypothesized that the potential counterbalancing effect induced by TMS on the left hemisphere would be more effective in the case of higher cognitive demand, especially in high-anxiety subjects. For this reason we verified the impact of the stimulus valence not only related to memory retrieval of the old stimuli, but also linked to the mechanisms for discarding irrelevant information during retrieval when a possible ‘semantic interference’ is produced. To do this we investigated the retrieval process in the presence of some distractors (new stimuli) that were semantically related or unrelated to the old stimuli.
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In the present study we were concerned primarily with the effects of anxiety on memory performance for emotional cues, with an emphasis on anxiety levels within the normal population. The main focus was on tasks that place significant demands on cognitive resources, such as emotional information retrieval when old (target) and new (distractors) stimuli have to be recognized. Valence effect and semantic interference were also considered to verify the contribution of the left DLPFC in highly complex retrieval processes in relationship with anxiety.
A first general consideration is related to the anxiety level effect. High-anxiety subjects had a generally reduced RT in retrieving emotional information compared to the low-anxiety subjects, as a function of stimulus valence. This result might be represented as a consistent attentional bias toward the potential threatening information by more anxious people. In contrast, low-anxiety subjects were equally responsive to positive and negative categories without significant differences in terms of effectiveness (accuracy) and efficiency (RT). Some support to the assumption that anxiety facilitates the detection of negative aversive information comes from previous studies on attentional bias,[33, 34] in which anxious individuals preferentially attend to or have delayed disengagement from threat-related stimuli. The assumption that anxiety typically reduces attentional control was also related to the existence of two attentional systems, a goal-directed attentional system influenced by knowledge and expectations, and a stimulus-driven attentional system responding to more salient stimuli. The latter should be recruited during the detection of relevant information, and anxiety might intervene to disrupt the balance between these two attentional systems.
A second main effect was related to the cortical correlates underlying the memory retrieval process in the case of emotional stimuli. The contribution of the left DLPFC in modulating the response to emotional cues was elucidated. An increased responsiveness to positive emotional cues was confirmed in the case of induced left DLPFC stimulation. Moreover, this effect was confirmed and accentuated with regard to the anxiety level. High-anxiety subjects had a clear main effect of left DLPFC on performance. The enhancement of the left brain activity produced an increased efficiency (reduced RT). This result would confirm the reduction of the ‘unbalance effect’, which produces an attentional bias toward the negative cues. The valence model of emotional cue processing may explain the subjects' performance.[9, 22] When a functional condition is restored between the two cortical systems deputed to elaborate, respectively, the positive and negative emotional cues, the high-anxiety subjects had a significant reduction of the pre-existing attentional bias. These conclusions are in line with previous results on clinical (such as panic disorder and post-traumatic stress disorder) and subclinical samples[12, 20] that postulated an anxiolytic effect of low-frequency TMS on the right DLPFC. An interesting study that applied low-frequency TMS (cortical de-potentiation) to the frontal left hemisphere identified increased attentional negative bias and a clear anxiety behavior.
Third, a possible interference effect was tested, by comparing semantically related/unrelated distractors. Specifically, we first found a significant increasing of the cognitive costs (worsening performance with higher RT) for the related distractors in the whole sample, with a significant reduced performance for distractors than targets. The related distractor processing may figure as the more complex and effortful cognitive condition, given that it includes both the necessity to reject the irrelevant information and to control the interference induced by the similarity with the target cues. This should have affected the general performance with significantly increased workload for the subjects, especially those with higher levels of anxiety.
The cortical modulation induced by TMS, however, produced a significant reduction of the semantic interference (for the related distractors) and a general improvement of the cognitive efficiency (for the unrelated distractors) in response to a specific stimulus valence. A more significant effect was found as a function of the anxiety level. In fact, for the high-anxiety subjects the TMS stimulation produced more significant and massive improvement in terms of both effectiveness (accuracy) and efficiency (RT) in recognizing the related positive distractors.
As a consequence, the present results provide evidence in favor of the assumption that the potentiation effect induced by TMS on the left frontal side would be more effective in the case of a need for a higher cognitive demand. It is possible that the left DLPFC intervenes to modulate these complex processes, because this is the more cognitively expensive condition, in that it requires specific competencies and a higher workload, with an increased effort for the cognitive system. In parallel, the high-anxiety subjects were more efficient in response to this cognitively effortful condition, benefiting in significant measure from the frontal left stimulation.