Mechanistic link between right prefrontal cortical activity and anxious arousal revealed using transcranial magnetic stimulation in healthy subjects

Abstract

Much of the mechanistic research on anxiety focuses on subcortical structures such as the amygdala; however, less is known about the distributed cortical circuit that also contributes to anxiety expression. One way to learn about this circuit is to probe candidate regions using transcranial magnetic stimulation (TMS). In this study, we tested the involvement of the dorsolateral prefrontal cortex (dlPFC), in anxiety expression using 10 Hz repetitive TMS (rTMS). In a within-subject, crossover experiment, the study measured anxiety in healthy subjects before and after a session of 10 Hz rTMS to the right dorsolateral prefrontal cortex (dlPFC). It used threat of predictable and unpredictable shock to induce anxiety and anxiety potentiated startle to assess anxiety. Counter to our hypotheses, results showed an increase in anxiety-potentiated startle following active but not sham rTMS. These results suggest a mechanistic link between right dlPFC activity and physiological anxiety expression. This result supports current models of prefrontal asymmetry in affect, and lays the groundwork for further exploration into the cortical mechanisms mediating anxiety, which may lead to novel anxiety treatments.

Low-frequency parietal repetitive transcranial magnetic stimulation reduces fear and anxiety

“…However, this distinction is not universal [71][72][73] . Consistent with this laterality effect, we recently measured fear-and anxiety-potentiated startle before and after 10 Hz stimulation to the right dlPFC, and found that 10 Hz stimulation increased anxiety-potentiated startle, suggesting that the right dlPFC may be important for anxiety expression rather than regulation 17 .…”

“…Sample size was based on our previous study exploring the effect of right dlPFC rTMS on anxiety, which used a similar design 17 . Twenty-five participants were enrolled in the study.…”

Patients with anxiety disorders rely on bilateral dlPFC activation during verbal working memory

“…Similarly, healthy subjects show elevated right dlPFC activity during complex cognitive tasks performed under threat of shock ( Oei et al , 2012 ; Balderston et al , 2017b 2017c ). However, this argument is inconsistent with neuromodulatory data targeting the right dlPFC, showing that excitatory repetitive transcranial magnetic stimulation (rTMS) increases anxiety ( Balderston et al , 2020 ) while inhibitory rTMS reduces anxiety ( Chen et al , 2013 ). In addition, retention interval activity is often left-lateralized, especially when verbal stimuli are used ( Altamura et al , 2010 ; Rottschy et al , 2012 ), making the functional significance of these anxiety-related right dlPFC changes unclear.…”

“…One critical region thought to be important for WM manipulation is the dorsolateral prefrontal cortex (dlPFC) ( Balderston et al , 2016b ). Using threat of shock to induce anxiety is one approach to studying the relationship between anxiety and cognition ( Robinson et al , 2013 ; Grillon et al , 2019 ); however, additional research is needed to determine whether this approach can shed light on the cognitive symptoms seen in anxious patients and inform the identification of treatment targets for anxiety disorders ( Balderston et al , 2020 ). Therefore, the purpose of this study is to examine the WM-related dlPFC activity in anxiety patients and controls and to examine whether this activity is affected by manipulations in anxiety state.…”

How representative are neuroimaging samples? Large-scale evidence for trait anxiety differences between fMRI and behaviour-only research participants.

“…Therefore, we set out to gather a large dataset of existing trait anxiety scores from labs across multiple institutions who routinely collect trait anxiety measures in their behavioural and MRI studies 1,25,[41][42][43][44][45][46][47][48][49][50][51][52][53][54] . In order to control for possible confounds and examine interaction effects, we additionally collected the following variables: gender, age, whether and how participants were screened for affective/psychiatric disorders, and whether the study involved the presence of a stressor and/or pharmacological manipulation (see Methods for details).…”