Generalized anxiety disorder (GAD) is a chronic psychiatric condition defined by excessive and uncontrollable worry, occurring more days than not for at least 6 months, and accompanied by at least 3 of 6 hyperarousal symptoms (restlessness, muscle tension, fatigue, irritability, difficulty in sleeping, concentration problems). Lifetime prevalence in the general population is 5.7%, and rates are higher in treatment-seeking samples such as primary care and psychiatric outpatients.1 GAD commonly co-occurs with other disorders, most often depression, which further complicates presentation and prognosis. The burden of GAD is substantial. At the individual level, GAD is associated with significant quality-of-life impairments and diminished physical health. At the systems level, GAD is associated with high use of health care services and high costs.
Pharmacotherapy (antidepressants and/or anxiolytics) is the most common treatment for GAD; cognitive-behavioral therapy (CBT) is the method of counseling with the strongest empirical support. Pharmacotherapy and CBT are superior to placebo, but one-third to half of patients do not achieve symptom remission. Since even the best existing treatments leave many GAD patients without relief, alternative treatments are needed.
Neuromodulation is a novel psychiatric treatment that targets specific brain circuits as a means to improve psychopathology. Transcranial magnetic stimulation (TMS) is the neuromodulation therapy with the largest research base and the only one of several such therapies with an FDA-approved indication for treatment-resistant MDD.
In the FDA-approved protocol, the magnet is applied to the scalp over the left dorsolateral prefrontal cortex (DLPFC) to deliver a series of high-frequency pulses intended to stimulate areas implicated in MDD. The efficacy of these stimulation parameters for depression has been supported in numerous clinical trials, and research suggests that anxiety symptoms in patients with MDD also improve.2 However, there has been far less research on using TMS to treat anxiety disorders and very little is known about use of TMS in GAD. (See Machado and colleagues3 for an in-depth review.)
Neurobiology of GAD
The rationale for considering TMS for GAD is based on neurobiological models of the disorder. GAD is characterized by abnormalities in the frontal and limbic structures as well as in the connectivity between these regions. The frontal regions most often implicated in GAD are the prefrontal cortex and anterior cingulate cortex, and the limbic region most often studied is the amygdala: increased attention has recently been directed toward the hippocampus. Although there are some inconsistencies across studies, structural abnormalities, as well as decreased structural and functional connectivity between frontal and limbic regions, have been documented in GAD patients.4-6
Functional neuroimaging further supports the hypothesis that GAD is characterized by inefficient biological mechanisms associated with emotion regulation. During worry induction, there is increased activation in the prefrontal cortex and decreased activity in the amygdala in both GAD patients and nonanxious control participants; however, unlike nonanxious control participants, GAD patients are not able to normalize this neural activity following worry induction.7
The results from studies that use tasks that require conflict monitoring and emotion regulation (although somewhat inconsistent) support a model of GAD characterized by hypoactivation in the prefrontal cortex and anterior cingulate cortex indicative of deficient top down emotional control.8
Although there are many possible neuromodulation targets to improve emotion regulation, this article focuses on the potential role of stimulation of the DLPFC, the region most often targeted in depression and the only region yet tested in patients with GAD. The DLPFC plays a central role in emotion regulation processes as a structure responsible for maintaining task goals and interacting with other brain regions to maximize goal attainment. TMS affects not only the stimulation target but also other cortical and subcortical regions with which it has connections.
Key regions in the regulation of anxiety that may be influenced by cascading effects of DLPFC stimulation are the dorsal anterior cingulate cortex (responsible for threat appraisal and conflict/error monitoring); the inferior frontal gyrus (implicated in risk aversion and selective inhibition); and the ventral anterior cingulate cortex and ventral medial prefrontal cortex, which integrate inputs from cortical regions and suppress limbic activity (through the uncinate fasciculus pathway to the amygdala and bed nucleus of the stria terminalis). Therefore, DLPFC stimulation may improve anxiety via enhanced functioning of and/or improved communication within fronto-limbic networks.
Dr Diefenbach is a Senior Scientist at the Anxiety Disorders Center at the Institute of Living in Hartford, Conn, and Assistant Professor of Psychiatry (Adjunct) at the Yale University School of Medicine in New Haven, Conn. Dr Goethe is Director of the Burlingame Center for Psychiatric Research and Education at the Institute of Living. Drs Diefenbach and Goethe report that they have received material support from Neuronetics. Dr Goethe reports that he has received speaker fees to discuss TMS at professional conferences and receives grant support from Bristol-Myers Squibb, Forest, Hoffmann-La Roche, Janssen, Merck, Schering-Plough, Neuronetics, NeoSync, Otsuka, Shire, and Takeda.
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