Abstract
We recently showed that deep brain stimulation (DBS) in the bed nucleus of the stria terminalis (BST) reduces obsessions, compulsions and associated anxiety in patients suffering from severe, treatment-refractory obsessive-compulsive disorder. Here, we investigated the anxiolytic effects of electrical BST stimulation in a rat model of conditioned anxiety, unrelated to obsessions or compulsions. Two sets of stimulation parameters were evaluated. Using fixed settings at 100 Hz, 40 μs and 300 μA (Set A), we observed elevated freezing and startle levels, whereas stimulation at 130 Hz, 220 μs and individually tailored amplitudes (Set B) appeared to reduce freezing. In a follow-up experiment, we evaluated the anxiolytic potential of Set B more extensively, by adding a lesion group and an additional day of stimulation. We found that electrical stimulation significantly reduced freezing, but not to the same extent as lesions. Neither lesions nor stimulation of the BST affected motor behavior or unconditioned anxiety in an open-field test. In summary, electrical stimulation of the BST was successful in reducing contextual anxiety in a rat model, without eliciting unwanted motor effects. Our findings underline the therapeutic potential of DBS in the BST for disorders that are hallmarked by pathological anxiety. Further research will be necessary to assess the translatability of these findings to the clinic.
Highlights
IntroductionAnxiety disorders are among the most prevalent psychiatric disorders, and cause substantial disability and suffering.[1,2] Over the years, multiple research groups have attempted to unravel the complex circuits and mechanisms that underlie fear and anxiety.Fear is commonly described as a phasic response in the presence of an imminent, specific threat; whereas anxiety is considered a sustained response in the possibility of future threat, triggered by diffuse stimuli.[3,4] In the lab, fear can be acquired by pairing an explicit cue (for example, a tone) with an aversive event (for example, a shock); while administering unpredictable, unsignaled shocks results in sustained anxiety.[5]Multiple structures have been shown to be involved in the network that underlies anxiety,[6,7] including the amygdala,[8,9] prefrontal cortex,[10,11,12] hippocampus,[13,14] nucleus accumbens[15,16] and, more recently, the medial forebrain bundle.[17,18] Together with the amygdala, the bed nucleus of the stria terminalis (BST) is one of the most extensively studied structures in this regard.[4,19,20,21,22,23,24]
We evaluated whether electrical bed nucleus of the stria terminalis (BST) stimulation reduces acquired anxiety in a rat model that is not confounded by the presence of obsessions and compulsions
We demonstrated that electrical stimulation in the BST reduces contextual freezing in a rat model of anxiety
Summary
Anxiety disorders are among the most prevalent psychiatric disorders, and cause substantial disability and suffering.[1,2] Over the years, multiple research groups have attempted to unravel the complex circuits and mechanisms that underlie fear and anxiety.Fear is commonly described as a phasic response in the presence of an imminent, specific threat; whereas anxiety is considered a sustained response in the possibility of future threat, triggered by diffuse stimuli.[3,4] In the lab, fear can be acquired by pairing an explicit cue (for example, a tone) with an aversive event (for example, a shock); while administering unpredictable, unsignaled shocks results in sustained anxiety.[5]Multiple structures have been shown to be involved in the network that underlies anxiety,[6,7] including the amygdala,[8,9] prefrontal cortex,[10,11,12] hippocampus,[13,14] nucleus accumbens[15,16] and, more recently, the medial forebrain bundle.[17,18] Together with the amygdala, the bed nucleus of the stria terminalis (BST) is one of the most extensively studied structures in this regard.[4,19,20,21,22,23,24]. Anxiety disorders are among the most prevalent psychiatric disorders, and cause substantial disability and suffering.[1,2] Over the years, multiple research groups have attempted to unravel the complex circuits and mechanisms that underlie fear and anxiety. Multiple structures have been shown to be involved in the network that underlies anxiety,[6,7] including the amygdala,[8,9] prefrontal cortex,[10,11,12] hippocampus,[13,14] nucleus accumbens[15,16] and, more recently, the medial forebrain bundle.[17,18] Together with the amygdala, the bed nucleus of the stria terminalis (BST) is one of the most extensively studied structures in this regard.[4,19,20,21,22,23,24]
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