Kelly Luyck

Electrical stimulation of the bed nucleus of the stria terminalis reduces anxiety in a rat model

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.

No effect of glucose administration in a novel contextual fear generalization protocol in rats

The excessive transfer of fear acquired for one particular context to similar situations has been implicated in the development and maintenance of anxiety disorders, such as post-traumatic stress disorder. Recent evidence suggests that glucose ingestion improves the retention of context conditioning. It has been speculated that glucose might exert that effect by ameliorating hippocampal functioning, and may hold promise as a therapeutic add-on in traumatized patients because improved retention of contextual fear could help to restrict its generalization. However, direct data regarding the effect of glucose on contextual generalization are lacking. Here, we introduce a new behavioral protocol to study such contextual fear generalization in rats. In adult Wistar rats, our procedure yields a gradient of generalization, with progressively less freezing when going from the original training context, over a perceptually similar generalization context, to a markedly dissimilar context. Moreover, we find a flattening of the gradient when the training-test interval is prolonged with 1 week. We next examine the effect of systemic glucose administration on contextual generalization with this novel procedure. Our data do not sustain generalization-reducing effects of glucose and question its applicability in traumatic situations. In summary, we have developed a replicable contextual generalization procedure for rats and demonstrate how it is a valuable tool to examine the neurobiological correlates and test pharmacological interventions pertaining to an important mechanism in the etiology of pathological anxiety.

Can electrical stimulation of the human bed nucleus of the stria terminalis reduce contextual anxiety? An unanswered question

In their paper, Baas et al. (2014), take the rather unique opportunity to conduct a human fear conditioning experiment in subjects with stimulation electrodes in the nucleus accumbens and internal capsule. Here, we argue that it might be premature to draw the strong conclusion that deep brain stimulation (DBS) does not impact contextual anxiety. We will elaborate on two aspects of the study that were not thoroughly discussed in the original paper, but that might help explain why no effects were found. Firstly, we will focus on the neuroanatomy and, secondly, on the behavioral procedure.

An evaluation of the effect of pulse-shape on grey and white matter stimulation in the rat brain

Despite the current success of neuromodulation, standard biphasic, rectangular pulse shapes may not be optimal to achieve symptom alleviation. Here, we compared stimulation efficiency (in terms of charge) between complex and standard pulses in two areas of the rat brain. In motor cortex, Gaussian and interphase gap stimulation (IPG) increased stimulation efficiency in terms of charge per phase compared with a standard pulse. Moreover, IPG stimulation of the deep mesencephalic reticular formation in freely moving rats was more efficient compared to a standard pulse. We therefore conclude that complex pulses are superior to standard stimulation, as less charge is required to achieve the same behavioral effects in a motor paradigm. These results have important implications for the understanding of electrical stimulation of the nervous system and open new perspectives for the design of the next generation of safe and efficient neural implants.

Distinct Activity Patterns of the Human Bed Nucleus of the Stria Terminalis and Amygdala during Fear Learning

The amygdala and, more recently, also the bed nucleus of the stria terminalis, have been widely implicated in fear and anxiety. Much of our current knowledge is derived from animal studies and suggests an intricate convergence and divergence in functions related to defensive responding. In a recent paper, Klumpers and colleagues set out to examine these functions in a human fear learning procedure using functional magnetic resonance imaging. Their main findings were a role for the bed nucleus of the stria terminalis in threat anticipation, and for the amygdala in threat confrontation. Here, we provide a critical summary of this interesting study and point out some important issues that were not addressed by its authors. In particular, we first take a closer look at the striking differences between both samples that were combined for the study, and, secondly, we provide an in-depth discussion of their findings in relation to existing neurobehavioral models.