Laura Luyten

Rating data are underrated: validity of US expectancy in human fear conditioning

BACKGROUND AND OBJECTIVES Human fear conditioning is widely regarded as one of the prime paradigms for the study of fear and anxiety disorders. We provide an evaluation of a commonly used subjective measure in the human fear conditioning paradigm, namely the US-expectancy measurement. METHODS We assess the validity of US-expectancy with respect to conditions of pathological fear and anxiety using four established criteria for scrutiny of a laboratory test or model (i.e., face validity, diagnostic validity, predictive validity, construct validity). RESULTS Arguably, there is sufficient evidence for the face validity, diagnostic validity, predictive validity and construct validity of the US-expectancy measure. LIMITATIONS Presumed limitations of the US-expectancy measure, including its susceptibility to experimental demand and memory bias, are discussed. CONCLUSIONS The US-expectancy measure is a valuable measurement method that can be effectively used in research that aims to enhance our understanding of fear and anxiety disorders.

Contextual conditioning in rats as an animal model for generalized anxiety disorder.

Animal models of psychiatric disorders are important translational tools for exploring new treatment options and gaining more insight into the disease. Thus far, there is no systematically validated animal model for generalized anxiety disorder (GAD), a severely impairing and difficult-to-treat disease. In this review, we propose contextual conditioning (CC) as an animal model for GAD. We argue that this model has sufficient face validity (there are several symptom similarities), predictive validity (it responds to clinically effective treatments), and construct validity (the underlying mechanisms are comparable). Although the refinement and validation of an animal model is a never-ending process, we want to give a concise overview of the currently available evidence. We suggest that the CC model might be a valuable preclinical tool to enhance the development of new treatment strategies and our understanding of GAD.

Electrical stimulation in the bed nucleus of the stria terminalis alleviates severe obsessive-compulsive disorder

In 1998, we proposed deep brain stimulation as a last-resort treatment option for patients suffering from severe, treatment-resistant obsessive-compulsive disorder (OCD). Here, 24 OCD patients were included in a long-term follow-up study to evaluate the effects of electrical stimulation in the anterior limbs of the internal capsule (ALIC) and bed nucleus of the stria terminalis (BST). We find that electrical stimulation in the ALIC/BST area is safe and significantly decreases obsessions, compulsions, and associated anxiety and depressive symptoms, and improves global functioning in a blinded crossover trial (n=17), after 4 years (n=18), and at last follow-up (up to 171 months, n=24). Moreover, our data indicate that BST may be a better stimulation target compared with ALIC to alleviate OCD symptoms. We conclude that electrical stimulation in BST is a promising therapeutic option for otherwise treatment-resistant OCD patients.

Micro-Positron Emission Tomography Imaging of Rat Brain Metabolism during Expression of Contextual Conditioning

Using 18F-fluorodeoxygluose microPET imaging, we investigated the neurocircuitry of contextual anxiety versus control in awake, conditioned rats (n = 7–10 per group). In addition, we imaged a group expressing cued fear. Simultaneous measurements of startle amplitude and freezing time were used to assess conditioning. To the best of our knowledge, no neuroimaging studies in conditioned rats have been conducted thus far, although visualizing and quantifying the metabolism of the intact brain in behaving animals is clearly of interest. In addition, more insight into the neurocircuitry involved in contextual anxiety may stimulate the development of new treatments for anxiety disorders. Our main finding was hypermetabolism in a cluster comprising the bed nucleus of the stria terminalis (BST) in rats expressing contextual anxiety compared with controls. Analysis of a subset of rats showing the best behavioral results (n = 5 per subgroup) confirmed this finding. We also observed hypermetabolism in the same cluster in rats expressing contextual anxiety compared with rats expressing cued fear. Our results provide novel evidence for a role of the BST in the expression of contextual anxiety.

Electrolytic lesions of the bed nucleus of the stria terminalis disrupt freezing and startle potentiation in a conditioned context

Expression of contextual anxiety in a previously shocked context is a widely used model of anxiety, with the main behavioral measures being freezing or startle amplitude. There is extensive evidence that the bed nucleus of the stria terminalis (BST) is involved in several anxiety paradigms, e.g., BST lesions disrupt contextual freezing. Surprisingly, studies investigating the effect on startle potentiation in a conditioned context are still lacking in the literature. In the present study, we found that post-training bilateral electrolytic lesions in the BST completely disrupted the expression of contextual anxiety, as quantified with combined measurements of startle amplitude and freezing.

Targeting Bed Nucleus of the Stria Terminalis for Severe Obsessive-Compulsive Disorder: More Unexpected Lead Placement in Obsessive-Compulsive Disorder than in Surgery for Movement Disorders

BACKGROUND In preparation for a multicenter study, a protocol was written on how to perform surgical targeting of the bed nucleus of the stria terminalis, based on the lead implantation experience in patients with treatment-refractory obsessive-compulsive disorder (OCD) at the Universitaire Ziekenhuizen Leuven (UZ Leuven). When analyzing the postoperative images, we were struck by the fact that the difference between the postoperative position of the leads and the planned position seemed larger than expected. METHODS The precision of targeting in four patients with severe OCD who received bilateral model 3391 leads (Medtronic) was compared with the precision of targeting in the last seven patients who underwent surgery at UZ Leuven for movement disorders (four with Parkinson disease and three with essential tremor; all received bilateral leads). Because the leads implanted in six of the seven patients with movement disorders were model 3387 leads (Medtronic), targeting precision was also analyzed in four patients with OCD in whom model 3387 leads were implanted in the same target as the other patients with OCD. RESULTS In the patients with OCD, every implanted lead deviated at least 1.3 mm from its intended position in at least one of three directions (lateral, anteroposterior, and depth), whereas in the patients with movement disorders, the maximal deviation of any of all implanted leads was 1.3 mm. The deviations in lead placement were comparable in patients with OCD who received a model 3387 implant and patients who received a model 3391 implant. In the patients with OCD, all leads were implanted more posteriorly than planned. CONCLUSIONS The cause of the posterior deviation could not be determined with certainty. The most likely cause was an increased mechanical resistance of the brain tissue along the trajectory when following the targeting protocol compared with the trajectories classically used for subthalamic nucleus or ventral intermediate nucleus of the thalamus stimulation.

Optimization of a contextual conditioning protocol for rats using combined measurements of startle amplitude and freezing: The effects of shock intensity and different types of conditioning

Contextual conditioning in rats is typically quantified using startle amplitude or freezing time. Our goal was to create a robust contextual conditioning protocol combining both startle amplitude and freezing time as measures of contextual anxiety. Comparison of 0.8 mA - 250 ms shocks with an established shock configuration (0.3 mA - 1 s) favoured the first parameters. Subsequently, we systematically investigated the effect of shock intensity (0.6 mA, 0.8 mA or 1.0 mA) and concurrently compared two different contextual conditioning procedures (shocks alone versus unpaired shock-tone presentations). In future experiments, this second type of contextual conditioning may form the optimal contrasting condition for a cued fear conditioning group, trained with explicit cue-shock pairings. The 0.8 mA shocks produced significant contextual freezing and startle potentiation, whereas the 0.6 mA and 1.0 mA shocks only led to a significant increase of freezing time. We found no major differences between the two types of conditioning, implying that these procedures might be equivalent. In conclusion, training with ten 0.8 mA - 250 ms shocks produced reliable contextual conditioning as measured with both startle amplitude and freezing time.

The effects of electrical stimulation or an electrolytic lesion in the mediodorsal thalamus of the rat on survival, body weight, food intake and running activity in the activity-based anorexia model

The glucose metabolism in the mediodorsal thalamus (MD) is increased in rats in the activity-based anorexia (ABA) model. In patients, electrical stimulation in hyperactive brain regions reduced symptoms in e.g. major depressive disorder and cluster headache. In two blinded randomised controlled experiments, we therefore examined the effects of high-frequency electrical stimulation and an electrolytic lesion in the MD in a validated rat model for anorexia nervosa. The ABA model was successfully replicated in all our experiments, with a reduction in body weight, food intake, and survival time and an increase in running activity. In a first experiment, we evaluated the effect of electrical stimulation or a curative lesion in the MD on survival, body weight, food intake and locomotor activity in ABA rats. Electrical MD stimulation or an electrolytic MD lesion did not improve the symptoms of rats in the ABA model, compared to control groups. In a second experiment, we investigated the effect of a preventive electrolytic lesion in the MD on rats in the ABA model. Although there was no significant improvement of survival, body weight and food intake, locomotor activity was significantly reduced in the lesion group compared to the control group. Apart from this positive effect on running activity, we found no convincing evidence for the suitability of the MD as a neuromodulation target for anorexia nervosa patients.

Rethinking Food Anticipatory Activity in the Activity-Based Anorexia Rat Model

When a rat is on a limited fixed-time food schedule with full access to a running wheel (activity-based anorexia model, ABA), its activity level will increase hours prior to the feeding period. This activity, called food-anticipatory activity (FAA), is a hypothesized parallel to the hyperactivity symptom in human anorexia nervosa. To investigate in depth the characteristics of FAA, we retrospectively analyzed the level of FAA and activities during other periods in ABA rats. To our surprise, rats with the most body weight loss have the lowest level of FAA, which contradicts the previously established link between FAA and the severity of ABA symptoms. On the contrary, our study shows that postprandial activities are more directly related to weight loss. We conclude that FAA alone may not be sufficient to reflect model severity, and activities during other periods may be of potential value in studies using ABA model.

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.