This article describes the use of non-invasive magnetic resonance (MR) methods for the characterization and monitoring of the pathophysiology of experimental brain injury in laboratory animals as a function of time and treatment. The impact of MR in brain research is primarily due to its non-invasive nature, thereby enabling repeated measurements in long-term studies, and due to the type of information that it provides. MR imaging (MRI) enables the measurement of the morphology/anatomy as well as the functional status of tissues under in vivo conditions. Compared to other in vivo imaging modalities, MRI has a high spatial resolution and allows for a remarkable soft tissue differentiation. MR spectroscopy (MRS) provides information on the biochemical/metabolic status of tissues. MR methods which have proven valuable in animal studies, can be readily translated to the clinical situation where MR-based diagnosis and treatment planning play a rapidly increasing role.

After a short introduction into the principles of MR, we will illustrate the remarkable versatility of MR in research on brain injury from recent animal studies. Examples will be mainly drawn from experiments on early injury in focal cerebral ischemia and from research on mechanical brain trauma and excitotoxic lesions. The article ends with a brief description of the perspectives of MR in neuropsychiatry.

In contrast to the research in panic disorder, not much neurobiological studies have been conducted in social phobia. In challenge-tests using lactate or pentagastrin general anxiety and anxiety symptoms were induced in social phobies, although not as frequent is in panic disorder patients, but no specific social phobic anxiety was induced. The role of neurotransmitters such as serotonin, dopamine and noradrenalin is, as yet, unclear. There are no indications for abnormal hypothalamic-pituitary-adrenal-axis activity or abnormal hypothalamic-pituitary-thyroid-axis activity in social phobia. To the present, preliminary findings in neuroimaging studies show no differences between patients and controls, except a possibly diminished and reversible metabolic activity.

A considerable amount of patients with panic disorder (25 – 30%) is refractory for the first line of treatment, mostly antidepressants, and for psychotherapy. Augmentation and combination strategies are discussed; and a protocol for the treatment of refractory patients with panic disorder is proposed with consists of five steps.

No patients is considered treatment refractory until they have had a trial with monoamine oxidase inhibitors.

Norharman is a ß-carboline, possibly of endogenous origin, although cigarette smoking and food are sources too. In brain specific binding sites have been demonstrated. In higher doses norharman binds to benzodiazepine receptors and has MAO-B inhibitory activity. From animal experiments it can be concluded that norharman induces sedation and muscle relaxation. A role in psychosis is unclear, a role in the pathogenesis in anxiety is possible, but has to be further substantiated. As current research suggests, norharman may be an important factor in addiction and withdrawal.

The research on anxiety disorders of the department of psychiatry of the Vrije Universiteit is briefly reviewed. Studies have included comparisons between pharmacotherapy and cognitive behaviour therapy and combination treatments of panic disorder and of obsessive-compulsive disorder. Also, the hyperventilation model of panic disorder could be rejected as a result of an ambulatory monitoring study. Provocation studies with adrenalin in panic disorder have shown less support for a psychological model of panic than expected. Recommendations for future research include studies on anxiety in the very young and in the elderly, studies on comorbidity in anxiety, especially with alcoholism and depression and the development of treatment manuals for general practice. The issue is raised whether investing in neuroimaging studies will critically advance our knowledge in the near future.

Research investigating the neurobiological underpinnings of anxiety disorder have mainly been focused on dysfunction of the GABA, noradrenergic and serotonergic (5-HT) neuronal systems. Just recently, in both animal and human studies, evidence has been found for a possible role of the cholecystokinin (CCK) neuronal system in the pathogenesis of anxiety disorder.

Behaviorally, animal studies revealed anxiogenic-like properties for the ‘central’ CCKB receptor agonists, while CCKB receptor antagonists displayed intrinsic anxiolytic properties. Similarly, in man, CCKB receptor agonists, like pentagastrin and CCK4, were found to be able to elicited panic attacks in both panic disorder (PD) patients and healthy volunteers. These effects appear due to stimulation of the CCKB receptor. In addition, clinically effective panicolytic agents reduce the sensitivity to CCK4 in PD patients. Taken together, these findings may suggest a role for CCK in the neurobiology of PD. On the other hand, there is circumstantial evidence for involvement of several other neuronal systems, such as the serotonergic, noradrenergic and GABA-ergic system, in the regulation of anxiety. Interestingly, evidence has been found for an interaction between CCK and 5-HT and that this interaction plays a role in the mediation of anxiety.

This presentation will critically discuss the evidence for the role of the CCKB receptor in anxiety and in addition, will focus on the putative evidence that the role of CCK in anxiety is mediated by its interaction with the serotonergic neuronal system.

In this review the results are discussed on the prediction of response to pharmacotherapy in panic disorder (PD) and social phobia (SP). From the literature it appears that in PD variables indicative of illness severity are predictors of non-response. In our own studies we found that non-responders to pharmacotherapy in PD are characterised by a higher score on the Blood-Injury subscale of the Fear Questionnaire, a higher plasma MHPG and a higher heart rate. In SP non-responders to pharmacotherapy were also characterised by a higher heart rate. They also appeared to have a higher blood pressure. Furthermore non-responders to pharmacotherapy in SP had higher scores on several psychometric scales, indicative of illness severity.

Patients with panic disorder (PD) report a transient feeling of anxiety upon inhalation of CO2 enriched air. They rate this experience as similar to symptoms of a panic attack. This hypersensitivity has been proposed as an experimental disease model. This paper examines the validity of single breath inhalation of 35% CO2 as a model for PD.