The long-term goal of this study is to better understand the neurobiological basis of susceptibility to panic disorder. Most neurobiological models of panic disorder propose one of two contrasting mechanisms of vulnerability: 1) dysfunction of a metabolically-governed """"""""alarm"""""""" system; or 2) a hypersensitive fear system. Applying new concepts in brain energy metabolism and proton MR spectroscopy (1H-MRS) methods, panic patients have recently been shown to.accumulate higher levels of brain lactate during,neural activation than control subjects. Lactate is a known panicogen. Consistent with metabolic """"""""alarm"""""""" models, this might represent a metabolic abnormality with a key role in pathogenesis. However, elevated lactate responses could be a consequence of a hypersensitive fear system and/or ongoing panic symptoms, rather than a metabolic abnormality with potential etiological significance. Combining 1H-MRS and fMRI methods, we aim to test the predictions of these two accounts of elevated brain lactate responses in panic disorder. We will measure fear system responses and brain lactate responses in 3 groups: 1) symptomatic, untreated panic patients, 2) treated, clinically improved panic patients, and 3) control subjects. The prediction of a hypersensitive fear system will be tested by measuring amygdala BOLD responses to fearful faces. The prediction of the metabolic model will be tested by measuring visual cortex lactate responses during visual stimulation with 1H-MRS. Preliminary data suggest both measures will be abnormally elevated in the untreated patients. Findings in the treated patients will help define the potential significance of the elevated lactate response. If the lactate response is normal in treated patients, it is unlikely to reflect an underlying and enduring metabolic abnormality. However, if amygdala responses normalize with clinical improvement but lactate responses do not, then elevated lactate responses may be independent of fear responses and ongoing panic symptoms. This would support the model of an underlying metabolic abnormality unaltered by clinical improvement or normalized fear responses. The R21 mechanism is requested because our methods and concepts represent a new approach to the study of panic disorder. Relevance: There are two leading theories about physical causes of panic disorder. This project will test predictions of each theory about fear responses and brain metabolism in panic patients in order to better understand what causes panic disorder. ? ? ?
| Maddock, Richard J; Buonocore, Michael H; Miller, Amber R et al. (2013) Abnormal activity-dependent brain lactate and glutamate+glutamine responses in panic disorder. Biol Psychiatry 73:1111-9 |
