Abnormal Activity-Dependent Brain Lactate and Glutamate plus Glutamine Responses in Panic Disorder

Background: Prior evidence suggests panic disorder (PD) is characterized by neurometabolic abnormalities, including increased brain lactate responses to neural activation. Increased lactate responses could reflect a general upregulation of metabolic responses to neural activation. However, prior studies in PD have not measured activity-dependent changes in brain metabolites other than lactate. Here we examine activity-dependent changes in both lactate and glutamate plus glutamine (glx) in PD. Methods: Twenty-one PD patients (13 remitted, 8 symptomatic) and 12 healthy volunteers were studied. A single-voxel, J-difference, magnetic resonance spectroscopy editing sequence was used to measure lactate and glx changes in visual cortex induced by visual stimulation. Results: The PD patients had significantly greater activity-dependent increases in brain lactate than healthy volunteers. The differences were significant for both remitted and symptomatic PD patients, who did not differ from each other. Activity-dependent changes in glx were significantly smaller in PD patients than in healthy volunteers. The temporal correlation between lactate and glx changes was significantly stronger in control subjects than in PD patients. Conclusions: The novel demonstration that glx responses are diminished and temporally decoupled from lactate responses in PD contradicts the model of a general upregulation of activity-dependent brain metabolic responses in PD. The increase in activity-dependent brain lactate accumulation appears to be a trait feature of PD. Given the close relationship between lactate and pH in the brain, the findings are consistent with a model of brain metabolic and pH dysregulation associated with altered function of acid-sensitive fear circuits contributing to trait vulnerability in PD.