1H magnetic resonance spectroscopy (MRS) will be used to measure lactate changes in response to intravenous 0.5 M sodium lactate infusion comparing panic disorder and control subjects. Information obtained from this research will advance our understanding of mechanisms responsible for lactate-induced panic and relate this to the neurobiology of panic. Lactate infusion is an established method to elicit psychological and physiological response characteristic of a spontaneous panic attack in susceptible individuals. This lactate responsiveness is a sensitive and specific marker for individuals experiencing panic but not for other psychiatric populations or normal controls. Although it is one of the most replicated findings in biological psychiatry, the mechanism responsible for lactate-induced panic remains undetermined. Direct measurement of increased lactate in cisternal fluid during intravenous lactate infusion in monkeys suggests that brain lactate may also increase. Thus, specific effects of increasing brain lactate, instead of long proposed but never demonstrated indirect effects through peripheral mechanisms, could be responsible for the production of panic. There is a body of literature suggesting that metabolic abnormalities and respiratory dysregulation may produce greater rises and decreased clearance of brain lactate among panic patients in response to lactate infusion. We have demonstrated the feasibility of using proton magnetic resonance spectroscopy (1H MRS) to detect increased whole brain lactate during lactate infusion in rats and localized 1H MRS to detect increased lactate in the temporal-parietal region of normal human controls. Pilot studies suggest that panic subjects who panic in response to lactate demonstrate greater increases in brain lactate and delayed clearance post- infusion compared to controls. Medicated panic patients who do not panic in response to lactate appear to have intermediate brain lactate rises more resembling controls. In this study, 25 normal control subjects and 45 unmedicated, actively symptomatic panic subjects will be evaluated by 1H MRS during lactate infusion. We will specifically test hypotheses that 1) brain lactate increases during lactate infusion, 2) panic subjects who panic in response to lactate infusion experience greater rises in brain lactate and delayed clearance of brain lactate post-infusion compared to controls, 3) excessive rise and delayed clearance of brain lactate is inversely related to hypocapnea but patient-control differences remain when end-tidal pCO2 effects are partialled out, and 4) following short-term treatment, asymptomatic panic patients will continue to exhibit excess brain lactate increases during repeat infusion despite normal respiration. Additional pilot studies will use chemical-shift imaging techniques to assess anatomical distribution of brain lactate during lactate infusion and assess the combined effects of lactate infusion and voluntary hyperventilation in healthy controls.
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