Glutamatergic Response to Heat Pain Stress in Schizophrenia

Abstract

Regulation of stress response involves top-down mechanisms of the frontal-limbic glutamatergic system. As schizophrenia is associated with glutamatergic abnormalities, we hypothesized that schizophrenia patients may have abnormal glutamatergic reactivity within the dorsal anterior cingulate cortex (dACC), a key region involved in perception of and reaction to stress. To test this, we developed a somatic stress paradigm involving pseudorandom application of safe but painfully hot stimuli to the forearm of participants while they were undergoing serial proton magnetic resonance spectroscopy to measure changes in glutamate and glutamine levels in the dACC. This paradigm was tested in a sample of 21 healthy controls and 23 patients with schizophrenia. Across groups, glutamate levels significantly decreased following exposure to thermal pain, while ratio of glutamine to glutamate significantly increased. However, schizophrenia patients exhibited an initial increase in glutamate levels during challenge that was significantly different from controls, after controlling for heat pain tolerance. Furthermore, in patients, the acute glutamate response was positively correlated with childhood trauma (r = .41, P = .050) and inversely correlated with working memory (r = -.49, P = .023). These results provide preliminary evidence for abnormal glutamatergic response to stress in schizophrenia patients, which may point toward novel approaches to understanding how stress contributes to the illness.

Fig. 1.

(A) Voxel placement in the dorsal anterior cingulate cortex, (B) representative spectrum (gray) with fit (red) and residual (gray line at top), with locations of major peaks for glutamate (Glu) and glutamine (Gln) identified by arrows.

Fig. 2.

Overview of integrated magnetic resonance spectroscopy (MRS)—thermal pain stress paradigm. Arrows indicate the 5 time-points of saliva collection. Bars between the dotted lines reflect the periods of MRS acquisition. Bar at the top indicates the period of heat stimulation. Dotted line indicates entry into and exit from the MRI scanner.

Fig. 3.

Levels of dACC glutamate (A) and glutamine/glutamate (B) levels during and following pain challenge. The raw values for the acute glutamate response (difference between glutamate levels during challenge and prechallenge level) by diagnosis is displayed in C whereas the group difference in acute glutamate response values predicted by a linear regression model correcting for age, gender, and heat pain tolerance is displayed in D. Similarly, raw values and predicted values from linear regression model for glutamine/glutamate response are shown in E and F, respectively. Error bars represent standard error.

Fig. 4.

Salivary cortisol responses to heat pain challenge in patients (n = 19; triangles) and controls (n = 17; circles). Bar between Pre-0 and Post 0 min indicates the period when heat pain stimuli were applied. The “resting baseline” was a saliva sample collected in a subset of participants (10 patients and 10 controls) at approximately the same time of day as the “prestress baseline,” but on a separate day when participants were not anticipating any stress challenge. Error bars represent standard error mean.