The brain is hypothermic in patients with mitochondrial diseases

Abstract

We sought to study brain temperature in patients with mitochondrial diseases in different functional states compared with healthy participants. Brain temperature and mitochondrial function were monitored in the visual cortex and the centrum semiovale at rest and during and after visual stimulation in seven individuals with mitochondrial diseases (n=5 with mitochondrial DNA mutations and n=2 with nuclear DNA mutations) and in 14 age- and sex-matched healthy control participants using a combined approach of visual stimulation, proton magnetic resonance spectroscopy (MRS), and phosphorus MRS. Brain temperature in control participants exhibited small changes during visual stimulation and a consistent increase, together with an increase in high-energy phosphate content, after visual stimulation. Brain temperature was persistently lower in individuals with mitochondrial diseases than in healthy participants at rest, during activation, and during recovery, without significant changes from one state to another and with a decrease in the high-energy phosphate content. The lowest brain temperature was observed in the patient with the most deranged mitochondrial function. In patients with mitochondrial diseases, the brain is hypothermic because of malfunctioning oxidative phosphorylation. Neuronal activity is reduced at rest, during physiologic brain stimulation, and after stimulation.

Figure 1

Visual cortex spectrum and brain temperature. 1H magnetic resonance (MR) unfitted spectrum (B) obtained from a voxel of 20 × 20 × 10 mm centered on the calcarine scissure of a healthy volunteer (A). Spectra acquisition parameters: point-resolved spectroscopy sequence (PRESS), repetition time (TR) 2,000 ms, echo time (TE) 270 ms. The MR signals corresponding to water (H₂O) and N-acetyl-aspartate (NAA) are identified. Brain temperature is obtained by measuring the resonance frequency of H₂O and NAA, according to the formula T°=228.2–72.2 × (δ_H2O−δ_NAA), where T° is temperature in degree Celsius and δ_H2O and δ_NAA are the resonance frequencies expressed in p.p.m., measured at the center of the water-fitted and NAA-fitted peaks. The digital sensitivity of this MR thermometry method is 0.0103 p.p.m./1°C. The actual measured sensitivity is within 0.20°C (see Supplementary File 1). The actual measured accuracy is within 0.20°C (see Supplementary File 1) as well. For these reasons, we rounded brain temperature values at 0.20°C steps.

Figure 2

The mean temperature (±s.d.) of the visual cortex in MDW/mtDNA patients and in healthy control participants at rest, during visual stimulation, and during recovery after visual stimulation. T_br remains flat and constantly lower in the MDW/mtDNA group than in the healthy control participants. In the control group, after a small decrease in the second part of stimulation, T_br increases during the first part of recovery. Stimulation 1, first part of visual stimulation; Stimulation 2, second part of visual stimulation; Recovery 1, first part of recovery from visual stimulation; Recovery 2, second part of recovery from visual stimulation.

Figure 3

Single phosphocreatine (PCr)+βATP values of patients at rest, during visual stimulation, and during recovery. Patient 1, solid diamond; Patient 2, solid triangle; Patient 3, x; Patient 4, solid circle; Patient 5, +; Patient 6, solid square; Patient 7, black bar. For the purpose of the study, the two stimulation and two recovery periods have each been pooled. The normal range for each condition is bounded by the dotted lines.

Figure 4

31-P spectra from a control subject and from a patient during recovery from visual activation. Spectra acquisition/processing parameters: sweep width=2,000 Hz, 2,048 digitalized points, convolution difference to remove broad signal (exponential line broadening=150 Hz), exponential multiplication (20 Hz) to improve signal-to-noise ratio, and no baseline correction. Please, note that both phosphocreatine (0 p.p.m.) and βATP (−19 p.p.m.) peaks are lower in the patient than in the control subject (whereas they started from similar values at rest, not shown here).