Energetic and cell membrane metabolic products in patients with primary insomnia: a 31-phosphorus magnetic resonance spectroscopy study at 4 tesla

Abstract

Study objectives: Primary insomnia (PI) is a sleep disorder characterized by difficulty with sleep initiation, maintenance, and/or the experience of nonrestorative sleep combined with a subsequent impairment of daytime functioning. The hyperarousal hypothesis has emerged as the leading candidate to explain insomnia symptoms in the absence of specific mental, physical, or substance-related causes. We hypothesized that the cellular energetic metabolites, including beta nucleoside triphosphate, which in magnetic resonance spectroscopy approximates adenosine triphosphate (ATP), and phosphocreatine (PCr), would show changes in PI reflecting increased energy demand.

Design and setting: Matched-groups, cross-sectional study performed at two university-based hospitals.

Patients: Sixteen medication-free individuals (eight males, eight females; mean ± standard deviation (SD) age = 37.2 ± 8.4 y) with PI and 16 good sleepers (nine males, seven females; mean ± SD age = 37.6 ± 4.7 y).

Measurements: Diagnosis was established for all individuals by unstructured clinical interview, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID), sleep diary, and actigraphy. Polysomnography was collected in individuals with PI. Phosphorous magnetic resonance spectroscopy (31P MRS) data were collected on all individuals at 4 Tesla. We assessed cell membrane (anabolic precursors and catabolic metabolites) and bioenergetic (ATP, phosphocreatine) metabolites in gray matter and white matter to determine their relationship to the presence and severity of PI.

Results: Individuals with PI showed lower phosphocreatine in gray matter and an unexpected decrease of phosphocholine, a precursor of the cell membrane compound phosphatidylcholine, in white matter. In addition, there was a trend toward a negative association between polysomnographically determined wake after sleep onset and gray matter beta-nucleoside triphosphate and white matter phosphocholine in the primary insomnia group.

Conclusions: These results support the hyperarousal hypothesis in PI based on lower phosphocreatine in gray matter in the PI group.

Keywords: Adenosine triphosphate (ATP); long-term potentiation; phosphocholine; phosphocreatine; sleep; spectroscopy.

Figure 1

Sagittal and axial T1-weighted images depicting 3-cm-thick CSI slab placement and positioning of the 4 × 4 submatrix voxel-grid. A representative in vivo human brain spectrum acquired with this protocol is shown with the residual (A), original data (B) and the fitted model (C). ATP, adenosine triphosphate; DPG, diphosphoglycerides; GPCho, glycerophosphocholine; GPEtn, glycerophosphoethanolamine; MP, membrane phospholipid; PCho, phosphocholine; PEtn, phosphoethanolamine; Pi, inorganic phosphate.

Figure 2

Model derived least squares means of phosphocreatine (PCr) area under the curve (error bars represent 95% confidence interval adjusted for multiple comparisons) extracted from theoretical voxels composed of 100% gray matter and 100% white matter. PCr showed a significant difference in association with insomnia between gray matter and white matter, in accordance with our hypothesis, when compared with change in white matter in patients with primary insomnia versus control patients (t₄₆₂ = 3.46; P = 0.0006). Post hoc analysis revealed significantly lower PCr in patients with primary insomnia compared with control patients in gray matter (t₄₆₃ = 2.35; P = 0.04) and significantly higher PCr in patients with primary insomnia when compared with control patients in white matter (t₂₆₇ = -3.72; P = 0.0005). The dashed line in blue is the total tissue effect in the model, and is depicted for comparison purposes.

Figure 3

Model-derived least squares means of phosphocholine (PCho) area under the curve adjusted for age and sex (error bars represent 95% confidence intervals adjusted for multiple comparisons) extracted from theoretical voxels composed of 100% gray matter and 100% white matter. Analysis of the PCho total tissue reduction in patients with primary insomnia revealed a significant difference in association with primary insomnia between gray matter and white matter (t₄₅₇ = -2.58; P = 0.04). Post hoc testing indicates that the observed reduction in PCho is occurring primarily in white matter (t₄₃₇ = 5.66; P < 0.0001) as opposed to gray matter (t₄₀₃ = -0.59; not significant). The dashed blue line is the total tissue main effect of the model (Table 1), which is depicted for comparison purposes.

Figure 4

Model-derived least squares means of glycerophosphocholine (GPCho) area under the curve adjusted for sex (error bars represent 95% confidence interval adjusted for multiple comparisons) extracted from theoretical voxels composed of 100% gray matter and 100% white matter. GPCho showed a statistical trend toward a different association with insomnia between gray matter and white matter (t₄₇₁ = -2.32; P = 0.08). Patients with insomnia had lower GPCho in white matter and higher GPCho in gray matter, though only the white matter change was significant in post hoc testing (t₄₅₄ = 2.83; P = 0.02, white matter: t₄₁₄ = -1.65; not significant, gray matter). The dashed blue line is the total tissue main effect of the model (Table 1), which is depicted for comparison purposes.