Reduced γ-Aminobutyric Acid in Occipital and Anterior Cingulate Cortices in Primary Insomnia: a Link to Major Depressive Disorder?

Abstract

Insomnia is closely related to major depressive disorder (MDD) both cross-sectionally and longitudinally, and as such, offers potential opportunities to refine our understanding of the neurobiology of both sleep and mood disorders. Clinical and basic science data suggest a role for reduced γ-aminobutyric acid (GABA) in both MDD and primary insomnia (PI). Here, we have utilized single-voxel proton magnetic spectroscopy (1H-MRS) at 4 Tesla to examine GABA relative to total creatine (GABA/Cr) in the occipital cortex (OC), anterior cingulate cortex (ACC), and thalamus in 20 non-medicated adults with PI (12 women) and 20 age- and sex-matched healthy sleeper comparison subjects. PI subjects had significantly lower GABA/Cr in the OC (p=0.0005) and ACC (p=0.03) compared with healthy sleepers. There was no significant difference in thalamic GABA/Cr between groups. After correction for multiple comparisons, GABA/Cr did not correlate significantly with insomnia severity measures among PI subjects. This study is the first to demonstrate regional reductions of GABA in PI in the OC and ACC. Reductions in GABA in similar brain regions in MDD using 1H-MRS suggest a common reduction in cortical GABA among PI and mood disorders.

The Pathophysiology of Insomnia

“…Despite contradictory evidence, 52 results have largely been interpreted within the context of the hyperarousal hypothesis. For example, increased 45 and decreased 46 GABA in the occipital cortex of patients with insomnia have been reported to be consistent with the hyperarousal model of insomnia. However, sleep regulatory molecules interact with each other in complex ways (described in more detail later), and many of their eff ects are dependent on the milieu of the brain state; that is, they are state-dependent.…”

Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity

“…The primary hypotheses were abnormal GABA/creatine, NAA/creatine and glutamate/creatine levels in the ACC, thalamus and cerebellum. Based on our previous GABA/Cr data obtained from the ACC in primary insomnia [17], we estimated 80% power to detect a difference between groups at α = 0.05, twosided with n = 15 in each group. Cramer-Rao % was used as an estimate of the signal:noise ratio.…”

Insomnia symptoms and heart rate recovery among patients in cardiac rehabilitation

“…It is now well-established that insomnia is associated with a pattern of 24-h physiological hyperarousal (Bonnet & Arand, 2010). Imaging studies have demonstrated that patients with insomnia have relatively lower levels of cortical c-aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system (Nofzinger et al, 2004;Plante et al, 2012), and increased glucose metabolism during sleep in areas of the brain that regulate arousal, emotion, and cognition (Nofzinger et al, 2004). This increased hyperarousal has important implications for cardiovascular parameters, including parasympathetic tone present during both wake and sleep (Riemann et al, 2010;Roth, 2007).…”