Myo-inositol in depressive and healthy subjects determined by frontal 1H-magnetic resonance spectroscopy at 1.5 tesla
Introduction
Phosphatidylinositol (PI) is a major component of neuronal cell membranes. The phosphoinositide cycle (Fig. 1) has been discovered as a major second messenger system (Berridge and Irvine, 1989). Receptor stimulation by neurotransmitters activates a phospholipase C enzyme in a number of membrane receptor signalling pathways. Phospholipase C triggers the breakdown of phosphatidylinositol-bis-phosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3), which releases calcium from internal stores. A series of phosphatases remove the phosphate groups from IP3 sequentially, releasing free inositol. Inositol is a 6-carbon cyclic polyol carbohydrate chemically closely related to glucose. The biologically active stereoisomer is called myo-inositol (mI). It is the theories about the action of lithium which have aroused the interest in the phosphoinositide (PI) cycle (Fig. 1) and its role in affective disorders. Lithium reduces the brain levels of inositol by inhibiting inositol monophosphatase (Hallcher and Sherman, 1980). Its therapeutic function in mania and depression might be a result of the mI depletion which slows down the PI cycle in overactive synaptic systems (Berridge and Irvine, 1989; Snyder, 1992; Kofman and Belmaker, 1993).
In cerebrospinal fluid, a markedly reduced level of mI has been reported in depressed patients with unipolar and bipolar affective disorder (Barkai et al., 1978). Myo-inositol levels in the human brain were analysed by gas-liquid chromatography post mortem (Shimon et al., 1997). These data revealed significantly reduced mI levels in the frontal cortex of bipolar affective disorder patients (n = 8) and suicide victims (n = 10) as compared with controls (n = 10). Inositol levels were 8.7±2.4 mmol\kg in the normal sample, but only 5.9±2.1 and 6.7±2.2 mmol\kg in bipolar disorder and suicides, respectively, i.e., reduced by 20–30%. There were similar but statistically non-significant intergroup differences in the occipital cortex. The authors found no correlation between age and cerebral inositol levels and no significant difference between inositol levels in males and females.
High doses of exogenously administered inositol may pass the blood–brain barrier sufficiently (Spector, 1988; Levine et al., 1993). Since mI has been widely appreciated as a key metabolic precursor of a second messenger system for numerous neurotransmitters, controlled trials of inositol treatment have been published (review paper: Levine, 1997). Under double-blind conditions, the intake of inositol 12 g\day led to an improvement in depression, which was significantly superior to placebo at week 4 (Levine et al., 1995).
Magnetic resonance spectroscopy (MRS) offers unique possibilities for non-invasive studies of biochemistry in the human brain in vivo. An atomic nucleus with a spin distinguished from zero has properties like a little magnetic dipole. In a strong external magnetic field, due to the quantum nature of matter, each magnetic dipole or spin aligns parallel or antiparallel to this field. As a result the spins are split into two distinct groups with different energy levels and slightly different population densities (Nuclear Zeeman effect). Transitions between these energy levels may occur by absorption or emission of electromagnetic radiation, in particular at the so called Larmor or resonance frequency. As the external magnetic field is shielded by the electron configuration of each molecule, the differences in energy, or frequency absorbed, depend not only on the external magnetic field strength and the particular species of nucleus (e.g., 1H or 31P) but also on the specific chemical compound. Protons within different molecular structures absorb and reemit energy in the radio frequency range at slightly different frequencies because of small differences in the local magnetic field induced by chemical binding. Thus, proton (1H)–MRS allows to detect biochemical compounds due to substance specific differences in resonance frequency. This frequency shift is referred to as chemical shift. A graph of the magnitude of energy absorption as a function of frequency is called MR spectrum (Fig. 2). It is well known, that the main resonance of mI appears at a chemical shift of 3.56 ppm (parts per million as a measure of normalized frequency) in human brain (Michaelis et al., 1991). Compounds must be present at concentrations of approximately 0.5–1.0 mmol\kg or greater to be visible with MR techniques used in human subjects in vivo. 1H-MRS studies published so far indicate that the free (MRS visible) mI concentration ranges between 3.9–8.1 mmol\kg in adults (review paper: Henriksen, 1995). In contrast to mI, the isomer scyllo-inositol yields a resonance at 3.35 ppm. Scyllo-inositol concentrations of about 0.5 mmol\kg were identified in 1H-MRS of human brain at 2.0 T (Michaelis et al., 1993).
Phosphorous-31-MRS showed abnormal phosphorous metabolism in bipolar disorder (Kato et al., 1991; Kato et al., 1992; Kato et al., 1993; Deicken et al., 1995) in the frontal lobe, presumably due to deviations in the phosphatidylinositol cycle. Moreover, the most consistent (but not specific) SPECT and PET findings in depressives have been regional deficits in the cerebral blood flow and metabolism of the frontal lobe (Hurwitz et al., 1990; Lesser et al., 1994; Kasper et al., 1994; Mozley et al., 1996). Thus, the left and right frontal lobes are the regions of interest in this investigation.
We hypothesized that reduced mI concentrations might be detected by means of 1H-MRS in the frontal lobe of depressive patients when compared to healthy subjects.
Section snippets
Subjects
1H-MRS was performed in 22 patients between 12\95–08\96 and compared to 22 healthy volunteers. The groups are described in Table 1Table 2: females and males aged between 18–60 years. The diagnostic entry criteria for the study were depressive episodes in unipolar or bipolar disorder according to ICD 10 (F32, F33, F31.3, F31.4). The Hamilton Depression Scale (HAM-D), 21 items (Arbeitsgemeinschaft fur Methodik und Dokumentation in der Psychiatrie, AMDP, 1986), scored higher than 17; case history
Results
Seven out of 88 spectra were discharged due to technical problems like patient movements or termination of the MRS examination by the patient.
Discussion
In the present study, it has been hypothesized that reduced mI concentrations in the frontal lobe of depressives might be detected by means of 1H-MRS when compared to healthy subjects. Indeed, in the left as well as in the right frontal lobe, mI\Cr mean values were lower in depressives than in controls, but the differences were not statistically significant. Both groups showed lower mI in the left hemisphere, but significant interhemispheric differences occurred neither in controls nor in
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2020, Journal of Psychiatric ResearchCitation Excerpt :This disturbance of glutamate concentration has also been linked with an absence of remission during follow-up in ultra-high risk of psychosis and could be linked with a psychosis risk (Egerton et al., 2014). Proton magnetic resonance spectroscopy (MRS) like 1H-MRS allows the measurement of various brain metabolites concentrations like N-acetyl aspartate (NAA), a marker of neuronal integrity, Choline (Cho), considered as a potential marker of membrane phospholipid metabolism (Yildiz-Yesiloglu and Ankerst, 2006), myo-inositol (mI), implicated in osmoregulation in glial cells (Frey et al., 1998) and glutamate (Glu) or glutamate + glutamine (Glx), reflecting both intracellular and extracellular glutamate and probably involved in metabolism and neurotransmission (Rothman et al., 2011). Anomalies in these brain metabolites have been found among people with schizophrenia such as an increase of Glx concentration in prefrontal white matter and the medial prefrontal cortex (mPFC) (Merritt et al., 2016) or a reduction in the concentration of NAA in the frontal, temporal lobe (Brugger et al., 2011) and the thalamus grey matter (Brugger et al., 2011; Iwata et al., 2018).
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2019, Brain Research BulletinCitation Excerpt :PI and its derivatives (PI-phosphates), as well as inositol triphosphate (IP3), participate in the operation of a very important intracellular second messenger system activated by Gq-protein coupled receptors. Several receptor types belonging to different neurotransmitter systems (e.g. adrenergic α1, serotonergic 5-HT1C and 5-HT2 and dopaminergic D1 receptors) are coupled to the Gq-proteins (Camfield et al., 2011; Frey et al., 1998; Kim et al., 2005; Mukai et al., 2014; Yu and Greenberg, 2016). There are several results – mainly from MRS studies – suggesting alterations of inositol metabolism in various kinds of mood disorders (Kim et al., 2005; Lirng et al., 2015; Njau et al., 2016; Yu and Greenberg, 2016).
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