Abstract
Recent studies on the pathophysiology of alcohol dependence suggest a link between peripheral calcium concentrations and alcohol craving. Here, we investigated the association between plasma calcium concentration, cue-induced brain activation, and alcohol craving. Plasma calcium concentrations were measured at the onset of inpatient detoxification in a sample of N = 115 alcohol-dependent patients. Alcohol cue-reactivity was assessed during early abstinence (mean 11.1 days) using a functional magnetic resonance imaging (fMRI) alcohol cue-reactivity task. Multiple regression analyses and bivariate correlations between plasma calcium concentrations, clinical craving measures and neural alcohol cue-reactivity (CR) were tested. Results show a significant negative correlation between plasma calcium concentrations and compulsive alcohol craving. Higher calcium levels predicted higher alcohol cue-induced brain response in a cluster of frontal brain areas, including the dorsolateral prefrontal cortex (dlPFC), the anterior prefrontal cortex (alPFC), and the inferior (IFG) and middle frontal gyri (MFG). In addition, functional brain activation in those areas correlated negatively with craving for alcohol during fMRI. Higher peripheral calcium concentrations during withdrawal predicted increased alcohol cue-induced brain activation in frontal brain areas, which are associated with craving inhibition and cognitive control functions. This might indicate that higher plasma calcium concentrations at onset of detoxification could modulate craving inhibition during early abstinence.Trial registration number: DRKS00003388; date of registration: 14.12.2011.
Highlights
The potential role of calcium metabolism as a target for treatment of alcohol dependence (AD) was rather undervalued for a long period until Spanagel and colleagues [23] published translational data, suggesting that calcium is the active component of one of the worldwide most frequently used anti-craving medication acamprosate
We investigated the association between plasma calcium concentrations and alcohol cue-induced neural response in 115 recently detoxified patients with alcohol dependence (AD) (32 females, 27.8%), who were recruited from the Department of Addictive Behavior and Addiction Medicine at the Central Institute for Mental Health (Mannheim, Germany) between 2008 and 2011 in the framework of a larger study that expanded from 2008 to 2015
The current study is the first to demonstrate a significant positive association between higher plasma calcium levels and alcohol cue-induced brain activation in a network of frontal brain areas, including the middle frontal gyri (MFG), inferior frontal gyrus (IFG), the antero-lateral prefrontal cortex (alPFC) (BA10), and dorsolateral prefrontal cortex (dlPFC) (BA9). While these results await replication by independent studies, preclinical data support the plausibility of the association between calcium levels and magnitude of the brain blood oxygenation level-dependent (BOLD) signal, e.g., by demonstrating that increased neuronal activation was correlated to astrocytic calcium signals and the BOLD functional magnetic resonance imaging (fMRI) signal [28] and by showing that astrocytic calcium signaling may be involved in neurovascular vessel dilation, which contributes to a positive BOLD fMRI signal [7, 12, 29]
Summary
The potential role of calcium metabolism as a target for treatment of alcohol dependence (AD) was rather undervalued for a long period until Spanagel and colleagues [23] published translational data, suggesting that calcium is the active component of one of the worldwide most frequently used anti-craving medication acamprosate (calcium-bis N-acetylhomotaurinate). Schulz and colleagues [18] compared fMRI and fiber-optic recordings of fluorescent calcium indicator signals in the somatosensory cortex of rats They found that BOLD responses could be predicted from simultaneously recorded fiber-optic signals. It was shown that calcium in drinking water has protective effects on cognitive decline in older persons (age > 65 years), depending on the given dosage [6] This effect was measurable at 86 mg/l calcium in the drinking water, but in higher calcium doses, the effect disappeared. In patients with depression, recent published data showed an association between higher serum calcium concentrations and neuropsychological processing, executive function, and global assessment of functioning [20], supporting the association between plasma calcium and cognitive functioning. Based on the preclinical evidence linking calcium to BOLD signal changes and the findings of a negative association between plasma calcium and craving in a previous study of our workgroup [19, 23], we expected to replicate the negative association between plasma calcium levels and alcohol craving and hypothesized to detect a positive association between plasma calcium levels and alcohol-cue-induced brain response in brain areas engaged in craving inhibition and cognitive control
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