اثر متفاوت لیتیوم درون زا بر عملکرد رفتاری عصبی: مطالعه شنوایی پتانسیل های برانگیخته

Lithium occurs naturally in food and water. Low environmental concentrations in drinking water are associated with mental illnesses and behavioural offences, and at therapeutic dosages it is used to treat psychiatric (especially affective) disorders, partly by facilitating serotonergic (5-HT) neurotransmission. As little is known about the psychophysiological role of nutritional lithium in the general population, endogenous lithium concentrations were hypothesised to be associated with measurable effects on emotional liability and the loudness dependence (LD) that is proposed as one of the most valid indicators of 5-HT neurotransmission. Auditory evoked potentials of healthy volunteers [N = 36] with high (> 2.5 μg/l) or low (< 1.5 μg/l) lithium serum concentrations were recorded. Emotional liability was assessed using the Brief Symptom Inventory (BSI). Low-lithium levels correlated with Somatisation while correlations between lithium and LD were not significant. Still, LD correlated positively with Paranoid Ideation, negatively with Anxiety and, in the high-lithium group, inversely with further aspects of emotional liability (Depression, Psychological Distress). In conclusion, the effects of low levels of endogenous lithium are associated with emotional liability, and high levels with some protective effects, although findings remain inconclusive regarding LD. Potential benefits of endogenous lithium on neurobehavioural functioning, especially in high-risk individuals, would have public health implications.

Lithium (Li) has been successfully used in psychiatric treatment for more than 50 years now (Cade, 1949). Therapeutic dosages of lithium are effective not only in acute mania, bipolar depression, as well as for prophylaxis, suicide prevention and augmentation of affective disorders (Goodwin et al., 1969, Stokes et al., 1971, De Montigny et al., 1985 and Cipriani et al., 2005), but also in other conditions such as aggression, impulsiveness, attention deficit/hyperactivity and non-affective psychosis (Sheard, 1971, Kingsbury and Garver, 1998 and Dorrego et al., 2002), and there is evidence that lithium inhibits deterioration in Alzheimer's disease (Nunes et al., 2007). Some studies showed heterogenous findings when lithium was given in therapeutic dosages to healthy volunteers, i.e., either a decrease of mood variability or no effect (Calil et al., 1990 and Barton et al., 1993). By contrast, little attention has been paid to the physiological role of endogenous lithium for neurobehavioural states in the normal population, as already shown for other environmental agents (Kunert et al., 2004). Nevertheless, first epidemiological studies showed inverse rates between lithium concentrations in the drinking water and urine and the occurrence of mental disorders and hospital admissions or homicide/suicide rates (Dawson et al., 1970 and Dawson et al., 1972) while other studies showed weaker or contradictory results (Voors, 1972, Pokorny et al., 1972 and Oliver et al., 1976). Schrauzer and Shrestha (1990) and Schrauzer et al. (1992) also detected fewer admissions to mental hospitals and fewer behavioural offences in regions with high-lithium water levels > 70 μg/l. It was proposed that high-risk populations would profit from elevated nutritional lithium concentrations. Lithium is the lightest, most solid and least reactive of all alkaline metals, occurring widely in soils and mineral springs (Kabata-Pendias and Pendias, 2001). The primary sources of nutritional lithium intake include drinking water, grains and vegetables. Lithium is easily absorbed from the intestinal tract, evenly distributed in the body fluids and is excreted through the kidneys (Fyrö and Sedvall, 1975). Endogenous serum levels in humans as well as their daily intake were found to highly vary (from 1.1 to 59.7 μg/l, or 104.1 μg/day to 1596–2568 μg/day respectively), greatly depending on the environmental occurrence of lithium and on dietary habits (Lehmann, 1994). Schrauzer (2002) proposed a provisional recommended dietary allowance of 1 mg Li per day for a 70-kg adult. However, these data allow no inferences about the lithium in the body, particularly the central nervous system. Suggestions that lithium may be a biological trace element essential for mammals, and possibly humans, too, are primarily based on animal depletion studies: It was shown that nutritional lithium is required for normal health and life expectancy, growth, weight and reproduction (Anke et al., 1983, Pickett and O'Dell, 1992, Schrauzer, 2002 and Schäfer, 2004). Lithium depletion in rats led to neurobehavioural alterations, including motor activity, response to handling, avoidance behaviour and social aggression (Ono and Wada, 1989 and Klemfuss and Schrauzer, 1995), while lithium treatment reversed depression-like behaviour of learned helplessness (Faria and Teixeira, 1993) or in forced swim tests (Nixon et al., 1994). However, mechanisms of action of lithium are not fully understood yet. As one mode of action in the brain, therapeutic lithium concentrations affect intracellular transduction of interneuronal signals and several neurotransmitters. Lithium reduces the activity in the dopaminergic and noradrenergic systems, but at the same time primarily functions as a serotonin (5-HT) agonist (e.g. Brunello, 2004). Facilitating effects on other 5-HT antidepressants are known as co-treatment with lithium augments 5-HT levels and functions in animals (De Montigny et al., 1983 and Wegener et al., 2003) and in humans (De Montigny et al., 1985 and Cowen et al., 1991). Taken together, lithium is thought to restore equilibrium in the various signalling pathways in the brain (Brunello, 2004). The clinical relevance of 5-HT receptor sensitisation by lithium becomes apparent since a dysfunctional 5-HT system is associated with several psychic disorders, including depression, impulsive aggression, suicidal behaviour and anxiety (Apter et al., 1990 and Maes and Meltzer, 1995). Obtaining a biologically non-invasive but valid measure of 5-HT neurotransmission, auditory evoked potentials (AEPs) were measured in this study. The primary auditory cortex, which has been identified as the electrical source generator of the large negative AEP component, N1, is highly innervated by 5-HT fibres from the raphe nuclei (Azmitia and Gannon, 1986). Hegerl and Juckel (1993) proposed that a steeper N1/P2 slope with increasing auditory stimulus intensity is associated with low 5-HT neurotransmission and vice versa. The particular relationship between this loudness dependence (LD) of the AEP with the primary but not the secondary auditory cortex was confirmed in cats (Juckel et al., 1997). In fact, electrophysiological observations of intra-individual stability of an augmenting/reducing (A/R) characteristic of the N1 and P2 amplitudes in response to stimuli of varying intensities in event-related potentials (ERPs) go back to the earlier 1970s (Buchsbaum and Silverman, 1968 and Buchsbaum et al., 1971). Clinically, an LD increase was found in neuropsychiatric disorders such as migraine (Wang et al., 1996), major depression (Gallinat et al., 2000), chronic ecstasy abuse (Tuchtenhagen et al., 2000), borderline personality disorder (Norra et al., 2003) as well as histrionic disorder (Wang et al., 2006), which are all characterised by 5-HT dysfunction. By contrast, a weaker LD as a function of enhanced 5-HT activity was seen in the serotonin syndrome (Hegerl et al., 1998), post-traumatic stress disorder (Paige et al., 1990), generalised anxiety disorder (Senkowski et al., 2003) and schizophrenia (Juckel et al., 2003). Psychopharmacological studies suggest that LD is a predictive marker for the clinical response to antidepressive 5-HT agents (Gallinat et al., 2000) and, in particular, prophylactic lithium has repeatedly been shown to induce a positive clinical response in patients with uni- or bipolar depression and a strong LD (Hegerl et al., 1987, Hegerl et al., 1992, Brocke et al., 2000 and Juckel et al., 2004), respectively, an augmenting pattern in visual evoked potentials (e.g. Baron et al., 1975). In order to understand the role of endogenous lithium in neurobiological functioning and emotional processing, the variability of serum lithium concentrations was hypothesised to be associated with measurable effects on LD (as a neurobiological indicator of overall 5-HT functioning) and emotional liability.