Clinical Neurophysiology 125 (2014) 2240–2246

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Acute effects of lithium on excitability of human motor cortex Annemarie Hübers a,b, Hanna Voytovych a, Tonio Heidegger a, Florian Müller-Dahlhaus a,c, Ulf Ziemann a,c,⇑ a

Department of Neurology, Goethe-University Frankfurt, Frankfurt, Germany Department of Neurology, University of Ulm, Ulm, Germany c Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls University Tübingen, Tübingen, Germany b

See Editorial, pages 2144–2145

a r t i c l e

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Article history: Accepted 15 March 2014 Available online 24 April 2014 Keywords: Lithium Transcranial magnetic stimulation Inverted U-shaped dose–response relationship Hormesis Motor cortex excitability Motor evoked potential

h i g h l i g h t s  Original data are provided on acute effects of lithium on TMS measures of human motor cortex

excitability.  Lithium modifies MEP input–output curve dose-dependently in an inverted U-shaped manner.  Findings are important for our understanding of therapeutic and toxic effects of lithium on the human

CNS.

a b s t r a c t Objective: Lithium has been widely used to treat bipolar affective disorder for over 60 years. Still, its acute effects in human cerebral cortex are poorly understood. This study aimed at investigating the acute effects of lithium on motor cortex excitability as measured by transcranial magnetic stimulation (TMS). Methods: Ten healthy young adults participated in a double-blind placebo-controlled randomized crossover study with four sessions, where a single oral dose of lithium carbonate (450 mg, 900 mg, or 1350 mg) or placebo was tested. Focal TMS of the hand area of left motor cortex was used to test resting and active motor thresholds, motor evoked potential input–output curve (MEP IO-curve), slope of the MEP IO-curve and paired-pulse measures of intracortical inhibition and facilitation before, and two and four hours after drug administration. Results: Two hours post drug administration, 450 mg of lithium carbonate increased the slope of the MEP IO-curve while 1350 mg tended to decrease it. Lithium had no effect on motor thresholds, or intracortical inhibition or facilitation. Conclusions: The acute effects of lithium on MEP IO-curve, a marker of corticospinal excitability, are consistent with an inverted U-shaped dose–response relationship. Significance: Findings are important for our understanding of the therapeutic and toxic effects of lithium on the human central nervous system. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction The monovalent cation lithium is being used for over 60 years as treatment of bipolar disorder (Geddes et al., 2004). The mecha⇑ Corresponding author at: Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen, HoppeSeyler-Straße 3, 72076 Tübingen, Germany. Tel.: +49 7071 2982049. E-mail address: [email protected] (U. Ziemann).

nisms of its therapeutic effects during long-term administration are still largely obscure (Phiel and Klein, 2001) but may include inhibition of intracellular signaling kinases and phosphatases, and up-regulation of neurotrophic factors (for review, Chiu and Chuang, 2010; Malhi et al., 2013). The therapeutic range of lithium is rather small. Acute neurotoxicity including tremor, seizures and coma may occur already at therapeutic (Grueneberger et al., 2009; Hay and Simpson, 1982; Speirs and Hirsch, 1978) or even subtherapeutic plasma levels of

http://dx.doi.org/10.1016/j.clinph.2014.03.035 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

A. Hübers et al. / Clinical Neurophysiology 125 (2014) 2240–2246

lithium (Prettyman, 1994). Acute effects of lithium on neuronal excitability may explain these sequelae but have only rarely been studied. Lithium dose-dependently stimulated the release of glutamate, the major excitatory neurotransmitter in the central nervous system (CNS), in slices of monkey cerebral cortex (Dixon et al., 1994), and this may lead to increased neuronal excitability through N-methyl-D-aspartate receptor (NMDAR) activation and intracellular calcium influx. Lithium increased (Colino et al., 1998; Valentin et al., 1997) or decreased (Lacaille et al., 1992) glutamatergic excitatory neurotransmission in various in vitro experimental preparations. Microdialysis studies in vivo in rat prefrontal cortex showed that acute application of lithium at an intermediate dose increased glutamate concentration but decreased it at a high dose, while lithium left the concentration of gamma-amino butyric acid (GABA), the major inhibitory transmitter in the CNS, unaffected at low and intermediate doses but increased it at a high dose (Antonelli et al., 2000). These findings may suggest that the acute effects of lithium on cortical excitability are dose-dependent with prevailing glutamatergic excitation at lower doses and a switch to predominating GABAergic inhibition at higher doses. Pharmaco-TMS offers the opportunity to study acute drug effects on cortical excitability in humans (for reviews, Paulus et al., 2008; Ziemann, 2004, 2013). Several TMS measures of motor cortical and corticospinal excitability have been extensively characterized. Resting and active motor thresholds represent axonal excitability that depends on voltage-gated sodium channels (Chen et al., 1997; Mavroudakis et al., 1994; Tergau et al., 2003; Ziemann et al., 1996b). MEP input–output curve (IO-curve) reflects corticospinal excitability that is depressed by positive modulators of the GABA type A receptor (GABAAR) (Boroojerdi et al., 2001; Kimiskidis et al., 2006; Schönle et al., 1989) and increased by enhancement of fast ionotropic glutamatergic neurotransmission via the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (Di Lazzaro et al., 2003). The paired-pulse TMS measure of short-interval intracortical inhibition is an indicator of neurotransmission through the GABAAR (Di Lazzaro et al., 2000; Ilic et al., 2002b; Ziemann et al., 1996a), while long-interval intracortical inhibition measures activity at GABABRs (McDonnell et al., 2006; Müller-Dahlhaus et al., 2008). The acute effects of lithium on TMS measures of motor excitability have been tested only in one previous study so far that came from our group and demonstrated no effect of a single oral dose of 900 mg lithium carbonate on MEP amplitude (Voytovych et al., 2012). Other TMS measures of motor excitability or other lithium doses have not been tested because that study focused on the acute effects of lithium on TMS-induced long-term potentiation-like plasticity. Here we sought, for the first time, to investigate systematically the acute effects of various single oral doses of lithium on a broad array of TMS measures of motor excitability at the systems level of human motor cortex. Findings will be pertinent to understanding the modes of therapeutic and neurotoxic action of lithium in humans.

2. Materials and methods 2.1. Subjects Ten healthy, right-handed subjects (mean age, 26.1 ± 3.4 years, 4 females) participated in this study. All subjects were healthy without any history of neurological, psychiatric or cardiac disease. All subjects gave written informed consent. The experiments conformed to the latest version of the declaration of Helsinki and were approved by the ethics committee of the faculty of medicine of the Goethe-University of Frankfurt am Main, Germany and by the

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Federal Institute for Drugs and Medical Devices of Germany (BfArM; EudraCT number: 2009-010639-41).

2.2. Study medication Subjects participated in four experimental sessions in a randomized double-blind placebo-controlled crossover design. Single oral doses of lithium carbonate (QuilonumÒ retard, GlaxoSmithKline) and/or placebo (PBO, Lichtenstein 8 mm placebo tablets, Winthrop Arzneimittel GmbH) were applied in the experimental sessions as follows: 1 tablet lithium carbonate à 450 mg (12.2 mmol; Li450) plus 2 tablets PBO; 2 tablets lithium carbonate à 450 mg (24.4 mmol; Li900) plus 1 tablet PBO; 3 tablets lithium carbonate à 450 mg (36.6 mmol; Li1350); 3 tablets PBO. Sessions in a given subject were separated by at least one week to avoid carryover effects. Plasma levels of lithium were determined at baseline, and two (post-2 h) and four (post-4 h) hours after drug intake.

2.3. EMG recordings Surface electromyography (EMG) was recorded from the first dorsal interosseous (FDI) muscle of the right hand using Ag–AgCl electrodes in a belly-tendon montage. EMG was amplified and band-pass filtered (0.02–2 kHz, Digitimer D360, Digitimer Ltd., UK), digitized at a sampling rate of 5 kHz per channel (Micro1401, Cambridge Electronic Design) and stored on a laboratory computer for online display and off-line analysis. Maintenance of a stable level of relaxation or isometric contraction was monitored by continuous audio–visual feedback of the EMG signal at gains of 50 lV/Div and 200 lV/Div, respectively. In recordings with the FDI at rest, trials contaminated by EMG activity were excluded from analysis. This occurred in 100% indicate facilitation of the test MEP, while values 0.4) (Fig. 1A). At post-2 h there were significant effects of DRUG (F3,27 = 3.94, p = 0.019) and the interaction between DRUG and STIMULUS INTENSITY (F6.74,60.67 = 3.03, p = 0.009) (Fig. 1B). Post hoc testing showed significant differences between the Li450 and Li1350 conditions (DRUG effect: F1,9 = 9.58, p = 0.013; DRUG  STIMULUS INTENSITY interaction: F2.81,25.30 = 6.38, p = 0.003) and between the Li900 and Li1350 conditions (DRUG effect: F1,9 = 7.00, p = 0.027; DRUG  STIMULUS INTENSITY interaction: F4.44,39.98 = 5.04, p = 0.002). These effects were explained by a depression of the MEP IO-curve by Li1350 compared to Li450 and Li900 in the range of high stimulus intensities (Fig. 1B). None of the other paired comparisons (PBO vs. any lithium condition, Li450 vs. Li900) showed significant effects (all p > 0.1). At post-4 h, there were no longer significant effects of DRUG or the interaction between DRUG and STIMULUS INTENSITY (all p > 0.2) (Fig. 1C). At post-2 h, the rmANOVA showed a significant effect of DRUG on slope m (F3,27 = 5.04, p = 0.007) (Fig. 2). Post hoc paired two-tailed ttests revealed significant differences for Li450 vs. PBO (p = 0.041),

Table 2 TMS measures of motor cortical excitability (means ± SD) before (Baseline) and 2 and 4 h after (Post-2 h and Post-4 h) application of placebo or lithium carbonate at doses of 450, 900 or 1350 mg. Baseline

Test MEP (mV)

Post-2 h

Test MEP (mV)

Post-4 h

Test MEP (mV)

AMT [%MSO]

PBO Li450 Li900 Li1350

30.5 ± 3.3 30.7 ± 2.9 29.9 ± 2.9 30.3 ± 4.1

30.2 ± 4.0 29.9 ± 2.2 30.0 ± 2.7 29.9 ± 3.3

30.1 ± 3.9 29.3 ± 2.3 29.8 ± 2.9 29.7 ± 4.4

RMT [%MSO]

PBO Li450 Li900 Li1350

37.7 ± 2.9 37.4 ± 3.9 37.2 ± 3.8 37.7 ± 4.5

37.5 ± 2.4 37.6 ± 3.8 38.5 ± 3.6 37.8 ± 4.0

37.7 ± 2.4 36.7 ± 3.5 39.0 ± 2.8 38.1 ± 3.4

SI1mV [%MSO]

PBO Li450 Li900 Li1350

49.8 ± 8.4 47.6 ± 7.1 48.3 ± 6.7 49.8 ± 8.4

47.8 ± 4.9 48.6 ± 7.5 49.1 ± 6.8 47.8 ± 4.9

48.7 ± 5.0 48.5 ± 6.2 48.8 ± 6.7 48.7 ± 5.0

SICI [%]

PBO Li450 Li900 Li1350

76.5 ± 33.7 77.0 ± 36.1 83.1 ± 29.4 69.5 ± 17.5

0.84 ± 0.3 0.93 ± 0.3 0.94 ± 0.3 0.96 ± 0.2

72.5 ± 21.4 77.8 ± 25.4 71.3 ± 34.7 83.0 ± 20.0

0.93 ± 0.2 1.12 ± 0.3 0.97 ± 0.3 1.00 ± 0.2

68.6 ± 28.4 73.1 ± 18.1 72.5 ± 34.7 86.7 ± 19.5

0.87 ± 0.3 0.91 ± 0.3 0.97 ± 0.2 0.93 ± 0.2

LICI [%]

PBO Li450 Li900 Li1350

65.9 ± 28.6 69.3 ± 28.6 80.5 ± 53.3 74.9 ± 27.8

0.94 ± 0.4 1.01 ± 0.3 1.01 ± 0.4 0.99 ± 0.3

69.3 ± 32.4 53.4 ± 28.3 79.5 ± 67.1 68.1 ± 31.7

0.99 ± 0.5 0.97 ± 0.2 0.98 ± 0.2 0.91 ± 0.3

80.5 ± 49.9 82.9 ± 80.7 63.2 ± 38.1 73.7 ± 43.7

0.96 ± 0.3 0.88 ± 0.3 0.99 ± 0.3 0.80 ± 0.2

SICF [%]

PBO Li450 Li900 Li1350

122.4 ± 21.2 125.6 ± 33.0 150.7 ± 47.7 158.0 ± 66.3

1.08 ± 0.2 1.20 ± 0.4 1.15 ± 0.3 1.11 ± 0.3

149.9 ± 43.7 127.9 ± 56.5 170.4 ± 98.5 142.6 ± 38.2

1.21 ± 0.3 1.34 ± 0.6 1.07 ± 0.4 1.15 ± 0.2

164.0 ± 77.5 144.0 ± 41.3 154.1 ± 37.3 142.6 ± 40.0

1.15 ± 0.3 0.90 ± 0.3 1.10 ± 0.2 1.13 ± 0.3

ICF [%]

PBO Li450 Li900 Li1350

114.2 ± 38.5 109.8 ± 38.2 118.9 ± 28.8 118.3 ± 18.6

0.97 ± 0.3 1.12 ± 0.2 1.13 ± 0.2 1.29 ± 0.3

122.7 ± 30.9 123.4 ± 38.2 115.1 ± 29.2 122.1 ± 33.3

1.06 ± 0.2 1.00 ± 0.2 1.09 ± 0.2 1.14 ± 0.3

118.4 ± 43.2 134.1 ± 45.4 141.9 ± 47.1 119.3 ± 18.7

1.14 ± 0.3 1.12 ± 0.4 1.13 ± 0.2 1.12 ± 0.3

RMT, resting motor threshold; AMT, active motor threshold; SI1mV, stimulus intensity of the test pulse adjusted to elicit an unconditioned MEP amplitude of 1 mV in the paired-pulse measurements; SICI, short-interval intracortical inhibition; LICI, long-interval intracortical inhibition; SICF, short-interval intracortical facilitation; ICF, intracortical facilitation. RMT, AMT and SI1mV are given in % of maximum stimulator output (MSO); SICI, LICI, SICF and ICF are given as ratios of mean conditioned over mean unconditioned motor evoked potentials  100%. All data are means ± SD. PBO, placebo; Li450, Li900 and Li1350, lithium carbonate at doses of 450, 900 and 1350 mg, respectively.

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Fig. 2. Individual data of the MEP IO-curve slope m (gray lines) in the placebo (PBO) and the three lithium conditions (Li450, Li900, Li1350) 2 h after drug administration. The thick black line represents the group means (±1 SEM). Slope m is given in mV over the stimulus intensity range between 80 and 120% SI1mV. ⁄Significant difference from PBO (p < 0.05), #significant difference from Li1350 (p < 0.05); §trend towards significant difference from PBO (p = 0.08).

Li450 vs. Li1350 (p = 0.013) and Li900 vs. Li1350 (p = 0.001) and a trend for Li1350 vs. PBO (p = 0.08) while the other comparisons (Li900 vs. PBO, Li450 vs. Li900) were not significant (all p > 0.2). These differences were explained by an increased slope m in the Li450 condition and a trend towards a decrease in slope m in the Li1350 condition (Fig. 2). At baseline and post-4 h, DRUG did not have a significant effect on slope m (all p > 0.2). Dm was not related to lithium plasma concentrations at any time or lithium dose (linear, logarithmic, and quadratic regression analyses, all p P 0.10). 3.4. Paired-pulse measurements One-way rmANOVAs revealed no effect of DRUG on SICI, LICI, SICF or ICF at any of the three time points. The mean data of all paired-pulse measurements are provided in Table 2. The table also shows that adjustments of SI1mV were very minor, and that the target value of 1 mV amplitude for the unconditioned test MEP was closely maintained for all paired-pulse measurements across all drug conditions and time points. Therefore, there was no variation in test MEP amplitude that could have accounted for the absence of Drug effects on the paired-pulse measures. 4. Discussion In this study we investigated, for the first time, acute dose– response effects of lithium on TMS measures of excitability in human motor cortex. We showed that lithium has an inverted U-shaped dose–response effect on MEP IO-curve, i.e. the lowest dose (Li450) resulted in an increase of the slope m of the MEP IO-curve, while the highest dose (Li1350) tended to decrease it when compared to placebo. Other TMS measures of motor cortex excitability (RMT, AMT, SICI, LICI, SICF, ICF) remained unaffected. The observed inverted U-shaped dose–response of lithium on MEP IO-curve is reminiscent of experimental data in rat hippocampal slices where the lowest dose (10 mM) of lithium had no effect on the amplitude of the antidromic population spike of dentate granule cells, the highest dose (40 mM) strongly reduced it, while an intermediate dose (20 mM) led to a paradoxical facilitation with

the appearance of a second population spike (MacVicar et al., 1981). In the following paragraphs we will discuss possible mechanisms of this inverted U-shaped dose–response effect on MEP IO-curve. MEP IO-curve represents recruitment of an increasing number of corticospinal neurons with increasing stimulus intensity (Hallett, 2000). In the medium- and high-intensity part of the MEP IO-curve, MEP amplitude is mainly generated by late I-waves, i.e. transsynaptic activation of corticospinal neurons via interneurons (Di Lazzaro and Ziemann, 2013). Previous pharmaco-TMS studies have demonstrated that positive allosteric modulators of the GABAAR depress the MEP IO-curve selectively in the highintensity part (Boroojerdi et al., 2001; Kimiskidis et al., 2006). This reduction in MEP amplitude is associated by a reduction in amplitude of the late I-waves as measured by epidural recordings of the descending corticospinal volley from the cervical spinal cord (Di Lazzaro et al., 2000). In contrast, positive modulators of the glutamatergic AMPA receptor dose-dependently increase MEP IO-curve over the entire intensity range, including a significant decrease in motor threshold (Di Lazzaro et al., 2003). In summary, alterations in MEP IO-curve can reflect changes in the balance between the GABAAergic inhibitory and glutamatergic excitatory system. The effects of lithium selectively on the high-intensity part of the MEP IO-curve in this study suggest that lithium acts predominantly via mechanisms that affect the excitability of late I-waves, such as GABAergic neurotransmission, or various neurotransmitter systems (see below) rather than mechanisms that affect axonal excitability, such as voltage-gated ion channels. In addition, as the late I-waves reflect activation of the corticospinal neurons through cortico-cortical inputs, e.g. from the premotor cortices (Di Lazzaro and Ziemann, 2013 #9265), the selective effect of lithium on the high-intensity part of the MEP IO-curve may suggest modulatory effects of lithium in cortical areas other than M1. In these contexts, a microdialysis study of rat prefrontal cortex showed that acute application of lithium dose-dependently increased glutamate concentration at an intermediate dose of 2 mmol/kg but decreased it at the highest dose of 4 mmol/kg, while GABA concentration increased at the highest dose (Antonelli et al., 2000). The decrease in glutamate concentration at the highest dose was reversed by additional application of a GABABR antagonist, suggesting that the lithium-induced increase in GABA concentration at high doses resulted in enhanced presynaptic GABABergic inhibitory control of the activity of excitatory neurons (Antonelli et al., 2000). These data are consistent with a dose-dependent increase in glutamate in slices of monkey cortex by acute lithium application (Dixon et al., 1994). It is not conclusively clear to what extent the impact of lithium on a variety of second messenger signal pathways mediated these effects of lithium on the concentrations of glutamate and GABA in cerebral cortex. Furthermore, various neuromodulating neurotransmitters change the high-intensity part of the MEP IO-curve. The most consistent effects that have been observed were increases of MEP amplitude by agonists in the noradrenergic (Boroojerdi et al., 2001; Ilic et al., 2003; Plewnia et al., 2001, 2002) and serotonergic systems (Gerdelat-Mas et al., 2005; Ilic et al., 2002a). It is well known that lithium exerts agonistic actions in these neuromodulating neurotransmitter systems (Chenu and Bourin, 2006). Acute application of an intermediate dose of lithium (2 mmol/kg) increased the concentration of noradrenaline in rat frontal cerebral cortex, while this effect was less pronounced with a toxic dose of 10 mmol/kg (Otero Losada and Rubio, 1984). During acute lithium intoxication in one patient with major depression and long-term pretreatment with lithium, the serum concentrations of the direct metabolites of noradrenaline and serotonin but not dopamine increased significantly, most prominently when the lithium serum concentration had fallen off to 1–1.5 mmol/l (Yoshimura et al., 2000). On the other hand, a 1-week administration of lithium at

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an average plasma level 0.82 mmol/l in healthy subjects did not lead to changes in noradrenaline serum concentration or urinary excretion rate of 5-hydroxyindoleacetic acid, the major metabolite of serotonin (Rudorfer et al., 1985). Together, these findings may point to a dose- and time-critical effect of lithium, as also observed in the present study where changes in MEP IO-curve were only observed at post-2 h but no longer at post-4 h, despite persistent lithium plasma concentrations (cf. Table 1). Of note, the individual effects on lithium on the slopes of the MEP IO-curves at post-2 h did not correlate with the lithium plasma concentrations. One parsimonious reason is that the concentrations of lithium in plasma and brain (as measured in the cerebrospinal fluid) after acute lithium exposure are not tightly related (Stokes et al., 1982; Terhaag et al., 1978). The referenced studies on lithium effects on the glutamatergic and GABAergic systems and on various monoaminergic systems are compatible with the lithium effects on MEP IO-curve in our study, but additional studies would be necessary to unravel the mechanisms that have been key in the observed modulation of MEP IO-curve (e.g. by combining lithium application with antagonists in the various neurotransmitter systems). Why were the lithium effects specific to MEP IO-curve while other TMS measures of motor cortex excitability remained unaffected (cf. Table 2)? The best explanation is that MEP IO-curve is more sensitive than all or most of other tested TMS measures to detect drug effects, as has been demonstrated in other studies (Boroojerdi et al., 2001; Plewnia et al., 2001, 2002). Another possibility is that the effects of lithium were truly specific to MEP IOcurve. This is less likely, however, because the proposed actions of lithium in the glutamatergic, GABAergic, noradrenergic and serotonergic systems would all be expected to be associated with significant changes in the paired-pulse TMS measures of motor cortex excitability (for reviews, Paulus et al., 2008; Ziemann, 2013). On a general note, inverted U-shaped (also called hormetic) dose–response relationships are very common in pharmacology and toxicology (Calabrese, 2010), for instance, hormetic dose– response relations prevail in behavioral effects of anxiolytic drugs (for review, Calabrese, 2008a) or modulation of epileptic seizure threshold by diverse CNS active agents (for review, Calabrese, 2008b). On this account, the observed inverted U-shaped dose– response of lithium on excitability in human motor cortex (Figs. 1B and 2) is not surprising. In conclusion, acute exposure to lithium results in an inverted U-shaped dose–response effect on excitability of human motor cortex, as indexed by an increase/decrease of MEP IO-curve slope at low/high doses of lithium. Findings may help in understanding the therapeutic and toxic effects on lithium in the human CNS, although the translation of the observed acute effects in healthy subjects to chronic effects of lithium and to patients will require further research. Acknowledgment We thank Dr. Sandra Schäfer for support in the preparatory phase of this study. Conflicts of interest: The authors declare that they have no conflicts of interest. References Antonelli T, Ferioli V, Lo gallo G, Tomasini MC, Fernandez M, O’Connor WT, et al. Differential effects of acute and short-term lithium administration on dialysate glutamate and GABA levels in the frontal cortex of the conscious rat. Synapse 2000;38:355–62. Boroojerdi B, Battaglia F, Muellbacher W, Cohen LG. Mechanisms influencing stimulus-response properties of the human corticospinal system. Clin Neurophysiol 2001;112:931–7. Calabrese EJ. An assessment of anxiolytic drug screening tests: hormetic dose responses predominate. Crit Rev Toxicol 2008a;38:489–542.

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Acute effects of lithium on excitability of human motor cortex.

Lithium has been widely used to treat bipolar affective disorder for over 60years. Still, its acute effects in human cerebral cortex are poorly unders...
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