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Effects of acute CDP-choline treatment on resting state brain oscillations in healthy volunteers
Neuroscience Letters 591 (2015) 121–125
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
Effects of acute CDP-choline treatment on resting state brain oscillations in healthy volunteers Verner Knott a,b,c,d,∗ , Sara de la Salle b , Dylan Smith c , Joelle Choueiry c , Danielle Impey b , Meaghan Smith b , Elise Beaudry b , Salman Saghir b , Vadim Ilivitsky d , Alain Labelle d a
University of Ottawa, Institute of Mental Health Research, Ottawa, ON, Canada School of Psychology, University of Ottawa, Ottawa, ON, Canada c Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada d Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada b
h i g h l i g h t s • CDP-choline affects human brain oscillations. • Oscillatory changes mimic nicotinic stimulation. • These observations allow extensions to clinical populations.
a r t i c l e
i n f o
Article history: Received 3 December 2014 Received in revised form 3 February 2015 Accepted 13 February 2015 Available online 17 February 2015 Keywords: Cytidine-5 -diphosphocholine Choline Nicotinic receptors Oscillations Cognition
a b s t r a c t CDP-choline (cytidine-5 -diphosphocholine) is a phospholipid used to treat cognitive disorders, presumably repairing and maintaining brain cell membranes. Additional mechanisms may include enhanced cholinergic neurotransmission as the ␣7 nicotinic receptor actions of choline and increased acetylcholine synthesis accompanying CDP-choline administration may modulate brain oscillations underlying cognitive processes. This study utilizes electroencephalographic (EEG) recordings in healthy volunteers to evaluate CDP-choline induction of an oscillatory response profile associated with nicotinic stimulation. Resting state EEG was acquired in 24 male volunteers administered low (500 mg) and moderate (1000 mg) doses of CDP-choline in a randomized placebo-controlled, crossover trial. Consistent with nicotinic agonist treatment, spectral analysis showed dose-dependent reductions in delta and increases in alpha oscillations, which were also accompanied by decreases in beta and gamma oscillatory activity. These findings support the posit that CDP-choline cognitive enhancement involves multiple mechanisms including facilitated nicotinic cholinergic action. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction CDP-choline, or citicoline is endogenous, an essential intermediate in the biosynthesis of structural phospholipids, chiefly phosphatidylcholine (PtdCho), in brain cell membranes [1]. CDPcholine treatment has shown clinical efficacy for cognitive disorders associated with cerebral vascular disease, head trauma, degenerative diseases (e.g., Alzheimer’s disease) and normal aging [2]. Although its suggested pharmacological action has been the restoration of phospholipid biosynthesis, with PtdCho helping to restore and preserve the structure/function integrity of neuronal
∗ Corresponding author at: University of Ottawa, Institute of Mental Health Research at the Royal Ottawa Mental Health Care Centre, 1145 Carling Avenue, Ottawa, Ontario K1Z 7K4, Canada. Tel.: +1 613 722 6521. E-mail address: [email protected] (V. Knott). http://dx.doi.org/10.1016/j.neulet.2015.02.032 0304-3940/© 2015 Elsevier Ireland Ltd. All rights reserved.
membranes in the damaged brain [3], its action appears to involve mechanisms beyond phospholipid metabolism. CDP-choline is a form of the essential nutrient choline, a precursor of PtdCho as well as a donor in the metabolic pathways for biosynthesis of the neurotransmitter acetylcholine (ACh). Both ACh and its precursor, choline, are full agonists at nicotinic acetylcholine receptors (nAChRs), which play a critical role in normal cognition and are promising targets for novel treatments of cognitive dysfunction [4,5]. Oral administration of single doses of CDP-choline [6] and choline [7] increase plasma choline levels, as well as extracellular free choline in the brain as measured by magnetic resonance spectroscopy, but the presumed major quantitative fate of brain choline – rapid intracellular uptake and metabolic conversion to choline-bound phospholipids, not to ACh, may attenuate the marked cholinergic-related functional changes that would otherwise occur with the free ACh [8].
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Putative cholinergic actions associated with CDP-choline may be investigated noninvasively with quantitative electroencephalography (EEG), a neuroimaging tool [9] frequently used during the preclinical and clinical stages of drug discovery [10]. Distinct pharmaco-EEG profiles are associated with the pharmacodynamic actions of different classes of drugs [11,12] including nicotinic agonists such as nicotine, which in smokers induces a stimulant-like [13] electrocerebral activation pattern in spectral EEGs – accelerating the dominant oscillatory frequency, and increasing power of high frequency oscillations (alpha, beta, gamma) while decreasing power in low frequency oscillations (delta, theta) [14,15]. This study aims to assess the pharmaco-EEG profile of single oral doses of CDP-choline to healthy non-smoking volunteers, specifically evaluating the consistency of spectral EEG changes with nAChR stimulation. Although CDP-choline’s clinically recommended dose range is 500–4000 mg, the range here was 500 and 1000 mg as nAChR activation is most evident with relatively low agonist concentrations, while high concentrations promote nAChR desensitization [16,17]. 2. Methods 2.1. Participants The study involved 24 healthy, right-handed males with a mean age of 21.3 years (SE = 0.99) recruited via local advertisements. Participants were screened initially by telephone and then by personal interview which included a medical exam and a personal and family psychiatric history assessment using the SCID-NP (Structured Clinical Interview–Nonpatient version for DSM-IV [18]) and FIGS (Family Interview for Genetic Studies [19]), respectively. Acceptance required no current medical or neurological illnesses, no personal or family psychiatric history (including substance abuse/dependence) and no use of medications. All were required to be nonsmokers, smoking less than 100 cigarettes in their lifetime (none in the past year) and exhibiting an expired air carbon monoxide level ≤ 3 parts per million, consistent with a nonsmoker status [20]. Participants were on normal diets, and reported no nutritionrelated medical problems. All signed an informed consent for the study, which was approved by the research ethics board of the Royal Ottawa Mental Health Care Group. 2.2. Design Participants were assessed in three test sessions (placebo and two doses of CDP-choline) conducted within a randomized, doubleblind, crossover design, with session order being counterbalanced and each session being separated by 8–12 days to allow for CDPcholine elimination. 2.3. Procedures Morning test sessions were between 9:00 a.m. and 11:00 a.m. following overnight abstinence from drugs, vitamins, food, and caffeine. Testing was initiated 4 h after treatment initiation and ended with assessment of adverse events and vital signs. 2.4. Treatment CDP-choline was administered orally in two active doses, 500 mg (2 × 250 mg capsules) and 1000 mg (4 × 250 mg capsules) using a “double dummy” approach in which 4 capsules were administered in each test session (e.g., 2 placebo capsules and 2 × 250 mg capsules comprised the 500 mg test dose condition), including the placebo (cellulose) session. Single doses of CDP-choline
dose-dependently raise choline plasma levels (peaking at 3–5 h), with an elimination half-life extending up to 56 h [21]. 2.5. EEG Three minutes of eyes-closed, vigilance-controlled resting state EEG activity was acquired in reference to the nose electrode, with scalp electrodes positioned at 8 regions (F3, Fz, F4, Cz, P3, Pz, P4, Oz) according to the 10–10 system [22]. An electrode at the midforehead site served as ground, and electrodes on orbital ridges and external canthi were used to monitor vertical (VEOG) and horizontal (HEOG) electro-oculographic activity. Electrode impedances were kept below 5 k and amplified signals (0.1–40.0 Hz amplifier bandpass filter) were digitized at 256 Hz. A minimum of 45 artifact-free 2-s duration EEG epochs were subjected to a Fast Fourier Transform algorithm (with a high-pass autoregressive filter, weighted by a 5% cosine taper) for computation of average absolute power (V2 ) in eight frequency bands as used previously [23] and include: delta (0.5–5 Hz); theta (6–8 Hz); alpha1 (8.5–10 Hz); alpha2 (10.5–12 Hz); alpha total (8.5–12 Hz); beta1 (12.5–18 Hz); beta2 (18.5–20.5 Hz) and beta3 (21–30 Hz) frequency bands at each scalp region. Spontaneous gamma oscillations (30–60 Hz) in humans have not been systematically examined with respect to nicotine but were included here as an exploratory focus, with emphasis on absolute power. 2.6. Analysis The Statistical Package for Social Sciences (SPSS, Chicago, IL) software was used to analyze log transformed absolute and relative (%) power value changes induced by CDP-choline treatment at the 8 scalp regions. Relative power values were derived by expressing power in each band as a percent of total power across all bands. Analysis of each absolute and relative band power index involved a separate repeated measures analysis of variance (ANOVA) with treatment (3 levels) and region (8 levels) as within-subject factors. Greenhouse–Geisser corrections were applied to all significant (p < 0.05) main and interaction effects, and Bonferroni-adjusted corrections were used in follow-up comparisons. To reduce the number of type I statistical errors, region affects were not followed up unless they interacted with treatment. 3. Results There were no significant serious adverse events associated with CDP-choline (vs. placebo) and no adverse events led to discontinuation from the study. Heart rate and blood pressure vital signs were not affected by CDP-choline treatment. Absolute power in the delta band was significantly affected by treatment (F = 3.64, df = 2/42, p < 0.041) and region (F = 28.83, df = 7/147, p < 0.0001). Compared to placebo, power was reduced (p < 0.03) with both doses of CDP-choline but reached significance only with the 1000 mg dose (Fig. 1). No significant treatmentinduced changes were observed for absolute power in theta and alpha bands but significant treatment x region interactions were shown with power in beta2 (F = 2.39, df = 14/294, p < 0.05) and beta3 bands (F = 2.55, df = 14/294, p < 0.04). For beta2 , power at F3 was reduced by the 1000 mg dose compared to both placebo (p < 0.05) and the 500 mg doses (p < 0.02), and similar reductions with 1000 mg were shown at F4 when compared to the placebo (p < 0.04) and 500 mg CDP-choline (p < 0.04) doses (Fig. 2). Power reductions were also evidenced at C3 (p < 0.04) but with the 1000 mg dose reducing power only when compared to placebo (Fig. 1). Beta3 power was also reduced at F3 (p < 0.05) and F4 (p < 0.05), as well as at C4 (p < 0.03) with the 1000 mg dose compared to placebo (Fig. 2). Follow-up comparisons of a significant
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Fig. 1. Mean (±SE) values (collapsed across sites) for absolute delta and relative delta, alpha1 , and alpha total power for each frequency band in the 3 test sessions (placebo and CDP-choline: 500 mg, 1000 mg) are shown in bar graphs.
treatment x region interaction (F = 3.27, df = 14/294, p < 0.01) found gamma to be reduced by the 1000 mg dose (vs. placebo) at F3 (p < 0.05), F4 (p < 0.05) and C4 (p < 0.05) scalp sites (Fig. 2). Relative power showed significant treatment effects with delta (F = 3.54, df = 2/42, p < 0.05), alpha1 (F = 4.56, df = 2/42, p < 0.02) and alpha total (F = 4.67, df = 2/42, p < 0.03) bands (Fig. 1). Reductions in relative delta appeared with both CDP-choline doses (vs. placebo) but were significant only with 1000 mg (p < 0.04). Alpha1 increases were found with both the 500 mg (p < 0.05) and 1000 mg (p < 0.02) doses of CDP-choline compared to placebo. Alpha total was similarly affected by CDP-choline (vs. placebo), being increased with both 500 mg (p < 0.05) and 1000 mg (p < 0.03) doses. Relative beta and gamma were not affected by treatment. 4. Discussion In this study, electrophysiological evidence showed that acute oral administration of CDP-choline penetrated the brain of healthy volunteers and altered resting state oscillatory activity. Oscillations in slow (delta) and several fast (alpha, beta) EEG bands were significantly changed with relatively low (500 mg) and moderate (1000 mg) doses, and both the reductions in delta and the increases in alpha oscillatory activity are consistent with nAChR agonism as a possible mechanism of action of CDP-choline in the human brain. Single doses of smoke-inhaled [24], intravenous [25], oral (gum) [26], transdermal [27], and nasal nicotine [28], the prototypical nAChR agonist, consistently induce a rightward shift in EEG power spectrum activity, with the resulting pharmaco-EEG profile being characterized by power suppression in slow frequency oscillations, an increased dominant (alpha) frequency, and power augmentation in fast oscillations. As these acute EEG alterations are usually observed in healthy smokers following smoking abstinence, which itself is associated with a sedation-like EEG pattern (i.e., leftward power spectrum shift to slow oscillations, predominantly theta), they likely reflect a “remediation” of a deficiency that may accompany the general disturbance in neural networks seen during acute nicotine withdrawal in chronic smokers [29–31]. In the few EEG resting state studies administering nicotine to nonsmokers, power reductions in theta [32] or power increments in alpha [33,34] have been reported without changes in delta or beta oscillatory power. Although the present findings with CDP-choline in healthy nonsmokers also showed increased power of alpha-band oscillations,
Fig. 2. Significant topographical absolute power changes induced by 1000 mg CDPcholine (vs. placebo) are displayed in color format. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
these changes were accompanied by reductions of both delta and beta oscillatory activity, resulting in a distinct pharmaco-EEG profile (vs. nicotine) in nonsmokers which may reflect the separate and combined actions of choline and ACh on brain nAChRs. This pharmaco-EEG profile was accompanied by power decreases in gamma and, to the best of our knowledge, this is the first time that spontaneous gamma has been shown to be modulated by an ␣7 nicotinic agonist in humans, supporting preclinical evidence of a role for cholinergic modulation in gamma oscillations [35]. nAChRs are expressed throughout the cortex and although there are many nAChR subtypes, the most abundant are heteromeric receptors that contain ␣4 and 2 subunits, or are homomeric receptors containing ␣7 subunits [36,37]. While the ␣42 nAChR containing subunits show high sensitivity/affinity to ACh and nicotine (i.e., non-selective agonists) and desensitize relatively slowly, ␣7 subunits have lower affinity for ACh and nicotine and exhibit rapid desensitization kinetics, but not at low nicotinic agonist concentrations [38,39]. Choline is a full selective agonist at ␣7 receptors, but not other nicotinic receptors subtypes, and choline-evoked electrophysiological responses from single cells are blocked by selective ␣7 antagonists [40–42]. The relatively minimal
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increase in free choline concentration in brain with low/moderate dosing of oral CDP-choline, due in part to rapid choline phosphorylation, may be sufficient to induce (and maintain) ␣7 receptor activation. These selective actions of choline may act additively or synergistically with synthesized ACh acting at ␣42 receptors, modulating oscillatory activity in different bands depending on the abundance, location, and conformational state of the receptors. EEG studies have not been reported with ␣7 agonist agents but the few investigations with selective ␣42 agonists have shown single doses to reduce delta, theta, and alpha1 oscillations and to increase dominant frequency and fast alpha [43–45]. Activation of nAChRs facilitates the release of multiple neurotransmitters and their role in nicotinic-modulated oscillatory activity has been investigated in a number of human pharmacological studies. Serotonin [44], norepinephrine [46], and glutamate [33] have been shown not to contribute to nicotine’s pharmacoEEG profile, but antagonists at nicotinic [47], dopaminergic [48], and opioidergic [49] receptors have differentially blocked slow and fast oscillatory changes induced by nicotine administration. The pharmacological actions of CDP-choline have not been extensively investigated, but as preclinical reports have shown it to modulate catecholamine brain levels [50], and as ␣7 receptors have been found to modulate glutamatergic signaling in prefrontal cortex [51], these and other neurotransmitters may act separately or in concert to mediate EEG oscillatory response to CDP-choline. Muscarinic cholinergic receptors are also activated by CDP-choline administration [52] and may have been involved in the increase in alpha1 with CDP-choline, as muscarinic antagonist treatment prevents power increases in this oscillatory band with acute nicotine [47]. Cytidine, a metabolite of CDP-choline, also increases delta but reduces alpha oscillations [53]. EEG oscillations can provide novel insights into the neuronal mechanisms underlying cognitive processes and are associated with specific functional roles including the coding of specific sensory information, setting and modulating brain attentional states and communicating information between neuronal populations [54,55]. Although, the functional implications of CDP-choline modulated EEG signals for cognition and amelioration of cognitive impairment needs to be addressed, the physiological relevance of the oscillatory pattern change is potentially important for cognitive disorders related to pathology of cortical and thalamic structures, the sites of highest ␣7 nAChR expression [56]. An important link between oscillations and brain computations is the observation that oscillatory rhythms establish precise synchronization and coordination of neural responses in segregated processing areas [57]. Whereas neural synchronization in the high frequencies (and ␥-bands) is mediated mainly by cortico-cortical connections that reciprocally link cells located in the same cortical region, but also cells distributed across different receptors and hemispheres, subcortical structures, and especially in the thalamus, play a major role in the generation and synchronization of oscillations in the low frequency bands (,,˛) [58]. As activity in specific oscillatory bands or combination of bands has been linked with a variety of cognitive operations [59], aberrant brain oscillations in cognitive disorders may be useful intermediate targets for novel nicotinic treatments [60]. Combining EEG with imaging techniques such as fMRI and PET during resting and task-evoked states is an obvious next step for localizing the electrophysiological effects of CDPcholine and their cognitive significance.
5. Conclusions Healthy volunteers administered single doses of CDP-choline exhibited changes in EEG oscillations similar to those reported with nicotinic agonists. These altered brain oscillations have
implications for cognitive treatments but need to be interpreted within study limitations, including use of a relatively small sample that included only young adult male nonsmokers, the testing of a restricted dose range, and no attempt to examine effects of repeated doses. Acknowledgements This work was supported in part by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC #210572-152799-2001) to VK, and from the University of Ottawa Medical Research Fund (UMRF) to VK and AL. References [1] G. Weiss, Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline, Life Sci. 56 (1995) 637–660. [2] J. Secades, J. Lorenzo, Citicoline: pharmacological and clinical review , 2006 update, Methods Find. Exp. Clin. Pharmacol. (2006) 1–56 (Suppl B). [3] J. Saver, Citicoline: update on a premixing and widely available agent for neuroprotection and neurorepair, Rev. Neurol. Dis. 5 (2008) 167–177. [4] E. Levin, Complex relationships of nicotinic receptor actions and cognitive functions, Biochem. Pharmacol. 86 (2013) 1145–1152. [5] A. Singh, A. Potter, P. Newhouse, Nicotinic acetylcholine receptor system and neuropsychiatric disorders, J. Drugs 7 (2004) 1096–2103. [6] S. Babb, K. Appelmans, P. Renshaw, R. Wurtman, B. Cohen, Differential effect of CDP-choline on brain systolic choline levels in younger and older subjects as measured by proton magnetic resonance spectroscopy, Psychopharmacology 127 (1996) 88–94. [7] B. Cohen, P. Renshaw, A. Stoll, R. Wurtman, D. Yurgelun-Todd, S. Babb, Decreased brain choline uptake in older adults, JAMA 274 (1995) 902–907. [8] W. Millington, R. Wurtman, Choline administration elevates brain phosphorylcholine concentrations, J. Neurochem. 38 (1982) 1748–1752. [9] C. Michel, M. Murray, Towards the utilization of EEG as a brain imaging tool, Neuroimage 61 (2012) 371–385. [10] J. Leiser, M. Dunlop, Aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research, Biochem. Pharmacol. 81 (2011) 1408–1421. [11] B. Saletu, P. Anderer, G. Saletu-Zyhlarz, O. Arndol, R. Pascual-Marqui, Classification and evaluation of the pharmacodynamics of psychotropic drugs by single-lead pharmaco-EEG, EEG mapping and tomography (LORETA), Methods Find. Exp. Clin. Pharmacol. 24 (2002) 97–120. [12] V. Knott, Quantitative EEG methods and measures in human psychopharmacological research, Hum. Psychopharmacol. 15 (2000) 479–498. [13] V. Knott, Neuroelectric approach to the assessment of psychoactivity in comparative substance use, in: D. Warburton (Ed.), Addiction Controversies, Harwood Academic Pub., Switzerland, 1990, pp. 66–89. [14] V. Knott, P. Venables, EEG alpha correlates of non-smokers: smoking and smoking deprivation, Psychophysiology 14 (1977) 150–156. [15] V. Knott, Electroencephalographic characterization of cigarette smoking behaviour, Alcohol 24 (2001) 95–97. [16] M. Alkondon, E. Albuquerque, Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons I. Pharmacological and functional evidence for distinct structural subtypes, J. Pharmacol. Exp. Ther. 266 (1993) 1455–1473. [17 Z. Zhang, S. Vijayaraghavan, D. Berg, Neuronal acetylcholine receptors that bind ␣-bungarotoxin with high affinity functions as ligand sated ion channels, Neuron 12 (1994) 167–177. [18] J. Williams, M. Gibbon, M. First, R. Spitzer, M. Davies, J. Borus, M. Howes, J. Kane, H. Pope Jr, B. Rounsaville, The structured clinical interview for the DSM-III-R (SCIDII). Multisite test-retest reliability, Arch. Gen. Psychiatry 49 (1992) 630–636. [19] M. Maxwell, Family interview for genetic studies [FIGS]: manual for FIGS, in: Clinical Neurogenetics Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, 1992. [20] K. Cropsey, G. Eldridge, M. Weiver, G. Villalobos, M. Stitzer, Expired carbon monoxide levels in self-reported smokers and non-smokers in prison, Nicotine Tob. Res. 8 (2006) 633–659. [21] R. Wurtman, M. Regun, J. Ulus, L. Yu, Effect of oral CDP-choline on plasma choline and uridine levels in humans, Biochem. Pharmacol. 60 (2000) 989–992. [22] G. Chatrian, E. Lettich, P. Nelson, Ten percent electrode system for topographic studies of spontaneous and evoked EEG activity, Am. J. EEG Technol. 25 (1985) 83–92. [23] G. Winterer, M. Ziller, H. Dorn, K. Frick, C. Mulert, Y. Wuebben, W.M. Herrmann, R. Coppola, Schizophrenia: reduced signal-to-noise ratio and impaired phase-locking during information processing, Clin. Neurophysiol. 111 (2000) 837–849. [24] V. Knott, Dynamic EEG changes during cigarette smoking, Neuropsychobiology 19 (1988) 54–60.
V. Knott et al. / Neuroscience Letters 591 (2015) 121–125 [25] M. Lindgren, L. Molander, C. Vesbnan, E. Lunell, I. Rosen, Electroencephalographic effects of intravenous nicotine – a dose response study, Psychopharmacology 145 (1999) 342–350. [26] W. Pickworth, R. Herning, J. Henningfield, Electroencephalographic effects of nicotine chewing gum in humans, Pharmcol. Biochem. Behav. 25 (1986) 879–882. [27] V. Knott, M. Bossman, C. Mahoney, V. Ilivitsky, K. Court, Transdermal nicotine: single dose effects on mood EEG, performance, and event-related potentials, Pharmacol. Biochem. Behav. 63 (1999) 253–261. [28] C. Teter, B. Asfaw, N. Lisong, M. Lutz, E. Domino, S. Guthrie, Comparative effects of smoking and nasal nicotine, Eur. J. Pharmacol. 58 (2002) 309–314. [29] R. Ashare, M. Falcone, S. Lerman, Cognitive function during nicotine withdrawal: implications for nicotine dependence treatment, Neuropharmacology 76 (2014) 581–591. [30] J. Beaver, C. Long, D. Cole, M. Durran, L. Bannon, R. Michara, P. Matthews, The effects of nicotine replacement on cognitive brain activity during smoking withdrawal: studies with simultaneous fMRI/EEG, Neuropsychopharmacology 36 (2011) 1792–1800. [31] D. Cole, C. Beckmann, C. Long, P. Matthews, M. Durran, J. Beaver, Nicotine replacement in abstinent smokers improves cognitive withdrawal symptoms with modulation of resting brain network dynamics, Neuroimage 52 (2010) 590–599. [32] V. Knott, J. McIntosh, A. Millar, D. Fisher, C. Villeneuve, V. Ilivitsky, E. Horn, Nicotine and smoker status moderate brain electric and mood activation induced by ketamine: an N-methyl-d-aspartate (NMDA) receptor antagonist, Pharmacol. Biochem. Behav. 85 (2006) 228–242. [33] D. Fisher, N. Jaworska, R. Daniels, A. Knobelsdorf, V. Knott, Effects of acute nicotine administration on resting EEG in nonsmokers, Exp. Clin. Psychopharmacol. 20 (2012) 71–75. [34] J. Foulds, K. McSoreley, J. Sneddon, C. Feyerabend, M. Jarvis, M. Russell, Effects of subcutaneous nicotine injections on EEG alpha frequency in non-smokers. A placebo-controlled pilot study, Psychopharmacology 115 (1994) 163–166. [35] J. Rodriguez, U. Kallenbach, W. Singer, M. Munk, Short- and long-term effects of cholinergic modulation on gamma oscillations and response synchronization in the visual cortex, J. Neurosci. 24 (2004) 10369–10378. [36] E. Albuquerque, E. Peteira, M. Kondon, S. Rogers, Mammalian nicotinic acetylcholine receptors: from structure to function, Physiol. Rev. 89 (2009) 73–120. [37] J. Dani, D. Bertrand, Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system, Ann. Rev. Pharmacol. Toxicol. 47 (2007) 699–729. [38] H. Mansvelder, D. McGhee, Cellular and synaptic mechanisms of nicotine addiction, J. Neurobiol. 53 (2003) 606–617. [39] J. Wooltorton, V. Pidoplichka, R. Brosde, J. Dani, Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas, J. Neurosci. 23 (2003) 3176–3185. [40] M. Alkondon, E. Pereira, W. Cortes, A. Maelicke, E. Albuquerque, Choline is a selective agonist of alpha 7 nicotinic acetylcholine receptors in the rat brain neurons, Eur. J. Neurosci. 9 (1997) 2734–2742. [41] E. Albuquerque, E. Pereira, M. Draga, M. Alkondon, Contribution of nicotinic receptors to the function of synapses in the central nervous system: the action of choline as a selective agonist of alpha 7 receptors, J. Physiol. Paris 92 (1998) 309–316. [42] D. Fayuk, J. Yakel, Regulation of nicotinic acetylcholine receptor channel function by acetylcholinesterase inhibitors in rat hippocampal CA1 interneurons, Mol. Pharmacol. 66 (2004) 658–666. [43] G. Dunbar, P. Boeijinga, A. Demazieres, C. Cisterni, R. Kuchibbatla, K. Wesnes, R. Luthringer, Effects of TC-1734 (AZD3480) a selective neuronal nicotinic
[44 [45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54] [55] [56]
[57]
[58]
[59]
[60]
125
receptor agonist, on cognitive performance and the EEG of young healthy male volunteers, Psychopharmacology 191 (2007) 919–929. G. Dunbar, R. Kochibbatla, Cognitive enhancement in man with ispronicline: a nicotinic partial agonist, J. Mol. Neurosci. 30 (2006) 169–172. M. Perugini, C. Mahoney, V. Ilivitsky, S. Young, V. Knott, Effects of tryptophan depletion on acute smoking abstinence symptoms and the acute smoking response, Pharmacol. Biochem. Behav. 74 (2003) 513–522. V. Knott, M. Raegele, D. Fisher, N. Robertson, A. Millar, J. McIntosh, V. Ilivitsky, Clonidine pre-treatment fails to block acute smoking-induced EEG arousal/mood in cigarette smokers, Pharmacol. Biochem. Behav. 80 (2005) 161–171. V. Knott, A. Harr, V. Ilivitsky, C. Mahoney, The cholinergic basis of the smoking-induced EEG activation profile, Neuropsychobiology 38 (1998) 97–107. D. Walker, C. Mahoney, V. Ilivitsky, V. Knott, Effects of haloperidol pretreatment on the smoking-induced EEG/mood activation response profile, Neuropsychobiology 43 (2001) 102–112. V. Knott, D. Fisher, Naltexone alteration of the nicotine-induced EEG and mood activation response in tobacco-deprived cigarette smokers, Exp. Clin. Psychopharmacol. 15 (2007) 368–381. R. Conantt, A. Schauss, Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature, Altern. Med. Rev. 9 (2004) 17–31. Y. Yang, C. Paspalas, L. Jin, M. Picciotto, A. Arnsten, M. Wong, Nicotinic ␣7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 12678–12683. Y. Ilcol, M. Cansev, M. Sertac, Y. Ilmaz, E. Hamurtekin, J. Ulus, Peripheral administration of CDP-choline and its cholinergic metabolites increases serum insulin: muscarinic and nicotinic acetylcholine receptors are both involved in their actions, Neurosci. Lett. 43 (2008) 71–76. V. Gallai, G. Mazzotta, C. Firenze, S. Montesin, Fr. Del Gatto, Study of the P300 and cerebral maps in subjects with multi-infarct dementia treated with cytidine, Pharmacology 103 (1991) 1–5. F. Lopes da Silva, EEG and MEG: relevance to neuroscience, Neuron 80 (2013) 1112–1128. X.-J. Wang, Neurophysiological and computational principles of cortical rhythms, Physiol. Rev. 90 (2010) 1195–1268. A. Ettrur, J. Mikkelsen, S. Lehel, J. Madsen, E. Nielsen, M. Painer, D. Timmermann, D. Peters, G. Knudson, 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measures, J. Nucl. Med. 52 (2011) 1449–1456. P. Uhlhaas, G. Pipa, B. Lima, L. Melloni, S. Neuenschwander, D. Nikolic, W. Singer, Neural synchrony in cortical networks: history, concept and current status, Front. Integr. Neurosci. 3 (2009) 17. P. Uhlhaas, W. Singer, Abnormal synchrony and oscillations in neuropsychiatric disorders, in: M. Bianchi, V. Caviness, S. Cash (Eds.), Network Approaches to Disease of the Brain, Bentham Science Pub., Sharjah, U.A.E, 2014, pp. 81–99. E. Basar, B. Guntekin, Review of delta, theta, alpha, beta, and gamma response oscillations in neuropsychiatric disorders. In: Applications of Brain Oscillations in Neuropsychiatric Disorders, E., Basar, C. Basar-Eroglu, A., Ozerdem, P., Rossini, G. Yener (Eds.), Supplement to Clin. Neurophysiol., 62 (2013) 303-341. G. Buzsaki, B. Watson, Brain rhythms and neural syntax: Implications for efficient coding of cognitive content and neuropsychiatric disease, Dialog. Clin. Neurosci. 14 (2012) 345–367.
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Research article
Effects of acute CDP-choline treatment on resting state brain oscillations in healthy volunteers Verner Knott a,b,c,d,∗ , Sara de la Salle b , Dylan Smith c , Joelle Choueiry c , Danielle Impey b , Meaghan Smith b , Elise Beaudry b , Salman Saghir b , Vadim Ilivitsky d , Alain Labelle d a
University of Ottawa, Institute of Mental Health Research, Ottawa, ON, Canada School of Psychology, University of Ottawa, Ottawa, ON, Canada c Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada d Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada b
h i g h l i g h t s • CDP-choline affects human brain oscillations. • Oscillatory changes mimic nicotinic stimulation. • These observations allow extensions to clinical populations.
a r t i c l e
i n f o
Article history: Received 3 December 2014 Received in revised form 3 February 2015 Accepted 13 February 2015 Available online 17 February 2015 Keywords: Cytidine-5 -diphosphocholine Choline Nicotinic receptors Oscillations Cognition
a b s t r a c t CDP-choline (cytidine-5 -diphosphocholine) is a phospholipid used to treat cognitive disorders, presumably repairing and maintaining brain cell membranes. Additional mechanisms may include enhanced cholinergic neurotransmission as the ␣7 nicotinic receptor actions of choline and increased acetylcholine synthesis accompanying CDP-choline administration may modulate brain oscillations underlying cognitive processes. This study utilizes electroencephalographic (EEG) recordings in healthy volunteers to evaluate CDP-choline induction of an oscillatory response profile associated with nicotinic stimulation. Resting state EEG was acquired in 24 male volunteers administered low (500 mg) and moderate (1000 mg) doses of CDP-choline in a randomized placebo-controlled, crossover trial. Consistent with nicotinic agonist treatment, spectral analysis showed dose-dependent reductions in delta and increases in alpha oscillations, which were also accompanied by decreases in beta and gamma oscillatory activity. These findings support the posit that CDP-choline cognitive enhancement involves multiple mechanisms including facilitated nicotinic cholinergic action. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction CDP-choline, or citicoline is endogenous, an essential intermediate in the biosynthesis of structural phospholipids, chiefly phosphatidylcholine (PtdCho), in brain cell membranes [1]. CDPcholine treatment has shown clinical efficacy for cognitive disorders associated with cerebral vascular disease, head trauma, degenerative diseases (e.g., Alzheimer’s disease) and normal aging [2]. Although its suggested pharmacological action has been the restoration of phospholipid biosynthesis, with PtdCho helping to restore and preserve the structure/function integrity of neuronal
∗ Corresponding author at: University of Ottawa, Institute of Mental Health Research at the Royal Ottawa Mental Health Care Centre, 1145 Carling Avenue, Ottawa, Ontario K1Z 7K4, Canada. Tel.: +1 613 722 6521. E-mail address: [email protected] (V. Knott). http://dx.doi.org/10.1016/j.neulet.2015.02.032 0304-3940/© 2015 Elsevier Ireland Ltd. All rights reserved.
membranes in the damaged brain [3], its action appears to involve mechanisms beyond phospholipid metabolism. CDP-choline is a form of the essential nutrient choline, a precursor of PtdCho as well as a donor in the metabolic pathways for biosynthesis of the neurotransmitter acetylcholine (ACh). Both ACh and its precursor, choline, are full agonists at nicotinic acetylcholine receptors (nAChRs), which play a critical role in normal cognition and are promising targets for novel treatments of cognitive dysfunction [4,5]. Oral administration of single doses of CDP-choline [6] and choline [7] increase plasma choline levels, as well as extracellular free choline in the brain as measured by magnetic resonance spectroscopy, but the presumed major quantitative fate of brain choline – rapid intracellular uptake and metabolic conversion to choline-bound phospholipids, not to ACh, may attenuate the marked cholinergic-related functional changes that would otherwise occur with the free ACh [8].
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Putative cholinergic actions associated with CDP-choline may be investigated noninvasively with quantitative electroencephalography (EEG), a neuroimaging tool [9] frequently used during the preclinical and clinical stages of drug discovery [10]. Distinct pharmaco-EEG profiles are associated with the pharmacodynamic actions of different classes of drugs [11,12] including nicotinic agonists such as nicotine, which in smokers induces a stimulant-like [13] electrocerebral activation pattern in spectral EEGs – accelerating the dominant oscillatory frequency, and increasing power of high frequency oscillations (alpha, beta, gamma) while decreasing power in low frequency oscillations (delta, theta) [14,15]. This study aims to assess the pharmaco-EEG profile of single oral doses of CDP-choline to healthy non-smoking volunteers, specifically evaluating the consistency of spectral EEG changes with nAChR stimulation. Although CDP-choline’s clinically recommended dose range is 500–4000 mg, the range here was 500 and 1000 mg as nAChR activation is most evident with relatively low agonist concentrations, while high concentrations promote nAChR desensitization [16,17]. 2. Methods 2.1. Participants The study involved 24 healthy, right-handed males with a mean age of 21.3 years (SE = 0.99) recruited via local advertisements. Participants were screened initially by telephone and then by personal interview which included a medical exam and a personal and family psychiatric history assessment using the SCID-NP (Structured Clinical Interview–Nonpatient version for DSM-IV [18]) and FIGS (Family Interview for Genetic Studies [19]), respectively. Acceptance required no current medical or neurological illnesses, no personal or family psychiatric history (including substance abuse/dependence) and no use of medications. All were required to be nonsmokers, smoking less than 100 cigarettes in their lifetime (none in the past year) and exhibiting an expired air carbon monoxide level ≤ 3 parts per million, consistent with a nonsmoker status [20]. Participants were on normal diets, and reported no nutritionrelated medical problems. All signed an informed consent for the study, which was approved by the research ethics board of the Royal Ottawa Mental Health Care Group. 2.2. Design Participants were assessed in three test sessions (placebo and two doses of CDP-choline) conducted within a randomized, doubleblind, crossover design, with session order being counterbalanced and each session being separated by 8–12 days to allow for CDPcholine elimination. 2.3. Procedures Morning test sessions were between 9:00 a.m. and 11:00 a.m. following overnight abstinence from drugs, vitamins, food, and caffeine. Testing was initiated 4 h after treatment initiation and ended with assessment of adverse events and vital signs. 2.4. Treatment CDP-choline was administered orally in two active doses, 500 mg (2 × 250 mg capsules) and 1000 mg (4 × 250 mg capsules) using a “double dummy” approach in which 4 capsules were administered in each test session (e.g., 2 placebo capsules and 2 × 250 mg capsules comprised the 500 mg test dose condition), including the placebo (cellulose) session. Single doses of CDP-choline
dose-dependently raise choline plasma levels (peaking at 3–5 h), with an elimination half-life extending up to 56 h [21]. 2.5. EEG Three minutes of eyes-closed, vigilance-controlled resting state EEG activity was acquired in reference to the nose electrode, with scalp electrodes positioned at 8 regions (F3, Fz, F4, Cz, P3, Pz, P4, Oz) according to the 10–10 system [22]. An electrode at the midforehead site served as ground, and electrodes on orbital ridges and external canthi were used to monitor vertical (VEOG) and horizontal (HEOG) electro-oculographic activity. Electrode impedances were kept below 5 k and amplified signals (0.1–40.0 Hz amplifier bandpass filter) were digitized at 256 Hz. A minimum of 45 artifact-free 2-s duration EEG epochs were subjected to a Fast Fourier Transform algorithm (with a high-pass autoregressive filter, weighted by a 5% cosine taper) for computation of average absolute power (V2 ) in eight frequency bands as used previously [23] and include: delta (0.5–5 Hz); theta (6–8 Hz); alpha1 (8.5–10 Hz); alpha2 (10.5–12 Hz); alpha total (8.5–12 Hz); beta1 (12.5–18 Hz); beta2 (18.5–20.5 Hz) and beta3 (21–30 Hz) frequency bands at each scalp region. Spontaneous gamma oscillations (30–60 Hz) in humans have not been systematically examined with respect to nicotine but were included here as an exploratory focus, with emphasis on absolute power. 2.6. Analysis The Statistical Package for Social Sciences (SPSS, Chicago, IL) software was used to analyze log transformed absolute and relative (%) power value changes induced by CDP-choline treatment at the 8 scalp regions. Relative power values were derived by expressing power in each band as a percent of total power across all bands. Analysis of each absolute and relative band power index involved a separate repeated measures analysis of variance (ANOVA) with treatment (3 levels) and region (8 levels) as within-subject factors. Greenhouse–Geisser corrections were applied to all significant (p < 0.05) main and interaction effects, and Bonferroni-adjusted corrections were used in follow-up comparisons. To reduce the number of type I statistical errors, region affects were not followed up unless they interacted with treatment. 3. Results There were no significant serious adverse events associated with CDP-choline (vs. placebo) and no adverse events led to discontinuation from the study. Heart rate and blood pressure vital signs were not affected by CDP-choline treatment. Absolute power in the delta band was significantly affected by treatment (F = 3.64, df = 2/42, p < 0.041) and region (F = 28.83, df = 7/147, p < 0.0001). Compared to placebo, power was reduced (p < 0.03) with both doses of CDP-choline but reached significance only with the 1000 mg dose (Fig. 1). No significant treatmentinduced changes were observed for absolute power in theta and alpha bands but significant treatment x region interactions were shown with power in beta2 (F = 2.39, df = 14/294, p < 0.05) and beta3 bands (F = 2.55, df = 14/294, p < 0.04). For beta2 , power at F3 was reduced by the 1000 mg dose compared to both placebo (p < 0.05) and the 500 mg doses (p < 0.02), and similar reductions with 1000 mg were shown at F4 when compared to the placebo (p < 0.04) and 500 mg CDP-choline (p < 0.04) doses (Fig. 2). Power reductions were also evidenced at C3 (p < 0.04) but with the 1000 mg dose reducing power only when compared to placebo (Fig. 1). Beta3 power was also reduced at F3 (p < 0.05) and F4 (p < 0.05), as well as at C4 (p < 0.03) with the 1000 mg dose compared to placebo (Fig. 2). Follow-up comparisons of a significant
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Fig. 1. Mean (±SE) values (collapsed across sites) for absolute delta and relative delta, alpha1 , and alpha total power for each frequency band in the 3 test sessions (placebo and CDP-choline: 500 mg, 1000 mg) are shown in bar graphs.
treatment x region interaction (F = 3.27, df = 14/294, p < 0.01) found gamma to be reduced by the 1000 mg dose (vs. placebo) at F3 (p < 0.05), F4 (p < 0.05) and C4 (p < 0.05) scalp sites (Fig. 2). Relative power showed significant treatment effects with delta (F = 3.54, df = 2/42, p < 0.05), alpha1 (F = 4.56, df = 2/42, p < 0.02) and alpha total (F = 4.67, df = 2/42, p < 0.03) bands (Fig. 1). Reductions in relative delta appeared with both CDP-choline doses (vs. placebo) but were significant only with 1000 mg (p < 0.04). Alpha1 increases were found with both the 500 mg (p < 0.05) and 1000 mg (p < 0.02) doses of CDP-choline compared to placebo. Alpha total was similarly affected by CDP-choline (vs. placebo), being increased with both 500 mg (p < 0.05) and 1000 mg (p < 0.03) doses. Relative beta and gamma were not affected by treatment. 4. Discussion In this study, electrophysiological evidence showed that acute oral administration of CDP-choline penetrated the brain of healthy volunteers and altered resting state oscillatory activity. Oscillations in slow (delta) and several fast (alpha, beta) EEG bands were significantly changed with relatively low (500 mg) and moderate (1000 mg) doses, and both the reductions in delta and the increases in alpha oscillatory activity are consistent with nAChR agonism as a possible mechanism of action of CDP-choline in the human brain. Single doses of smoke-inhaled [24], intravenous [25], oral (gum) [26], transdermal [27], and nasal nicotine [28], the prototypical nAChR agonist, consistently induce a rightward shift in EEG power spectrum activity, with the resulting pharmaco-EEG profile being characterized by power suppression in slow frequency oscillations, an increased dominant (alpha) frequency, and power augmentation in fast oscillations. As these acute EEG alterations are usually observed in healthy smokers following smoking abstinence, which itself is associated with a sedation-like EEG pattern (i.e., leftward power spectrum shift to slow oscillations, predominantly theta), they likely reflect a “remediation” of a deficiency that may accompany the general disturbance in neural networks seen during acute nicotine withdrawal in chronic smokers [29–31]. In the few EEG resting state studies administering nicotine to nonsmokers, power reductions in theta [32] or power increments in alpha [33,34] have been reported without changes in delta or beta oscillatory power. Although the present findings with CDP-choline in healthy nonsmokers also showed increased power of alpha-band oscillations,
Fig. 2. Significant topographical absolute power changes induced by 1000 mg CDPcholine (vs. placebo) are displayed in color format. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
these changes were accompanied by reductions of both delta and beta oscillatory activity, resulting in a distinct pharmaco-EEG profile (vs. nicotine) in nonsmokers which may reflect the separate and combined actions of choline and ACh on brain nAChRs. This pharmaco-EEG profile was accompanied by power decreases in gamma and, to the best of our knowledge, this is the first time that spontaneous gamma has been shown to be modulated by an ␣7 nicotinic agonist in humans, supporting preclinical evidence of a role for cholinergic modulation in gamma oscillations [35]. nAChRs are expressed throughout the cortex and although there are many nAChR subtypes, the most abundant are heteromeric receptors that contain ␣4 and 2 subunits, or are homomeric receptors containing ␣7 subunits [36,37]. While the ␣42 nAChR containing subunits show high sensitivity/affinity to ACh and nicotine (i.e., non-selective agonists) and desensitize relatively slowly, ␣7 subunits have lower affinity for ACh and nicotine and exhibit rapid desensitization kinetics, but not at low nicotinic agonist concentrations [38,39]. Choline is a full selective agonist at ␣7 receptors, but not other nicotinic receptors subtypes, and choline-evoked electrophysiological responses from single cells are blocked by selective ␣7 antagonists [40–42]. The relatively minimal
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increase in free choline concentration in brain with low/moderate dosing of oral CDP-choline, due in part to rapid choline phosphorylation, may be sufficient to induce (and maintain) ␣7 receptor activation. These selective actions of choline may act additively or synergistically with synthesized ACh acting at ␣42 receptors, modulating oscillatory activity in different bands depending on the abundance, location, and conformational state of the receptors. EEG studies have not been reported with ␣7 agonist agents but the few investigations with selective ␣42 agonists have shown single doses to reduce delta, theta, and alpha1 oscillations and to increase dominant frequency and fast alpha [43–45]. Activation of nAChRs facilitates the release of multiple neurotransmitters and their role in nicotinic-modulated oscillatory activity has been investigated in a number of human pharmacological studies. Serotonin [44], norepinephrine [46], and glutamate [33] have been shown not to contribute to nicotine’s pharmacoEEG profile, but antagonists at nicotinic [47], dopaminergic [48], and opioidergic [49] receptors have differentially blocked slow and fast oscillatory changes induced by nicotine administration. The pharmacological actions of CDP-choline have not been extensively investigated, but as preclinical reports have shown it to modulate catecholamine brain levels [50], and as ␣7 receptors have been found to modulate glutamatergic signaling in prefrontal cortex [51], these and other neurotransmitters may act separately or in concert to mediate EEG oscillatory response to CDP-choline. Muscarinic cholinergic receptors are also activated by CDP-choline administration [52] and may have been involved in the increase in alpha1 with CDP-choline, as muscarinic antagonist treatment prevents power increases in this oscillatory band with acute nicotine [47]. Cytidine, a metabolite of CDP-choline, also increases delta but reduces alpha oscillations [53]. EEG oscillations can provide novel insights into the neuronal mechanisms underlying cognitive processes and are associated with specific functional roles including the coding of specific sensory information, setting and modulating brain attentional states and communicating information between neuronal populations [54,55]. Although, the functional implications of CDP-choline modulated EEG signals for cognition and amelioration of cognitive impairment needs to be addressed, the physiological relevance of the oscillatory pattern change is potentially important for cognitive disorders related to pathology of cortical and thalamic structures, the sites of highest ␣7 nAChR expression [56]. An important link between oscillations and brain computations is the observation that oscillatory rhythms establish precise synchronization and coordination of neural responses in segregated processing areas [57]. Whereas neural synchronization in the high frequencies (and ␥-bands) is mediated mainly by cortico-cortical connections that reciprocally link cells located in the same cortical region, but also cells distributed across different receptors and hemispheres, subcortical structures, and especially in the thalamus, play a major role in the generation and synchronization of oscillations in the low frequency bands (,,˛) [58]. As activity in specific oscillatory bands or combination of bands has been linked with a variety of cognitive operations [59], aberrant brain oscillations in cognitive disorders may be useful intermediate targets for novel nicotinic treatments [60]. Combining EEG with imaging techniques such as fMRI and PET during resting and task-evoked states is an obvious next step for localizing the electrophysiological effects of CDPcholine and their cognitive significance.
5. Conclusions Healthy volunteers administered single doses of CDP-choline exhibited changes in EEG oscillations similar to those reported with nicotinic agonists. These altered brain oscillations have
implications for cognitive treatments but need to be interpreted within study limitations, including use of a relatively small sample that included only young adult male nonsmokers, the testing of a restricted dose range, and no attempt to examine effects of repeated doses. Acknowledgements This work was supported in part by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC #210572-152799-2001) to VK, and from the University of Ottawa Medical Research Fund (UMRF) to VK and AL. References [1] G. Weiss, Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline, Life Sci. 56 (1995) 637–660. [2] J. Secades, J. Lorenzo, Citicoline: pharmacological and clinical review , 2006 update, Methods Find. Exp. Clin. Pharmacol. (2006) 1–56 (Suppl B). [3] J. Saver, Citicoline: update on a premixing and widely available agent for neuroprotection and neurorepair, Rev. Neurol. Dis. 5 (2008) 167–177. [4] E. Levin, Complex relationships of nicotinic receptor actions and cognitive functions, Biochem. Pharmacol. 86 (2013) 1145–1152. [5] A. Singh, A. Potter, P. Newhouse, Nicotinic acetylcholine receptor system and neuropsychiatric disorders, J. Drugs 7 (2004) 1096–2103. [6] S. Babb, K. Appelmans, P. Renshaw, R. Wurtman, B. Cohen, Differential effect of CDP-choline on brain systolic choline levels in younger and older subjects as measured by proton magnetic resonance spectroscopy, Psychopharmacology 127 (1996) 88–94. [7] B. Cohen, P. Renshaw, A. Stoll, R. Wurtman, D. Yurgelun-Todd, S. Babb, Decreased brain choline uptake in older adults, JAMA 274 (1995) 902–907. [8] W. Millington, R. Wurtman, Choline administration elevates brain phosphorylcholine concentrations, J. Neurochem. 38 (1982) 1748–1752. [9] C. Michel, M. Murray, Towards the utilization of EEG as a brain imaging tool, Neuroimage 61 (2012) 371–385. [10] J. Leiser, M. Dunlop, Aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research, Biochem. Pharmacol. 81 (2011) 1408–1421. [11] B. Saletu, P. Anderer, G. Saletu-Zyhlarz, O. Arndol, R. Pascual-Marqui, Classification and evaluation of the pharmacodynamics of psychotropic drugs by single-lead pharmaco-EEG, EEG mapping and tomography (LORETA), Methods Find. Exp. Clin. Pharmacol. 24 (2002) 97–120. [12] V. Knott, Quantitative EEG methods and measures in human psychopharmacological research, Hum. Psychopharmacol. 15 (2000) 479–498. [13] V. Knott, Neuroelectric approach to the assessment of psychoactivity in comparative substance use, in: D. Warburton (Ed.), Addiction Controversies, Harwood Academic Pub., Switzerland, 1990, pp. 66–89. [14] V. Knott, P. Venables, EEG alpha correlates of non-smokers: smoking and smoking deprivation, Psychophysiology 14 (1977) 150–156. [15] V. Knott, Electroencephalographic characterization of cigarette smoking behaviour, Alcohol 24 (2001) 95–97. [16] M. Alkondon, E. Albuquerque, Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons I. Pharmacological and functional evidence for distinct structural subtypes, J. Pharmacol. Exp. Ther. 266 (1993) 1455–1473. [17 Z. Zhang, S. Vijayaraghavan, D. Berg, Neuronal acetylcholine receptors that bind ␣-bungarotoxin with high affinity functions as ligand sated ion channels, Neuron 12 (1994) 167–177. [18] J. Williams, M. Gibbon, M. First, R. Spitzer, M. Davies, J. Borus, M. Howes, J. Kane, H. Pope Jr, B. Rounsaville, The structured clinical interview for the DSM-III-R (SCIDII). Multisite test-retest reliability, Arch. Gen. Psychiatry 49 (1992) 630–636. [19] M. Maxwell, Family interview for genetic studies [FIGS]: manual for FIGS, in: Clinical Neurogenetics Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, 1992. [20] K. Cropsey, G. Eldridge, M. Weiver, G. Villalobos, M. Stitzer, Expired carbon monoxide levels in self-reported smokers and non-smokers in prison, Nicotine Tob. Res. 8 (2006) 633–659. [21] R. Wurtman, M. Regun, J. Ulus, L. Yu, Effect of oral CDP-choline on plasma choline and uridine levels in humans, Biochem. Pharmacol. 60 (2000) 989–992. [22] G. Chatrian, E. Lettich, P. Nelson, Ten percent electrode system for topographic studies of spontaneous and evoked EEG activity, Am. J. EEG Technol. 25 (1985) 83–92. [23] G. Winterer, M. Ziller, H. Dorn, K. Frick, C. Mulert, Y. Wuebben, W.M. Herrmann, R. Coppola, Schizophrenia: reduced signal-to-noise ratio and impaired phase-locking during information processing, Clin. Neurophysiol. 111 (2000) 837–849. [24] V. Knott, Dynamic EEG changes during cigarette smoking, Neuropsychobiology 19 (1988) 54–60.
V. Knott et al. / Neuroscience Letters 591 (2015) 121–125 [25] M. Lindgren, L. Molander, C. Vesbnan, E. Lunell, I. Rosen, Electroencephalographic effects of intravenous nicotine – a dose response study, Psychopharmacology 145 (1999) 342–350. [26] W. Pickworth, R. Herning, J. Henningfield, Electroencephalographic effects of nicotine chewing gum in humans, Pharmcol. Biochem. Behav. 25 (1986) 879–882. [27] V. Knott, M. Bossman, C. Mahoney, V. Ilivitsky, K. Court, Transdermal nicotine: single dose effects on mood EEG, performance, and event-related potentials, Pharmacol. Biochem. Behav. 63 (1999) 253–261. [28] C. Teter, B. Asfaw, N. Lisong, M. Lutz, E. Domino, S. Guthrie, Comparative effects of smoking and nasal nicotine, Eur. J. Pharmacol. 58 (2002) 309–314. [29] R. Ashare, M. Falcone, S. Lerman, Cognitive function during nicotine withdrawal: implications for nicotine dependence treatment, Neuropharmacology 76 (2014) 581–591. [30] J. Beaver, C. Long, D. Cole, M. Durran, L. Bannon, R. Michara, P. Matthews, The effects of nicotine replacement on cognitive brain activity during smoking withdrawal: studies with simultaneous fMRI/EEG, Neuropsychopharmacology 36 (2011) 1792–1800. [31] D. Cole, C. Beckmann, C. Long, P. Matthews, M. Durran, J. Beaver, Nicotine replacement in abstinent smokers improves cognitive withdrawal symptoms with modulation of resting brain network dynamics, Neuroimage 52 (2010) 590–599. [32] V. Knott, J. McIntosh, A. Millar, D. Fisher, C. Villeneuve, V. Ilivitsky, E. Horn, Nicotine and smoker status moderate brain electric and mood activation induced by ketamine: an N-methyl-d-aspartate (NMDA) receptor antagonist, Pharmacol. Biochem. Behav. 85 (2006) 228–242. [33] D. Fisher, N. Jaworska, R. Daniels, A. Knobelsdorf, V. Knott, Effects of acute nicotine administration on resting EEG in nonsmokers, Exp. Clin. Psychopharmacol. 20 (2012) 71–75. [34] J. Foulds, K. McSoreley, J. Sneddon, C. Feyerabend, M. Jarvis, M. Russell, Effects of subcutaneous nicotine injections on EEG alpha frequency in non-smokers. A placebo-controlled pilot study, Psychopharmacology 115 (1994) 163–166. [35] J. Rodriguez, U. Kallenbach, W. Singer, M. Munk, Short- and long-term effects of cholinergic modulation on gamma oscillations and response synchronization in the visual cortex, J. Neurosci. 24 (2004) 10369–10378. [36] E. Albuquerque, E. Peteira, M. Kondon, S. Rogers, Mammalian nicotinic acetylcholine receptors: from structure to function, Physiol. Rev. 89 (2009) 73–120. [37] J. Dani, D. Bertrand, Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system, Ann. Rev. Pharmacol. Toxicol. 47 (2007) 699–729. [38] H. Mansvelder, D. McGhee, Cellular and synaptic mechanisms of nicotine addiction, J. Neurobiol. 53 (2003) 606–617. [39] J. Wooltorton, V. Pidoplichka, R. Brosde, J. Dani, Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas, J. Neurosci. 23 (2003) 3176–3185. [40] M. Alkondon, E. Pereira, W. Cortes, A. Maelicke, E. Albuquerque, Choline is a selective agonist of alpha 7 nicotinic acetylcholine receptors in the rat brain neurons, Eur. J. Neurosci. 9 (1997) 2734–2742. [41] E. Albuquerque, E. Pereira, M. Draga, M. Alkondon, Contribution of nicotinic receptors to the function of synapses in the central nervous system: the action of choline as a selective agonist of alpha 7 receptors, J. Physiol. Paris 92 (1998) 309–316. [42] D. Fayuk, J. Yakel, Regulation of nicotinic acetylcholine receptor channel function by acetylcholinesterase inhibitors in rat hippocampal CA1 interneurons, Mol. Pharmacol. 66 (2004) 658–666. [43] G. Dunbar, P. Boeijinga, A. Demazieres, C. Cisterni, R. Kuchibbatla, K. Wesnes, R. Luthringer, Effects of TC-1734 (AZD3480) a selective neuronal nicotinic
[44 [45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54] [55] [56]
[57]
[58]
[59]
[60]
125
receptor agonist, on cognitive performance and the EEG of young healthy male volunteers, Psychopharmacology 191 (2007) 919–929. G. Dunbar, R. Kochibbatla, Cognitive enhancement in man with ispronicline: a nicotinic partial agonist, J. Mol. Neurosci. 30 (2006) 169–172. M. Perugini, C. Mahoney, V. Ilivitsky, S. Young, V. Knott, Effects of tryptophan depletion on acute smoking abstinence symptoms and the acute smoking response, Pharmacol. Biochem. Behav. 74 (2003) 513–522. V. Knott, M. Raegele, D. Fisher, N. Robertson, A. Millar, J. McIntosh, V. Ilivitsky, Clonidine pre-treatment fails to block acute smoking-induced EEG arousal/mood in cigarette smokers, Pharmacol. Biochem. Behav. 80 (2005) 161–171. V. Knott, A. Harr, V. Ilivitsky, C. Mahoney, The cholinergic basis of the smoking-induced EEG activation profile, Neuropsychobiology 38 (1998) 97–107. D. Walker, C. Mahoney, V. Ilivitsky, V. Knott, Effects of haloperidol pretreatment on the smoking-induced EEG/mood activation response profile, Neuropsychobiology 43 (2001) 102–112. V. Knott, D. Fisher, Naltexone alteration of the nicotine-induced EEG and mood activation response in tobacco-deprived cigarette smokers, Exp. Clin. Psychopharmacol. 15 (2007) 368–381. R. Conantt, A. Schauss, Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature, Altern. Med. Rev. 9 (2004) 17–31. Y. Yang, C. Paspalas, L. Jin, M. Picciotto, A. Arnsten, M. Wong, Nicotinic ␣7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 12678–12683. Y. Ilcol, M. Cansev, M. Sertac, Y. Ilmaz, E. Hamurtekin, J. Ulus, Peripheral administration of CDP-choline and its cholinergic metabolites increases serum insulin: muscarinic and nicotinic acetylcholine receptors are both involved in their actions, Neurosci. Lett. 43 (2008) 71–76. V. Gallai, G. Mazzotta, C. Firenze, S. Montesin, Fr. Del Gatto, Study of the P300 and cerebral maps in subjects with multi-infarct dementia treated with cytidine, Pharmacology 103 (1991) 1–5. F. Lopes da Silva, EEG and MEG: relevance to neuroscience, Neuron 80 (2013) 1112–1128. X.-J. Wang, Neurophysiological and computational principles of cortical rhythms, Physiol. Rev. 90 (2010) 1195–1268. A. Ettrur, J. Mikkelsen, S. Lehel, J. Madsen, E. Nielsen, M. Painer, D. Timmermann, D. Peters, G. Knudson, 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measures, J. Nucl. Med. 52 (2011) 1449–1456. P. Uhlhaas, G. Pipa, B. Lima, L. Melloni, S. Neuenschwander, D. Nikolic, W. Singer, Neural synchrony in cortical networks: history, concept and current status, Front. Integr. Neurosci. 3 (2009) 17. P. Uhlhaas, W. Singer, Abnormal synchrony and oscillations in neuropsychiatric disorders, in: M. Bianchi, V. Caviness, S. Cash (Eds.), Network Approaches to Disease of the Brain, Bentham Science Pub., Sharjah, U.A.E, 2014, pp. 81–99. E. Basar, B. Guntekin, Review of delta, theta, alpha, beta, and gamma response oscillations in neuropsychiatric disorders. In: Applications of Brain Oscillations in Neuropsychiatric Disorders, E., Basar, C. Basar-Eroglu, A., Ozerdem, P., Rossini, G. Yener (Eds.), Supplement to Clin. Neurophysiol., 62 (2013) 303-341. G. Buzsaki, B. Watson, Brain rhythms and neural syntax: Implications for efficient coding of cognitive content and neuropsychiatric disease, Dialog. Clin. Neurosci. 14 (2012) 345–367.