Psychopharmacology (2015) 232:733–744 DOI 10.1007/s00213-014-3706-z
ORIGINAL INVESTIGATION
Dose-dependent effects of intravenous alcohol administration on cerebral blood flow in young adults Nicole M. Strang & Eric D. Claus & Vijay A. Ramchandani & Ariel Graff-Guerrero & Isabelle Boileau & Christian S. Hendershot
Received: 2 May 2014 / Accepted: 31 July 2014 / Published online: 12 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Rationale Functional magnetic resonance imaging (fMRI) studies involving alcohol challenge are important for identifying neural correlates of alcohol’s psychopharmacological effects. However, evaluating acute alcohol effects on blood oxygen level-dependent (BOLD) signal change is complicated by alcohol-related increases in cerebral blood flow (CBF). Objectives The present study aimed to further characterize acute alcohol effects on CBF using intravenous alcohol administration to maximize control over brain alcohol exposure. Methods Twenty heavy-drinking young adults (M = 19.95 years old, SD=0.76) completed alcohol and placebo imaging sessions in a within-subject, counter-balanced, placebo-controlled design. Arterial spin labeling (ASL) provided estimates of perfusion change at two target blood alcohol concentrations (40 and 80 mg%) relative to baseline and relative to a saline control infusion.
Results Voxel-wise analyses showed widespread and dosedependent effects of alcohol on CBF increase. Region-ofinterest analyses confirmed these findings, also indicating regional variation in the magnitude of perfusion change. Additional findings indicated that lower self-reported sensitivity to alcohol corresponded with reduced perfusion change during alcohol administration. Conclusions This study provides further evidence for widespread effects of acute alcohol on cerebral perfusion, also demonstrating regional, dose-dependent, and inter-individual variation. Further research is needed to evaluate implications of these effects for the design and interpretation of pharmacological fMRI studies involving alcohol challenge.
Electronic supplementary material The online version of this article (doi:10.1007/s00213-014-3706-z) contains supplementary material, which is available to authorized users.
Advances in human neuroimaging paradigms have allowed progress in characterizing functional and structural brain correlates of alcohol use and alcohol dependence (Bühler and Mann 2011). An increasing number of studies have integrated alcohol challenge and neuroimaging methods (Bjork and Gilman 2013), generating novel information about acute alcohol effects on neural correlates of cognitive control (Anderson et al. 2010; Marinkovic et al. 2012b; Kareken et al. 2013; Gan et al. 2014), affective processing (Gilman et al. 2008, 2012), and genetic moderators of pharmacodynamic effects (Ramchandani et al. 2011; Kareken et al. 2013). Despite increased attention to these questions, knowledge about acute alcohol effects on neuroimaging phenotypes remains limited overall (e.g., Rickenbacher et al. 2011; Marinkovic et al. 2012a). Functional magnetic resonance imaging (fMRI) studies typically rely on the blood oxygen level-dependent (BOLD) signal, an indirect measure of neuronal activity (Logothetis and Pfeuffer 2004) that is influenced by a number of factors,
N. M. Strang : A. Graff-Guerrero : I. Boileau : C. S. Hendershot (*) Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, 100 Stokes Street, Toronto, ON M6J 1H4, Canada e-mail: [email protected] E. D. Claus The Mind Research Network and Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM, USA V. A. Ramchandani Section on Human Psychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA A. Graff-Guerrero : I. Boileau : C. S. Hendershot Department of Psychiatry, University of Toronto, Toronto, ON, Canada
Keywords Alcohol intoxication . Alcohol clamp . Alcohol sensitivity . Cerebral perfusion . FMRI . Self-rating of the effects of alcohol
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including cerebral blood flow (CBF). An important consideration for psychopharmacological fMRI studies is the degree to which drug challenge alters resting CBF. This issue is particularly relevant for alcohol challenge studies given that alcohol (a vasodilator) reliably increases CBF (for review see Marxen et al. 2014; Rickenbacher et al. 2011). Because differences in BOLD activation as a function of alcohol administration may reflect changes in neuronal activity, CBF, or both, characterizing acute alcohol effects on CBF has implications for the design and interpretation of psychopharmacological fMRI studies involving alcohol challenge (Rickenbacher et al. 2011). Acute alcohol effects on CBF have been evaluated using several imaging methods. Early studies reported increases in CBF subsequent to alcohol administration using positron emission tomography (PET), single-photon emission computed tomography (SPECT), and the Xe-133 technique (Newlin et al. 1982; Mathew and Wilson 1986; Sano et al. 1993; Volkow et al. 1988; Schwartz et al. 1993; Tiihonen et al. 1994). In addition to consistent findings of alcohol-related increases in CBF, some findings suggested regional variability in the effect of alcohol on CBF (Newlin et al. 1982; Volkow et al. 1988; Tiihonen et al. 1994). More recently, the development of arterial spin labeling (ASL) has permitted noninvasive investigations of CBF using MRI. The principle of ASL is that blood in the carotid arteries is magnetically labeled (tagged) using radio-frequency pulses. The labeled blood then acts like a contrast agent as it perfuses through the brain, enabling quantification of regional blood flow (Liu and Brown 2007). To date, the few ASL studies examining acute effects of alcohol on CBF have produced somewhat mixed results. Although all placebo-controlled investigations have reported alcohol-related increases in CBF (Khalili-Mahani et al. 2011; Tolentino et al. 2011; Rickenbacher et al. 2011; Marxen et al. 2014), one investigation reported that the increase in CBF was only present for half the participants (Khalili-Mahani et al. 2011) and another study reported the increase in CBF was present for men, but not women (Rickenbacher et al. 2011). Initial evidence also suggests that alcohol-induced perfusion may vary based on individual differences relevant to the etiology of alcohol use disorders. For example, those classified as having lower sensitivity to alcohol showed attenuated CBF change in response to alcohol versus placebo (Tolentino et al. 2011). Other findings suggested that alcohol-related CBF change correlated with a measure of antisocial personality, perhaps consistent with differences in alcohol-related dopamine response as a function of impulsive traits (Rickenbacher et al. 2011). Most neuroimaging studies of alcohol and CBF have relied on oral alcohol administration, which is associated with high variability in blood alcohol concentration (BAC) profiles due to large individual differences in alcohol pharmacokinetics
Psychopharmacology (2015) 232:733–744
(Ramchandani et al. 1999; Zimmermann et al. 2013). This variability can pose a particular barrier for neuroimaging paradigms, during which breath alcohol concentration (BrAC) measurements are often not feasible. Moreover, imaging protocols are often time-intensive, resulting in changes in blood alcohol limb (ascending vs. descending) during data collection. Given evidence that alcohol-induced CBF changes vary by BAC level (Volkow et al. 1988; Sano et al. 1993), oral alcohol administration can be considered a limitation of most prior studies. Intravenous alcohol administration can address many of these barriers by circumventing primary sources of between-subject variability, including absorption and firstpass metabolism. Additionally, alcohol clamp procedures (O’Connor et al. 1998; Ramchandani et al. 1999) can be used to achieve pseudo-constant BAC during neuroimaging paradigms (e.g., Gilman et al. 2008, 2012; Kareken et al. 2013; Ramchandani et al. 2011). A recent ASL study involving intravenous alcohol administration reported increases in CBF across most of the brain as BAC approached 60 mg%, also demonstrating close temporal coupling between BAC change and CBF increases on the ascending limb (Marxen et al. 2014). This study did not replicate the finding of Rickenbacher and colleagues (2011) that only men demonstrate an increase in CBF subsequent to alcohol administration; instead, there was some evidence that alcohol-induced CBF increases were more pronounced in women (Marxen et al. 2014). Marxen and colleagues estimated a global perfusion increase of ~7 % at 60 mg%, although this estimate was extrapolated from perfusion values obtained when measured BrAC approximated 50 mg%. Other studies using ASL to evaluate acute alcohol effects on CBF have similarly obtained peak BACs in the range of 40–60 mg%. BAC levels among heavy drinkers will regularly exceed this range, necessitating studies with higher BAC levels. Given regional differences in alcohol’s effect on CBF (Marxen et al. 2014), examining regional variation in dose-dependent changes (Sano et al. 1993; Volkow et al. 1988) is also important. The present investigation sought to further quantify acute alcohol effects on CBF using intravenous alcohol administration to maximize pharmacokinetic control. Heavy-drinking young adults received alcohol or saline infusions in the context of a double-blind, within-subject, counter-balanced design. To extend findings from a recent study (Marxen et al. 2014), the current study incorporates direct comparisons of CBF values at specified BAC levels (40 mg%, 80 mg%), including a higher maximum BAC that reflects a clinically relevant threshold (NIAAA 2004). Additionally, whereas the study by Marxen and colleagues involved pulsed ASL (PASL), the current study used pseudo-continuous ASL (pCASL), which has advantages over PASL with respect to between-scan reproducibility and signal-to-noise ratio (Chen et al. 2011). Finally, we examined the relevance of individual difference factors by examining a self-report measure of
Psychopharmacology (2015) 232:733–744
alcohol sensitivity (Schuckit et al. 1997) in relation to alcoholrelated perfusion change.
Materials and methods Participants The sample included 20 heavy-drinking young adults (nine females) between the age of 19 and 21 (mean age 19.95 years, standard deviation (SD)=0.76). Participants were recruited through Internet advertisements on public and university websites and flyers on university campuses, which requested social drinkers for participation in alcohol administration research. Eligibility criteria included the following: age 19–21, at least one heavy drinking episode (4+ drinks for women/5+ drinks for men) in the past 30 days, no evidence of alcoholrelated problems or current desire/attempts to reduce drinking, no medical contraindications to alcohol administration, no current psychiatric disorder or illicit drug use (except cannabis), and right-handedness. Smokers scored
ORIGINAL INVESTIGATION
Dose-dependent effects of intravenous alcohol administration on cerebral blood flow in young adults Nicole M. Strang & Eric D. Claus & Vijay A. Ramchandani & Ariel Graff-Guerrero & Isabelle Boileau & Christian S. Hendershot
Received: 2 May 2014 / Accepted: 31 July 2014 / Published online: 12 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Rationale Functional magnetic resonance imaging (fMRI) studies involving alcohol challenge are important for identifying neural correlates of alcohol’s psychopharmacological effects. However, evaluating acute alcohol effects on blood oxygen level-dependent (BOLD) signal change is complicated by alcohol-related increases in cerebral blood flow (CBF). Objectives The present study aimed to further characterize acute alcohol effects on CBF using intravenous alcohol administration to maximize control over brain alcohol exposure. Methods Twenty heavy-drinking young adults (M = 19.95 years old, SD=0.76) completed alcohol and placebo imaging sessions in a within-subject, counter-balanced, placebo-controlled design. Arterial spin labeling (ASL) provided estimates of perfusion change at two target blood alcohol concentrations (40 and 80 mg%) relative to baseline and relative to a saline control infusion.
Results Voxel-wise analyses showed widespread and dosedependent effects of alcohol on CBF increase. Region-ofinterest analyses confirmed these findings, also indicating regional variation in the magnitude of perfusion change. Additional findings indicated that lower self-reported sensitivity to alcohol corresponded with reduced perfusion change during alcohol administration. Conclusions This study provides further evidence for widespread effects of acute alcohol on cerebral perfusion, also demonstrating regional, dose-dependent, and inter-individual variation. Further research is needed to evaluate implications of these effects for the design and interpretation of pharmacological fMRI studies involving alcohol challenge.
Electronic supplementary material The online version of this article (doi:10.1007/s00213-014-3706-z) contains supplementary material, which is available to authorized users.
Advances in human neuroimaging paradigms have allowed progress in characterizing functional and structural brain correlates of alcohol use and alcohol dependence (Bühler and Mann 2011). An increasing number of studies have integrated alcohol challenge and neuroimaging methods (Bjork and Gilman 2013), generating novel information about acute alcohol effects on neural correlates of cognitive control (Anderson et al. 2010; Marinkovic et al. 2012b; Kareken et al. 2013; Gan et al. 2014), affective processing (Gilman et al. 2008, 2012), and genetic moderators of pharmacodynamic effects (Ramchandani et al. 2011; Kareken et al. 2013). Despite increased attention to these questions, knowledge about acute alcohol effects on neuroimaging phenotypes remains limited overall (e.g., Rickenbacher et al. 2011; Marinkovic et al. 2012a). Functional magnetic resonance imaging (fMRI) studies typically rely on the blood oxygen level-dependent (BOLD) signal, an indirect measure of neuronal activity (Logothetis and Pfeuffer 2004) that is influenced by a number of factors,
N. M. Strang : A. Graff-Guerrero : I. Boileau : C. S. Hendershot (*) Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, 100 Stokes Street, Toronto, ON M6J 1H4, Canada e-mail: [email protected] E. D. Claus The Mind Research Network and Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM, USA V. A. Ramchandani Section on Human Psychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA A. Graff-Guerrero : I. Boileau : C. S. Hendershot Department of Psychiatry, University of Toronto, Toronto, ON, Canada
Keywords Alcohol intoxication . Alcohol clamp . Alcohol sensitivity . Cerebral perfusion . FMRI . Self-rating of the effects of alcohol
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including cerebral blood flow (CBF). An important consideration for psychopharmacological fMRI studies is the degree to which drug challenge alters resting CBF. This issue is particularly relevant for alcohol challenge studies given that alcohol (a vasodilator) reliably increases CBF (for review see Marxen et al. 2014; Rickenbacher et al. 2011). Because differences in BOLD activation as a function of alcohol administration may reflect changes in neuronal activity, CBF, or both, characterizing acute alcohol effects on CBF has implications for the design and interpretation of psychopharmacological fMRI studies involving alcohol challenge (Rickenbacher et al. 2011). Acute alcohol effects on CBF have been evaluated using several imaging methods. Early studies reported increases in CBF subsequent to alcohol administration using positron emission tomography (PET), single-photon emission computed tomography (SPECT), and the Xe-133 technique (Newlin et al. 1982; Mathew and Wilson 1986; Sano et al. 1993; Volkow et al. 1988; Schwartz et al. 1993; Tiihonen et al. 1994). In addition to consistent findings of alcohol-related increases in CBF, some findings suggested regional variability in the effect of alcohol on CBF (Newlin et al. 1982; Volkow et al. 1988; Tiihonen et al. 1994). More recently, the development of arterial spin labeling (ASL) has permitted noninvasive investigations of CBF using MRI. The principle of ASL is that blood in the carotid arteries is magnetically labeled (tagged) using radio-frequency pulses. The labeled blood then acts like a contrast agent as it perfuses through the brain, enabling quantification of regional blood flow (Liu and Brown 2007). To date, the few ASL studies examining acute effects of alcohol on CBF have produced somewhat mixed results. Although all placebo-controlled investigations have reported alcohol-related increases in CBF (Khalili-Mahani et al. 2011; Tolentino et al. 2011; Rickenbacher et al. 2011; Marxen et al. 2014), one investigation reported that the increase in CBF was only present for half the participants (Khalili-Mahani et al. 2011) and another study reported the increase in CBF was present for men, but not women (Rickenbacher et al. 2011). Initial evidence also suggests that alcohol-induced perfusion may vary based on individual differences relevant to the etiology of alcohol use disorders. For example, those classified as having lower sensitivity to alcohol showed attenuated CBF change in response to alcohol versus placebo (Tolentino et al. 2011). Other findings suggested that alcohol-related CBF change correlated with a measure of antisocial personality, perhaps consistent with differences in alcohol-related dopamine response as a function of impulsive traits (Rickenbacher et al. 2011). Most neuroimaging studies of alcohol and CBF have relied on oral alcohol administration, which is associated with high variability in blood alcohol concentration (BAC) profiles due to large individual differences in alcohol pharmacokinetics
Psychopharmacology (2015) 232:733–744
(Ramchandani et al. 1999; Zimmermann et al. 2013). This variability can pose a particular barrier for neuroimaging paradigms, during which breath alcohol concentration (BrAC) measurements are often not feasible. Moreover, imaging protocols are often time-intensive, resulting in changes in blood alcohol limb (ascending vs. descending) during data collection. Given evidence that alcohol-induced CBF changes vary by BAC level (Volkow et al. 1988; Sano et al. 1993), oral alcohol administration can be considered a limitation of most prior studies. Intravenous alcohol administration can address many of these barriers by circumventing primary sources of between-subject variability, including absorption and firstpass metabolism. Additionally, alcohol clamp procedures (O’Connor et al. 1998; Ramchandani et al. 1999) can be used to achieve pseudo-constant BAC during neuroimaging paradigms (e.g., Gilman et al. 2008, 2012; Kareken et al. 2013; Ramchandani et al. 2011). A recent ASL study involving intravenous alcohol administration reported increases in CBF across most of the brain as BAC approached 60 mg%, also demonstrating close temporal coupling between BAC change and CBF increases on the ascending limb (Marxen et al. 2014). This study did not replicate the finding of Rickenbacher and colleagues (2011) that only men demonstrate an increase in CBF subsequent to alcohol administration; instead, there was some evidence that alcohol-induced CBF increases were more pronounced in women (Marxen et al. 2014). Marxen and colleagues estimated a global perfusion increase of ~7 % at 60 mg%, although this estimate was extrapolated from perfusion values obtained when measured BrAC approximated 50 mg%. Other studies using ASL to evaluate acute alcohol effects on CBF have similarly obtained peak BACs in the range of 40–60 mg%. BAC levels among heavy drinkers will regularly exceed this range, necessitating studies with higher BAC levels. Given regional differences in alcohol’s effect on CBF (Marxen et al. 2014), examining regional variation in dose-dependent changes (Sano et al. 1993; Volkow et al. 1988) is also important. The present investigation sought to further quantify acute alcohol effects on CBF using intravenous alcohol administration to maximize pharmacokinetic control. Heavy-drinking young adults received alcohol or saline infusions in the context of a double-blind, within-subject, counter-balanced design. To extend findings from a recent study (Marxen et al. 2014), the current study incorporates direct comparisons of CBF values at specified BAC levels (40 mg%, 80 mg%), including a higher maximum BAC that reflects a clinically relevant threshold (NIAAA 2004). Additionally, whereas the study by Marxen and colleagues involved pulsed ASL (PASL), the current study used pseudo-continuous ASL (pCASL), which has advantages over PASL with respect to between-scan reproducibility and signal-to-noise ratio (Chen et al. 2011). Finally, we examined the relevance of individual difference factors by examining a self-report measure of
Psychopharmacology (2015) 232:733–744
alcohol sensitivity (Schuckit et al. 1997) in relation to alcoholrelated perfusion change.
Materials and methods Participants The sample included 20 heavy-drinking young adults (nine females) between the age of 19 and 21 (mean age 19.95 years, standard deviation (SD)=0.76). Participants were recruited through Internet advertisements on public and university websites and flyers on university campuses, which requested social drinkers for participation in alcohol administration research. Eligibility criteria included the following: age 19–21, at least one heavy drinking episode (4+ drinks for women/5+ drinks for men) in the past 30 days, no evidence of alcoholrelated problems or current desire/attempts to reduce drinking, no medical contraindications to alcohol administration, no current psychiatric disorder or illicit drug use (except cannabis), and right-handedness. Smokers scored
