brain imaging and the effects of caffeine and nicotine

5 92

+ R E V I E W A R T I C L E *

Brain imaging and the effects of caffeine * e . and nicotine

Stephen R Dager',2j3 and Seth D Friedman2

Caffeine and nicotine are the most common psychostimulant drugs used worldwide. Structural neuroimaging findings associated with caffeine and nicotine consumption are limited and primarily reflect the putative relationship between smoking and white matter hyperintensities (WMH), a finding that warrants further appraisal of its clinical implications. The application of newer brain imaging modalities that measure subtle haemodynamic changes or tissue-based chemistry in order to better elucidate brain functional processes, including mechanisms underlying addiction to nicotine and caffeine and the brain functional consequences, provide intriguing findings. Potential influences of caffeine and nicotine on the functional contrast, or metabolic response, to neural activation also necessitates the careful appraisal of the effects that these commonly used drugs may have on the results of functional imaging.

Key words: brain imaging; caffeine; functional imaging; magnetic resonance imaging; nicotine; magnetic resonance spectroscopy.

Ann Med 2000; 32: 592-599.

Introduction

Tremendous advances made in brain imaging technology during the past two decades have provided both improved 2-D and 3-D structural definition and quantitative assessment of discrete brain substructures (1, 2), as well as the ability to systematically appraise brain functionality. The latter application has garnered substantial interest in the scientific community, initially with positron emission tomography (PET) and single- photon emission tomography (SPECT) and more recently through the use of magnetic resonance (MR) techniques ( 3 ) . Although it is outside the scope of this article to provide an in-depth review of magnetic

From the Departments of 'Psychiatry and Behavioral Sciences, 'Radiology and 'Bioengineering, University of Washington, Seattle, WA, USA.

Correspondence: Stephen R Dagcr, MD, University of Washington School of Medicine, Departments of Psychiatry and Behavioral Sciences, Radiology and Bioengineering, 4225 Roosevelt Way NE, Suite 306-C, Seattle, WA 98105-6099 USA. E-mail: srd~u.washinaton.edu. Fax: +1 206 5437565.

resonance imaging and spectroscopy (MRI/MRS) (see (3-5)), these noninvasive MR techniques go beyond structural assessment of the brain. Expanded MR capabilities allow clinical appraisal of tissue- based chemical composition, metabolic regulation and functional activation, the latter resulting from regional decoupling between energy demand and blood flow in response to neural activation (6, 7).

These expanded brain imaging capabilities are being used increasingly to elucidate the patho- physiological underpinnings of addiction and the brain consequences of drug abuse (8). However, relatively little research has been undertaken in humans to evaluate the structural and functional consequences in brain of caffeine and nicotine consumption, the most commonly used psychoactive substances worldwide. The focus of this article is to survey neuroimaging findings related to caffeine and nicotine and to discuss the potential effects of these agents on physiological mechanisms responsible for the functional contrast underlying MR functional imaging techniques, most typically the regional mapping of blood oxygen level determination (BOLD fMRI) or lactate elevations (fMRS) (3) .

0 The Finnish Medical Society Duodecim, Ann Med 2000; 32: 592-599

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5 93 BRAIN IMAGING A N D THE EFFECTS OF CAFFEINE AND NICOTINE

Caffeine

Caffeine and its methylxanthine derivatives are generally consumed via dietary intake from beverages and foods that include coffee, tea, soft drinks, chocolate and a variety of over-the-counter medications. The caffeine (equivalent) content of beverages and food is quite variable, ranging from 40 to 180 mg per/100 mL for coffee, 2 to 8 mg/15O mL for decaffeinated coffee, 16 to 50 mg/150 mL for tea, 15 to 40 mg/lSO mL for soft drinks, and 1 to 118 mg per 28 g for chocolates (reviewed in (9)). Per capita caffeine consumption averages about 75 mg/person/day worldwide but there are wide cultural differences with some ethnic groups, such as Scandinavians, reporting rates of caffeine consumption exceeding 400 mg/person/day (10).

Because of its strong hydrophobic properties, there is no blood-brain barrier to caffeine; absorption and brain uptake of ingested caffeine typically occurs within about 45 min (11-14). Caffeine has a plasma half-life of approximately 3-8 h, and brain levels remain stable for at least 1 h following peak absorption. The half-life of caffeine is markedly increased during the neonatal period as a result of an inactive cytochrome P-450 hepatic enzyme system (1.9, but otherwise there are no clear age-related changes in caffeine pharmacokinetics (12-14). The half-life of caffeine can be reduced by up to 30-50% among smokers (16) and approximately doubled by oral contraceptives or medications that alter liver metabolism, including psychotropic medications such as fluoxetine or fluvoxamine (12-14).

The widespread use of caffeine as the psychostimulant of choice primarily reflects its effects on subjective enhancement of energy, efficiency, self- confidence, alertness, and sociability ( 13), although double-blind tests have not demonstrated convincingly objective evidence of these effects in regular caffeine users (reviewed in (9)). Although caffeine is not generally considered a substance of abuse (17), dependency does occur among individuals who habitually use caffeine. When caffeine consumption is abruptly stopped, mild-to-moderate withdrawal symp- toms can occur within 14-48 h, for some individuals persisting up to a week, (9, 13, 18).

The primary physiological effect of caffeine for the concentration range normally consumed is the competitive blockage of endogenous adenosine (19, 20). Adenosine, a normal cellular constituent, is widely distributed and strongly inhibits neurotransmitter release. Adenosine may have a role in homeostatic regulation by matching the rate of energy consumption with the amount of substrate supply, such as in response to hypoxia, as adenosine production is increased in situations of energy deprivation (19). In contrast to other stimulants, such as amphetamine,

that increase both energy metabolism and cerebral blood flow (CBF), caffeine increases energy metabolism while at the same time markedly reducing CBF by 30% or more (20). As a consequence of its decoupling effects that produce concurrent acceleration of energy metabolism and reduction in CBF, caffeine ingestion in humans produces regional increases in brain lactate that can be measured by MRS (21).

Unlike reports of a possible association between nicotine use and discrete white matter lesions (discussed elsewhere in this paper), caffeine is not known to cause brain structural changes detectable by imaging studies. However, the long-term brain consequences of caffeine consumption have not been addressed directly in the available literature on imaging. Although caffeine consumption has been identified as a potential cardiovascular risk factor (22), more recent evidence fails to support this hypothesis and, in fact, suggests an inverse relationship between the risk of fatal or nonfatal stroke and caffeine consumption (23). Moreover, not only does chronic caffeine consumption appear to not increase the risk of cerebral vascular accidents, it may in fact decrease the extent of associated hypoxic damage (24). This latter observation presumably reflects the neuroprotective effects of adenosine receptors up- regulated by caffeine (19, 24). Recent epidemiological findings from a large cohort of Japanese-American males also raises the intriguing possibility that caffeine consumption may provide prophylaxis against the occurrence of Parkinson’s disease ( 2 9 , possibly through enhancement of dopaminergic transmission, but confirmatory imaging studies and studies on receptor binding in humans are needed.

A number of PET studies have documented diffuse reductions in CBF, up to 30% or more, that occur rapidly in response to orally or intravenously (iv) administrated caffeine (26-28). More recent imaging work has capitalized on caffeine’s dual mechanisms of increasing energy expenditure while reducing CBF, allowing measurement of regional brain lactate changes in response to caffeine ingestion (21). A rapid MRS imaging technique, proton echoplanar spectroscopic imaging (PEPSI) (29), was used to demonstrate differential brain lactate increases among caffeine-sensitive individuals who avoided caffeinated products in comparison to regular caffeine consumers in response to administration of oral caffeine (10 mg/kg caffeine citrate) (Figs l a and 1b). To further evaluate the effects of tolerance to the metabolic actions of caffeine, a subgroup of regular caffeine consumers, who were able to discontinue all caffeinated food or beverages for one month, were rechallenged with the same oral caffeine dose; a marked amplification of brain lactate response oc- curred in the subjects during this period of caffeine holiday as shown in Figure lc. In contrast to the


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DAGER FRIEDMAN 5 94

a NAA

Baseline

l r l After caffeine

ingestion J I I

2.5 2.0- 1.5 1.0 0.5 Chemical shift (ppm)

b

0 .- c e a a ? al m 0 m -J

c

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U-El Caffeine-intolerant subjects ( n = 9) W Regular caffeine users (n = 9)

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Caffeine ingestion

0.06

- fo L7 Ib $0 do do sb $0 Time (min)

0-0 Regular caffeine users ( n = 5 ) Caffeine holiday (n = 5)

0.10

0.04 -20 -10 0 10 20 30 40 50 60

Time (min)

Figure 1. Characteristic spectra acquired from a subject at baseline and 1 h after caffeine ingestion are shown in (a). The differential brain lactate response (expressed as mean lactate/ N,acetyl aspartate (NAA) ratios) to caffeine ingestion for caffeine- intolerant individuals and regular caffeine users are demonstrated in (b). The strikingly different metabolic response to caffeine among regular caffeine users following a 1 -month caffeine holiday is shown in (c). (Adapted from (21) with permission).

effects of caffeine on globally reducing CBF, brain lactate rises in response to caffeine demonstrated time-dependent regional changes that correspond to brain regions associated with arousal or anxiety. In

this study, observations that grey matter demonstrated greater lactate response to caffeine ingestion than white matter probably reflects differential brain energy expenditure between compartments (21).

Following abrupt cessation of caffeine, CBF globally increases with a similar time course as the clinical withdrawal state (18). The magnitude and duration of caffeine withdrawal and related CBF increases appear to be closely associated with the prior amount of daily caffeine consumption and presumably reflect enhanced adenosine activity. Excess regional brain lactate elevations observed in response to caffeine rechallenge among regular caffeine users following a 1-month caffeine holiday are also postulated to reflect enhanced effects of caffeine on adenosine receptors that have been down-regulated (or not up-regulated) in the absence of caffeine (21). As will be further discussed below, state-dependent metabolic effects of caffeine have the potential to substantially impact the interpretation of functional imaging findings.

Nicotine

Similar to caffeine, nicotine is the drug-of-choice among large segments of the general population (30). In studies evaluating smoking prevalence within patient and control groups, approximately 30% of subjects are smokers, a rate markedly elevated among certain psychiatric populations, most notably schizo- phrenics (reviewed in (31)). The most common sources of nicotine are cigarettes, chewable forms of tobacco and, more recently, nicotine patches or gum utilized to promote smoking cessation. Regardless of the route of administration, nicotine is rapidly ab- sorbed into the blood stream reaching peak plasma levels within a few minutes (32). The lipophyllic structure of nicotine allows it to cross the blood-brain barrier rapidly, with brain uptake and elimination only slightly lagging behind changes in blood levels (33). The plasma and elimination half-lives of nicotine are approximately 45 min and 2 h, respectively, suggesting a corresponding time course in brain pharmacokinetics, although, to our knowledge, this has not been measured for the human brain (32-34). Similar to caffeine, nicotine metabolism is 3-4 times longer in newborns, also reflecting the previously noted liver enzyme deficits in infancy (35).

As with caffeine, the widespread use of nicotine stems from its reinforcing effects, as has been borne out by a number of investigations demonstrating dopaminergic changes following nicotine administration (13, 36, 37), and from subjective behavioural effects such as improvements in attention, arousal and reaction time (38) . In humans, nicotine administration causes neural activation and produces a variety of physiological effects involving the cardiovascular


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5 95 BRAIN IMAGING AND THE EFFECTS OF CAFFEINE AND NICOTINE

system, including increases in CBF (39). Nicotine consumption also stimulates the down-regulation of neuronal nicotinic receptors (NAChRs) and produces secondary effects involving multiple neurotransmitter systems (ie dopamine and glutamate), mechanisms that have been extensively reviewed elsewhere (40). The high rate of nicotine use among schizophrenic patients may reflect the ability of nicotine to regulate dopaminergic innervation to limbic structures, regions putatively involved in schizophrenia (31). Moreover, several investigators have suggested a decreased risk for Parkinson’s disease and other motoric disorders with nicotine use, possibly, the result of similar dopaminergic modulatory effects (41).

It is well recognized that cigarette smoke also contains an abundance of other substances that affect the rate of nicotine absorption in addition to creating an additive burden on respiratory and cardiovascular health (eg carbon monoxide and formaldehyde) (42). The occurrence of impairments in endothelial- dependent vasodilatation (EDV) among smokers is indicative of potential systemic vascular compromise over the long term (43, 44).

White matter hyperintensities (WMH), a common brain structural finding visible by MRI, have been suggested to reflect small vessel disease (45). An example of typical MRI findings of WMH is shown in Figure 2. Several investigators have noted a marked increase in WMH among smokers without other known risk factors and an increased prevalence among those smokers diagnosed with dementia (46) or bipolar disorder (47), suggesting that nicotine may be a specific risk factor for such vascular lesions. A

causal relationship between lifetime nicotine dose and the severity of WMH findings has been proposed as MRI-defined WMH changes may parallel worsening EDV over time (47). However, it must be emphasized that WMH clearly have myriad aetiology; similarly, not all patients who smoke demonstrate white matter pathology (47, 48). The clinical significance of WMH also remains uncertain, as there may not be associated clinical antecedents or deleterious clinical outcome (48). Thus, further work integrating perfusion measures and quantitative WMH measurements is needed to help clarify the relationship between vascular health and lesion load. Additionally, routine character- ization of smoking behaviour within neuroimaging studies will aid in evaluating the general relationship between WMH and smoking.

In contrast to the effect of caffeine on reducing global CBF by 30% or more, cigarette smoking or iv nicotine administration increases CBF, as demonstrated by a xenon 133 SPECT study that showed an approximately 16% average CBF increase (39). In an elegant blood flow study with transcranial Doppler, rapid (-10 s) blood flow increases within four cerebral vessels were demonstrated during smoking, a response that was directly related to nicotine dose and decreased at a similar time course following smoking cessation (49). Moreover, in the latter study, simultaneous measurements of radial artery blood flow demonstrated decreased flow during smoking, illus- trating the differential effects of nicotine on the peripheral vasculature. Regional accentuation of nicotine-induced CBF increases have been demonstrated within the frontal lobes and cerebellum with

Figure 2. Standard T,-weighted magnetic resonance images (MRl)s from two patients demonstrating the presence of white matter hyperintensities (WMH), as indicated by the arrows. (Adapted from (45) with permission).


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5 96 DAGEK FRIEDMAN

PET (50), although not all human CBF studies have demonstrated consistently unidirectional regional CBF increases in response to nicotine. For example, a PET study that investigated the effects of nicotine on attention following a low-dose nicotine infusion over 80 min also demonstrated regional CBF decreases in cingulate and cerebellum (51).

Recent investigations utilizing BOLD fMRI during nicotine infusion and statistical models derived from increasing plasma nicotine levels (52, 5 3 ) have shown regional brain increases in BOLD response (neuronal activation) that parallel brain areas implicated in

nicotine craving or abuse, as well as regions of increased NAChR receptor density (52). The number of activated regions increased in conjunction with increasing nicotine dose, although a dose-related magnitude of response was not demonstrated. The absence of a clear dose response between nicotine and CBF may result from the cumulative dosing paradigm employed, or from the inherent difficulty in quantify- ing conventional BOLD fMRI signal response ( 3 ) . As the investigators expressly noted, BOLD fMRI responses in the negative direction were not evaluated, which might have helped to address regional bi-

a

b Signal intensity (MR-units)

Time (seconds)

Figure 3. In (a) four adjacent axial echoplanar images through the visual cortex are shown for a healthy control during visual stimulation under conditions of normocapnia (end-tidal pC0, = 40 mm Hg) and hypocapnia (end-tidal pC0, = 19 mm Hg), demonstrating loss of functional magnetic resonance imaging (fMRI) functional contrast. In (b) the time course of signal intensity response to hyperventilation (indicated by dark horizontal line) during repeated visual stimulation (indicated by grey vertical lines is demonstrated). (Reproduced from (64) with permission.)


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BRAIN IMAGING A N D THE EFFECTS OE CAFFEINE AND NICOTINE 597

directional CBF responses to nicotine administration (53).

Some consideration is necessary regarding the interactive nature of caffeine and nicotine use. The majority of smokers also consume substantial quan- tities of caffeine (54), and a decrease in smoking frequency can also be associated with increased caffeine intake (and vice versa) (55). Recent work evaluating cardiovascular response to combined caffeine and nicotine administration indicates that the resultant blood pressure and heart rate increases from the resting state reflect additive effects of these two drugs (56). Conversely, blood pressure response to physical exertion, such as standing, is reduced through the combined actions of caffeine or nicotine administration that are presumably mediated by the effects of adenosine (56). This later observation emphasizes the importance of state-dependent influences on the actions of both nicotine and caffeine.

Influences of caffeine and nicotine on functional imaging results

The ability to model or separate out the relative contributions to signal response from neuronal activation and blood flow mechanisms observed in human neuroimaging studies remains a significant challenge. For example, recent work, in which a rat model was used to investigate the relationship between oxygen delivery and blood flow with a 'H MRS technique edited for carbon ( I3C), showed significant increases in CBF and global brain metabolic rates following nicotine administration (approximately 41 YO and 30% increases from baseline anaesthetized values, respectively), similar to the effects of sensorimotor stimulation (34% and 26% increases, respectively) (57). Future technical developments that allow multiple perfusion or activation measures to partial out the nonspecific effects of generalized blood flow or metabolic changes from discrete measures of activation will greatly enhance our ability to characterize neural response patterns. However, in the context of not yet having fully achieved this goal, the con- founding effects of caffeine consumption and smoking (both acute and chronic) on CBF and metabolism, as well as associated changes in receptor density, have implications for interpretation of fMRI and fMRS results.

Current MR functioning imaging methods depend upon subtle changes in CBF (oxyhaemoglobin levels) or energy metabolism (lactate) to provide indices of task-specific neural activation (3, 7). Although earlier functional imaging studies with PET provided quantitative assessment of changes in regional CBF or glucose metabolism from baseline, if assumptions of a two-compartment model could be met, sensitivity

Brain imaging technology can characterize the brain metabolic and chemical consequences o f caffeine and nicotine consumption in the brain: similarly, careful appraisal o f the influences that these commonly used drugs have on interpretation o f functional imaging findings is critical.

constraints did nor allow for the appraisal of individual response patterns (7). On the other hand, BOLD fMRI techniques, which allow substantially improved temporal resolution and more precise anatomical coregistration, also provide sufficient sensitivity to evaluate single-subject dynamic response patterns of brain activation that can be monitored in near-real time (3). However, a general limitation of all current functional imaging techniques has been the assumption that links between CBF or energy metabolism and neuronal activity are invariant, such that disease states or drug effects do not alter these relationships (7).

In addition to the previously noted effects of caffeine habituation on functional MRS brain lactate response (21), respiratory status can also influence brain lactate levels substantially, presumably through alterations in CBF regulation, with different patterns of functional MRS brain lactate response to controlled hyperventilation found for specific clinical populations (58). In the case of BOLD fMRI, additional problems arise from basal differences in CBF as a result of inherent difficulties in quantitating signal response or establishing baseline conditions, although newer MR functional imaging techniques, such as quantitative T,-weighted mapping of functional water changes, may reduce this problem (59). For the currently available fMRI techniques a variety of factors, such as gender (60), age (61), respiratory status (62) or drug use (63), can signifdandy influence the pattern of BOLD fMRI signal response and confound the interpretation of results. For example, investigators have directly evaluated the effects of respiratory-induced alterations in CBF on BOLD fMRI signal response, demonstrating abolishment of functional contrast within the visual cortex to light activation under conditions of hyperventilation (64). An example of this work is shown in Figures 3a and 3b. Further investigation has demonstrated that the fMRI signal response is directly proportional to end-tidal CO, between 20 and 60 mmHg, consistent with the linear relationship for CBF and PaCO, between those ranges (65). As caffeine and nicotine substantially affect CBF, brain metabolism and neural activation, their use would also be expected to influence the BOLD fMRI signal contrast to a considerable degree, producing


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DACER FREDMAN 598

differential effects in the acute state, with chronic usage and under withdrawal conditions. These variable

We thank Marie Domsalla for her help with manuscript preparation. This work was supported, in part, by a NARSAD

systematically.

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brain imaging and the effects of caffeine and nicotine

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