4.1. INTRODUCTION AND SCOPE

After detoxification, patients suffering from a drug addiction show high relapse risks. For example, among alcoholics up to 85% of all patients relapse, independent of whether they have been treated as inpatients until complete remission of physical withdrawal symptoms (Boothby and Doering 2005). Current brain-imaging studies have tried to identify the neuronal correlates of learning processes involved in relapse such as behavioral mechanisms including classical Pavlovian and instrumental conditioning. The goal of such studies is to provide insight into the neurobiology of drug addiction as well as to provide new options for specific behavioral intervention or pharmacological modification of alcohol craving and the risk of relapse. In this chapter, we will discuss the theoretical background and the results of neuroimaging studies that identified alterations and relevant neurotransmitter systems that are associated with cue-induced brain activation and alcohol craving, and their impact on neuronal networks that are activated by drug-specific cues.

4.2. METHODICAL APPROACHES TO STUDY NEURONAL SYSTEMS RELEVANT FOR ALCOHOL ADDICTION

Blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) studies allow us to assess brain activity by measuring the ratio of oxygenated and deoxygenated blood in humans. Functional MRI measures the hemodynamic response related to neuronal activity in the brain and is one of the most prominent neuroimaging techniques because of its noninvasiveness, lack of radiation exposure, and relatively wide availability. Changes in blood flow and blood oxygenation in the brain are closely linked to neuronal activity (Kwong et al. 1992; Logothetis 2002; Ogawa et al. 1990). Neuronal activity causes an immediate need for energy; that is, oxygen. The local response to this oxygen utilization is an increase in blood flow to regions of increased neuronal activity, occurring after a delay of approximately 5 seconds. This hemodynamic response rises to a peak before falling back to baseline and typically to a slight undershoot. This leads to local changes in the relative concentration of oxyhemoglobin and deoxyhemoglobin, and changes in local cerebral blood volume and local cerebral blood flow. The difference in magnetic susceptibility (degree of magnetization) between oxyhemoglobin and deoxyhemoglobin leads to magnetic signal variation, which can be detected using an MRI scanner.

In the neurosciences, subjects are commonly exposed to alternating presentations of, for example, affective stimuli (neutral, positive, and negative words) and a fixation (baseline) condition (crosshair). This design enables investigators to examine the main effects of brain activity related to different stimuli relative to a neutral condition (e.g., negative word vs. fixation). In this context the nature of the stimuli that are used, and their explicit versus implicit emotional valence is a critical issue, since all data reflect relative differences and there is no absolute baseline. A passive resting or fixation cross baseline condition under the conditions of fMRI scanning appears not be emotionally neutral, because it involves unpredictable mental states (Gusnard and Raichle 2001;Stark and Squire 2001) and environmental confinement and noise, and the relatively unconstrained experience of the subjects during the presentation of baseline conditions may be more uncertain and ambiguous than familiar unambiguous stimuli (e.g., neutral words). For example, a study by our group showed that unconstrained processing of an affectively undefined symbol such as a fixation cross in the potentially anxiogenic (narrow, dark, and loud) environment of an MRI scanner elicited increased amygdala activation in serotonin transporter (5HTT) reduced function s (short) carriers versus ll (long/long) homozygotes compared with relatively more visual processing of affectively neutral stimuli (Heinz et al. 2007b).

fMRI offers several advantages including high spatial resolution and noninvasiveness as well as an economic utilization. A disadvantage of this method is that effects of different stimuli on brain activation (particularly neuronal afferent input) are only indirectly reflected in the BOLD response (Logothetis 2002). Furthermore, there is rather poor temporal resolution (e.g., versus EEG), and specific neurotransmitter systems can only be assessed by measuring effects of systemically applied agonists and antagonists.

In contrast to the measurement of cerebral blood flow with fMRI, positron emission tomography (PET) as well as single photon emission computed tomography (SPECT) allow for measurement of an absolute baseline of activation. Furthermore, they can quantify neuroreceptor and transporter availabilities (with the potential confound of endogenous neurotransmitter concentration competing for binding of receptors/transporters with radioligands [Heinz et al. 2004b; Kumakura et al. 2007; Laruelle 2000]). An example is the radioligand [¹²³I]beta-CIT, which is widely used with SPECT to measure the availability of central dopamine and serotonin transporters. Such monoamine transporters regulate the reuptake of released neurotransmitters. In a study of our group, neurotransmitter concentrations measured in vivo with microdialysis were negatively correlated with the availability of monoamine transporters measured with [¹²³I]beta-CIT and SPECT (Heinz et al. 1999). However, this negative correlation could also be caused by a competition between the endogenous neurotransmitter and the radioligand for transporter binding sites (Fisher et al. 1995) (see Figure 4.1). This finding suggests that radioligand binding reflects the availability of D2 receptors that are currently not occupied by endogenous dopamine rather than the absolute density of D2 receptors.

FIGURE 4.1

Blockade of dopamine D2 receptors by endogenous dopamine (top: high-endogenous dopamine and low-radioligand binding; bottom: low-endogenous dopamine and high-radioligand binding).

Disadvantages are the application of a radioactive contrast agent, which exposes the patient to gamma radiation, and the rather short half-life period of the tracer, as well as the high expenses and the complex measuring procedure.

Another methodological approach is the combination of both methods: the correlation of neuronal activation measured with fMRI and functions of neurotransmitter system measured with PET or SPECT (e.g., dopamine receptor D2 availability or dopamine synthesis rate). This is an elegant way to link certain brain functions with certain neurotransmitter systems, like linking dopamine with the brain network that controls reward, pleasure, and motivation.

Furthermore, human studies often use the startle response as a neurophysiological indicator of appetitive or aversive reactions toward visual stimuli. In alcohol-dependent patients, it has been observed that alcohol cues often elicit a physiological response similar to appetitive cues, which is not necessarily reflected in a conscious feeling of attraction or pleasure (Heinz et al. 2003). Indeed, conditioned reactions can be assessed on multiple levels and these levels of reactions differ conceptually and can be influenced by the conditioned stimulus with different intensity (Carter and Tiffany 1999).

4.3. NEUROTRANSMITTER SYSTEMS IMPLICATED IN CRAVING FOR ALCOHOL AND OTHER DRUGS OF ABUSE

It has been suggested that different neurotransmitter systems interact with specific relapse situations elicited by an alcohol priming dose, an alcohol-associated cue, or stress exposure in drug and alcohol dependence (Heinz 2002; Shalev et al. 2000). PET imaging has been most useful in such studies, because specific neurotransmitter systems can be identified. This model provides an example of how PET can be used to study the neurotransmitter mediation of important events related to addiction. One mainstay of the neurobiological research in alcohol and drug addiction is the observation that alcohol and all other drugs of abuse induce dopamine release in the ventral striatum, including the nucleus accumbens, and thus reinforce drug intake (Wise 1988).

Animal experiments also revealed that alcohol and drug-associated stimuli activate dopamine and endorphin release in the medial prefrontal cortex and the ventral striatum (Dayas et al. 2007; Di Chiara 2002; Shalev et al. 2000).

However, observing that a drug reinforces behavior does not necessarily imply that the drug effect is subjectively pleasant. Robinson and Berridge (1993) distinguished between hedonic or pleasant drug effects ("liking") and the craving for such a positive effect ("wanting"). They suggested that drug effects associated with drug liking are mediated by opioidergic neurotransmission in the ventral striatum including the nucleus accumbens, and that pleasurable effects during consumption of primary reinforcers such as food are also caused by endorphin release in this brain area (Berridge and Robinson 1998). Imaging studies are increasingly able to evaluate both of these limbs of the reward systems. Moreover, these hypotheses can be studied by using scores for drug craving as a proxy for wanting and scales measuring pleasure as a proxy for liking.

Dopamine release in the striatum is itself regulated by the hippocampus, which plays a major role in memory processes and reflects the appearance of novel stimuli (Lisman and Grace 2005). Stimulation of glutamatergic neurons in the hippocampus induces dopamine release in the ventral striatum of rats that previously consumed cocaine, and this glutamatergic-driven dopamine release can lead to a relapse in drug intake (Vorel et al. 2001). Therefore, experimental hippocampus stimulation reflects real-life situations in which drug-associated, contextual stimuli activate the hippocampus and trigger memories associated with previous drug use (Figure 4.2). The activation of this specific hippocampal circuit in turn activates dopamine neurons in the ventral tegmentum, which elicit dopamine release in the ventral striatum, thus facilitating new drug intake (Floresco et al. 2001). Indeed, both cocaine sensitization (Goto and Grace 2005b) and amphetamine sensitization (Lodge and Grace 2008) increase hippocampal drive of the nucleus accumbens, ultimately leading to increased responsivity of the dopamine (DA) system.

FIGURE 4.2

Model of a neuronal network that includes dopamine-related prediction of unexpected or novel reward and reward-associated stimuli: The discrepancy between expected and actual sensory information is calculated in the hippocampus (CA1) and activates dopaminergic (more...)

Berridge and Robinson (1998) suggested that a neurobiological correlate of “wanting” is phasic dopamine release in the ventral striatum, as shown by Schultz et al. (1997), which is not necessarily accompanied by positive feelings. Indeed, Schultz et al. had observed that the arrival of an unexpected reward elicits a burst of spikes in dopaminergic neurons, which does not occur if this incident is predicted by a conditioned cue that temporarily predicts the subsequent arrival of a reward (Figure 4.3). The discharge of dopaminergic neurons occurs immediately after the presentation of such a conditioned cue and indicates the magnitude of the anticipated reward (Tobler et al. 2005). When the reward itself arrives as predicted (anticipated), it no longer elicits a dopamine discharge, because the received and the expected reward do not differ and there is thus no error of prediction, which is expressed by dopamine cell firing (Schultz et al. 1997) (Figure 4.3), as described below in a separate section. Robinson and Berridge (1998) suggested that phasic dopamine release not only represents this prediction error but also facilitates the allocation of attention toward salient, reward-indicating stimuli, which can thus motivate an individual to display a particular behavior in order to receive the reward. Dopamine thus contributes to the control of goal-directed behavior because it encodes the expected magnitude of a potential reinforcer and attributes incentive salient to reward-indicating stimuli. As a consequence, the nucleus accumbens acts as a “sensory-motor gateway,” which controls the effects of salient environmental stimuli on prefrontal and limbic brain areas that regulate attention and motor output (Tobler et al. 2005).

FIGURE 4.3

Reward-associated error signaling by short-term ("phasic") dopamine release (cf. Schultz et al. 1997). Top: An unexpected reward (banana pellets for rhesus monkeys), which was not predicted by previous stimuli, generates an error in reward prediction (more...)

PET can assess several aspects of dopaminergic function: D2 receptor number/ availability, dopamine synthesis rate, and dopamine release rate can be measured indirectly by evaluating the effect of amphetamine on D2 receptor occupation. Brain imaging studies among detoxified alcoholics that used PET and measured radioligand binding to central dopamine D2 receptors revealed a reduction in dopamine D2 receptor availability and sensitivity, which may reflect a homeostatic, compensatory downregulation of D2 receptors after chronic alcohol-associated dopamine release. Prospective studies showed that the degree of downregulation during early abstinence is associated with the subsequent relapse risk (Heinz et al. 1996; Volkow et al. 1996). Further PET studies showed that alcohol craving was specifically correlated with a reduced D2 receptor availability and a low dopamine synthesis capacity measured with F-DOPA PET in the ventral striatum including the nucleus accumbens (Heinz et al. 2004a, 2005c). During detoxification and early abstinence, dopamine dysfunction can further be increased, because alcohol-associated dopamine release is suddenly stopped and extracellular dopamine concentration decreases rapidly during detoxification (Rossetti et al. 1992). Stimulation of dopamine release with amphetamine during early abstinence confirmed that dopamine storage and stimulant-induced dopamine release is significantly reduced in detoxified alcohol dependents compared with healthy control subjects (Martinez et al. 2005). Altogether, these studies indicate that after alcohol detoxification, overall dopaminergic neurotransmission in the ventral striatum is reduced rather than sensitized. Therefore, it is quite unlikely that the presentation of alcohol-associated cues during early abstinence can cause a significant dopamine release that triggers reward craving or relapse.

Some animal studies confirmed that the presentation of drug- and alcohol-associated cues can lead to relapse even if no dopamine release can be observed in the ventral striatum (Shalev et al. 2002). However, these findings do not rule out that dopamine dysfunction plays a major role in the relapse risk of alcohol-dependent patients during early detoxification; rather, the assumed direction of dopamine dysfunction has to be reconsidered: According to the above-discussed animal experiments and human studies, a reduction in dopamine synthesis capacity, stimulant-induced dopamine release, and D2 receptor availability and sensitivity is associated with high alcohol craving, increased processing of alcohol-associated cues in the anterior cingulate and medial prefrontal cortex, and an increased relapse risk (Heinz et al. 2004a, 2005c). This hypothesis can be directly tested by simultaneously measuring dopaminergic neurotransmitters with PET and cue-reactivity with fMRI. Indeed, increased craving was associated with a low level of DA transmission. The decrease in DA levels could thereby serve as a drive for the individual to consume alcohol to boost low dopaminergic neurotransmission during early abstinence.

Imaging approaches can also be used to identify effects on the opioid component of the reward system. In human alcohol-dependent patients, an increase of mu-opiate receptors was observed in the ventral striatum, and high availability of mu-opiate receptors in the ventral striatum and medial prefrontal cortex correlated with the severity of alcohol craving (Heinz et al. 2005b). Naltrexone application in alcohol-dependent patients blocked alcohol-associated pleasurable feelings (the subjective "high"), indicating that drug liking may be associated with alcohol-induced activation of mu-opiate receptors and suggesting that a blockade of this interaction contributes to the relapse-preventing effects of naltrexone in alcoholism (O'Brien 2005; Volpicelli et al. 1995). Different human clinical studies showed that naltrexone treatment reduces the relapse risk of alcoholics (Srisurapanont and Jarusuraisin 2005; Streeton and Whelan 2001, but see Krystal et al. 2001).

4.4. BEHAVIORAL DESIGN OF STUDIES THAT MEASURE NEURONAL SYSTEMS ACTIVATED BY ALCOHOL-ASSOCIATED CUES

Functional MRI as well as PET or SPECT can be used to assess neuronal activation elicited by alcohol-associated cues via computation of the BOLD response associated with stimulus presentation. The key methodological issue in conducting such studies is not the imaging methodology that is used to conduct the study but the behavioral parameters used to engage neural circuits. In this next section, we review key studies that provide examples of the challenges involved in using drug stimuli themselves.

Brain-imaging studies have been used to describe neuronal networks responding to drugs of abuse, to link cue-induced brain activation with the prospective relapse risk (Braus et al. 2001; Drummond 2000; George et al. 2001; Grüsser et al. 2004), and to associate cue-induced brain activation with the effects of drugs that are supposed to block alcohol- or drug-specific effects.

These approaches that link brain activity to behavioral state have identified core regions that were activated in most studies (de Mendelssohn et al. 2004; Weiss 2005). These core regions include the following:

• the orbitofrontal cortex (OFC), which is involved in the evaluation of reward and punishment (Myrick et al. 2004; Wrase et al. 2002)
• the anterior cingulate and adjacent medial prefrontal cortex, which is involved in attention and memory processes and in the encoding of the motivational value of stimuli (Grüsser et al. 2004; Heinz et al. 2004a; Myrick et al. 2004; Tapert et al. 2004)
• the ventral striatum (including the nucleus accumbens), which connects motivational aspects of salient stimuli with motor reactions (Braus et al. 2001; Myrick et al. 2008; Wrase et al. 2002, 2007)
• the dorsal striatum, which has been implicated in habit formation and consolidates stimulus-reaction patterns (Grüsser et al. 2004; Modell and Mountz 1995)
• the basolateral amygdala, which specifies the emotional salience of stimuli and initiates conditioned and unconditioned approach and avoidance behavior (Schneider et al. 2001)

Similar brain areas are also activated when drug-specific stimuli were presented to patients addicted to other drugs of abuse, such as cocaine or opiates (de Mendelssohn et al. 2004; Weiss 2005).

However, these brain imaging studies revealed considerable interindividual variance in response to the presentation of alcohol-related stimuli, which may be due to differences in chosen populations, availability of alcohol, and motivation to remain sober as well as the design of the behavioral study.

4.5. ALCOHOL CRAVING: A LEARNED RESPONSE? HOW TO ASSESS THE IMPACT OF LEARNING

Drug addictions such as alcohol dependence are characterized by criteria that include the development of tolerance to drug effects, withdrawal symptoms upon cessation of drug intake, craving for the drug of abuse, and reduced control of drug intake (American Psychiatric Association 1994; World Health Organization 1992). Koob (2003) suggested that tolerance can be understood as an adaptation of the brain to chronic drug intake, which results in a new homeostatic balance. This balance is thought to be disturbed when alcohol intake is suddenly interrupted, and the resulting homeostatic imbalance can clinically manifest as withdrawal symptoms. To methodologically assess these questions, neuroreceptor alterations (adaptations) can be studied during drug intake and compared with the state of acute detoxification and prolonged abstinence. Indeed, it has been observed that the sedative effects of alcohol and other drugs of abuse are mediated by stimulation of GABAergic neurotransmission; alcohol has also been shown to inhibit glutamatergic neurotransmission, thus effectively interfering with excitatory brain activation (Krystal et al. 2006; Tsai et al. 1995). Once alcohol intake is suddenly stopped during withdrawal, GABAergic receptors are no longer activated by alcohol, and upregulated glutamate receptors are no longer functionally inhibited by direct ethanol effects. The imbalance may result in withdrawal symptoms, even as severe as epileptic seizures (Krystal et al. 2006; Tsai et al. 1995). It is obvious that patients can relapse while experiencing such aversive and potentially life-threatening withdrawal symptoms. However, it has also been observed that such withdrawal symptoms can manifest even when acute detoxification and withdrawal symptoms have ceased for a considerable amount of time. These can be assessed with questionnaires such as the Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) that measure the severity of withdrawal symptoms preceding relapse in detoxified patients (Heinz et al. 2003).

It has been suggested that manifestation of withdrawal symptoms during abstinence can be explained in part as a conditioned reaction elicited by conditioned stimuli, that is, cues that have been regularly associated with alcohol intake, which can elicit conditioned responses such as craving for the rewarding effects of alcohol or neurobiological effects such as a counteradaptive neuronal response that is aimed at counteracting the expected drug effect (Siegel 1975; Siegel et al. 1982; Wikler 1948). Indeed, it has been suggested that in alcohol dependence, contextual cues that characterize situations in which alcohol is available can act as conditioned stimuli that trigger counteradaptive alterations in neurotransmitter systems such as the glutamate and GABA systems, inducing increased glutamatergic and decreased GABAergic neurotransmission. If alcohol intake does not occur as expected, the resulting hyperexcitation can manifest as withdrawal symptoms and trigger relapse (Verheul et al. 1999). It has been suggested that in such situations, patients may experience craving for alcohol's sedative effects, which are motivated by the desire to relieve the aversive experience of conditioned withdrawal. In a clinical study, about 30% of all alcohol-dependent patients described that their last relapse was preceded by a sudden manifestation of withdrawal symptoms, which often occurred long after acute detoxification and which were triggered by being exposed to previously typical drinking situations (Heinz et al. 2003).

Conditioned stimuli may not only trigger neurobiological effects that are meant to counteract the expected drug response, as described above for opiates; but it has also been suggested that drugs of abuse, particularly those with a strong dopaminergic component, may also trigger expectation of the motivation or reinforcing effects of the drug of abuse (Heinz et al. 2003; Stewart et al. 1984; Verheul et al. 1999). Thus, when a rat is given a stimulant within a particular context (e.g., their home cage), the rat will show sensitization, or increased response to the same dose of the drug, when it is tested in the same context in which it had been administered (Vezina et al. 1989; Badiani et al. 2000; Crombag et al. 2000). A learning theory suggests that originally neutral stimuli can be associated with alcohol's affectively positive effects (unconditioned response, UCR) or with a compensatory, homeostatic counteradaptive process (Koob 2003; Siegel 1999). These cues thus become conditioned stimuli (CS), which have been associated with the subjectively pleasant or counteradaptive drug effects. Conditioned stimuli can thus elicit an urge or “craving” as a conditioned response (CR) for the affectively positive effects of alcohol or other drugs of abuse or for the alleviation of an aversive, homeostatic counteradaptive process (Bigelow 2001; Drummond 2000; Verheul et al. 1999) (Figure 4.4). It is important to note that such formerly neutral stimuli, which are associated with the effects of a drug of abuse, can be both internal or external cues, for example, the context or environment that characterized former alcohol consumption or internal stimuli such as feelings of loneliness or memories of conflict situations, which had previously been associated with excessive alcohol consumption (Drummond 2000; Heinz et al. 2003; Verheul et al. 1999). Small quantities of the substance itself can also trigger craving via conditioned responses. Therefore some groups studied—for example, nondetoxified alcohol-dependent patients—were given a sip of alcohol to elicit craving (Myrik et al. 2004). These studies show that it is methodogically important to distinguish between different stimuli that elicit craving (alcohol sips, pictures, or other cues) and the associated urges (i.e., craving for positive drug effects or for the alleviation of aversive withdrawal symptoms).

FIGURE 4.4

Model of conditioned alcohol craving: A previously neutral stimulus (e.g., beer glass) can become associated with (a) an increase in blood alcohol concentration that elicits an affectively positive response (UCR). The CS can then elicit an attenuated (more...)

4.5.1. Clinical Studies Trying to Link Craving and Relapse: Identifying Craving

In alcohol dependence, the empirical connection between craving for alcohol and the following relapse risk is not well explored. Although animal experiments strongly support the hypothesis that conditioned drug reactions are involved in the development and maintenance of addictive behavior and relapse (Di Chiara 2002; Robbins and Everitt 2002; Robinson and Berridge 1993), human studies often did not find a positive correlation between subjective, or conscious, alcohol craving and relapse (Drummond and Glautier 1994; Grüsser et al. 2004; Junghanns et al. 2005; Kiefer et al. 2005; Litt et al. 2000; Rohsenow et al. 1994). However, some other studies did observe such relationship (Bottlender and Soyka 2004; Cooney et al. 1997; Heinz et al. 2005c; Ludwig and Wikler 1974; Monti et al. 1990). In contrast to these rather heterogeneous results, changes in physiological parameters elicited by alcohol-associated cues, including neuronal activation measured with functional imaging, seem to be more closely connected to relapse (Abrams et al. 1988; Braus et al. 2001; Drummond and Glautier 1994; Grüsser et al. 2004; Rohsenow et al. 1994). Assessing such physiological responses may therefore be more promising to achieve reliable results.

One explanation for the poor correlation between alcohol craving and the prospective relapse risk may be due to the fact that reactions such as conscious craving to alcohol and alcohol-associated cues differ with respect to different levels of description (subjective, motor, and physiological responses), even if these reactions manifest at the same time point after cue exposure (Figure 4.5). Tiffany (1990) suggested that conscious craving only occurs if the automatic process of drug intake is interrupted. Whenever this is not the case, conditioned stimuli may trigger dramatic drug intake even in the absence of conscious urges for drugs of abuse. This theoretical framework suggests that behavioral patterns associated with drug intake can be activated in the absence of conscious correlates such as craving. This hypothesis is supported by studies that identified subcortical brain areas associated with motor behavior such as the striatum and that linked this cue-induced brain activation and relapse (Grüsser et al. 2004). It is unlikely that striatal activation per se is associated with conscious cognitive correlates; thus automated drug intake may occur against a conscious decision to remain abstinent.

FIGURE 4.5

Measuring of “cue-reactivity referring” to Drummond (2000). The reactions triggered by drug- or alcohol-associated stimuli ("cues") can be measured on different levels, on which they are distinguished differently depending on the individual (more...)

Furthermore, heterogeneous research methods, settings and samples, and confounding effects of nicotine abuse, particularly in alcohol dependence, may explain inhomogeneous data concerning the association between craving and relapse as mentioned before. For example, cue-induced craving and enhanced drug-like arousal were not associated in abstaining alcoholics, indicating that the psychological and physiological levels are dissociated (Breese et al. 2005). Likewise, Weiss et al. (2003) showed in a study with cocaine-addicted patients that an effective psychosocial treatment aimed at the reduction of drug craving helped patients to stay abstinent in spite of the persistence of subjectively high craving. It has even been suggested that a conscious sensation of alcohol craving can serve as a warning sign, which helps patients to look for help and thus to maintain abstinence (Drummond and Glautier 1994; Monti et al. 1990). However, craving appears to induce relapse if it occurs in stressful situations (Breese et al. 2005; Cooney et al. 1997). Assessment of the specific context that elicits drug urges and relapse thus appears very important.

4.6. USING IMAGING TO MAKE CLINICAL DIAGNOSES

So far imaging cannot be applied to facilitate diagnosis of alcohol dependence. However, functional imaging studies can help to identify patients who display strong physiological cue reactivity and who are thus at risk to suffer a relapse when confronted with alcohol-associated cues. Currently, imaging techniques such as fMRI are too expensive for broad clinical use. However, less complicated techniques, such as the affect-modulated startle response, which assesses physiological responses to affectively positive or negative as well as drug-associated stimuli, may help to identify patients with a particularly high relapse risk. Physiological markers such as the startle response that reflect an appetitive response toward drug cues are particularly important because many patients deny alcohol craving during the presentation of alcohol cues but show strong appetitive reactions when assessed with the startle response (Heinz et al. 2003).

Patients who suffer from strong cue-reactivity and a high risk of relapse may specifically profit from certain psychotherapeutic treatments such as cue exposure. Cue exposure has repeatedly been investigated in therapeutic studies; however, to date this treatment approach does not seem to yield significantly better results than standard therapy with cognitive behavioral and supporting interventions (Kavanagh et al. 2004; Lober et al. 2006). However, cue exposure may work best among patients with strong neuronal responses to alcohol cues, and identification of such patients may thus help to treat this subgroup of patients with greater success.

Brain imaging may also be used to assess the effects of additive pharmacotherapy on cue-induced neuronal activation patterns. Hermann and co-workers (2006) showed in one pilot study that cue-induced activation of the thalamus is blocked by acute application of amisulpride in detoxified alcoholics. The group of Anton and co-workers (Myrick et al. 2008) was able to show that cue-induced activation of limbic brain areas is reduced by naltrexone and by the combination of naltrexone and ondansetron in detoxified alcoholics, and alterations in the response to affective cues have been suggested to predict relapse (Heinz et al. 2007a) and may help to identify new pharmacological treatment strategies such as modulation of central stress responses (George et al. 2008).

4.7. SUMMARY AND OUTLOOK

Neurobiological research on different mechanisms of relapse may help to identify individually vulnerable patterns and can be used to adapt treatment toward the individual needs of patients. Moreover, neuroscientiflc research may help to reduce the stigma of addiction, because it shows that alcohol-dependent patients do not suffer from “weak willpower” or “bad intentions,” as suggested early during the 20th century. Instead, brain imaging studies suggest that alcohol-associated cues activate limbic brain areas, which appear to be in part genetically influenced and to respond in an automated, habitlike manner that is hardly influenced by conscious intentions (Heinz et al. 2005a, 2003). Indeed, cue-induced brain activation predicted the relapse risk of alcohol-dependent patients better than conscious craving, a finding that is not surprising when taking into consideration that activation of brain areas such as the striatum is hardly associated with conscious experiences. Therefore, it seems plausible that patients experience drug-craving and drug-seeking behavior "against their own conscious will"; these should not be blamed for their behavior, but instead be treated with the same respect as other patients in the health care system.

Acknowledgment

We thank Professor Fred Rist (Institute of Psychology I: Psychological Diagnostics and Clinical Psychology, University of Münster, Germany) for his expert counseling in describing learning theories of addiction. This work was supported by the Deutsche Forschungsgemeinschatf (HE 2597/4-3m HE 2597/7-3) and the BMBF (NGFN Plus 01GS08159).

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