ReviewEffects of non-invasive neurostimulation on craving: A meta-analysis
Introduction
Substance dependence is a chronic relapsing brain disorder that inflicts great costs to affected patients and society in general (Kalivas, 2005). Alcohol dependence alone accounts for approximately 4% of the global mortality rate and substance dependence in general ranks as the 8th cause of death globally (Rehm et al., 2009, WHO, 2010). Furthermore, alcohol and other substance use disorders account for 5.4% of the total global burden of disease (WHO, 2010). During the development of substance dependence, incentive salience of drug related stimuli increases whereas the salience of natural reinforcers declines (Everitt and Robbins, 2005, Hyman, 2005). Impaired inhibitory control, increased salience and craving for the abused substance are related to the development, continuation, and relapse in addictive disorders (Perry and Carroll, 2008). These cognitive and motivational changes are associated with important changes in brain functions in addictive disorders (Kalivas, 2005, Koob and Volkow, 2010). Firstly, repeated drug or alcohol use has been found to lead to neuro-adaptations in the ventral striatum and ventral tegmental areas, which in turn result in decreased dopamine secretion (Volkow et al., 2009). Evidence from both human and rodent studies suggests that these changes are accompanied by increased saliency and craving for the abused substance, and the increased cue-reactivity related to increased salience has its neural basis in increased striatal and orbitofrontal responses to addiction-related cues (Baler and Volkow, 2006, Berridge, 2007, Everitt and Robbins, 2005, Koob and LeMoal, 2008). Secondly, diminished functioning of the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) is present in addictive disorders, presumably underlying diminished cognitive and behavioural control and a higher tendency to cue-induced relapse in alcohol or drug use (Garavan, 2007, van Holst and Schilt, 2011). Furthermore, diminished functioning of frontal brain circuits is related to a higher susceptibility to stress and stress-induced relapse, in the rat brain (Capriles et al., 2003). Together, these compromised brain activity patterns are associated with a higher chance to relapse in methamphetamine, nicotine and cocaine dependent subjects (Janes et al., 2010, Kosten et al., 2006, Paulus et al., 2005).
Drug craving is assumed to be an important risk factor for relapse in patients with substance dependence and, higher craving has indeed been found to be related to higher relapse rates (Oslin et al., 2009, Sinha et al., 2006). Although craving poses a risk for relapse, it can be counteracted by exerting cognitive and behavioural control over the increased motivational drive of craving. Therefore, craving for substances in persons with an addictive disorder presents a problem specifically when the ability to inhibit the drive to use the relevant substance is affected.
Craving for food has been, and often still is, a useful and adaptive process through which the body communicates its needs. For example, craving has been important from an evolutionary perspective for building food reserves during periods of food shortage, and one may crave meat when low on iron (Levin, 2007). However, with the current widespread availability of (processed) high sugar and fat foods in western countries, those previously beneficial cravings pose a risk for developing obesity or binge-eating disorder (May et al., 2012). There is a growing body of evidence suggesting a role for craving in the obesity epidemic (Pelchat, 2009a). Furthermore, there is an ongoing debate on whether there is something like ‘food addiction’ (Corsica and Pelchat, 2010, Ziauddeen and Fletcher, 2013) and if so whether this is mainly true for binge eating behaviour (Gearhardt et al., 2011, Smith and Robbins, 2013, Umberg et al., 2012). Independent of the debate on food addiction, craving for food is well documented (Hill, 2007, Sobik et al., 2005). Furthermore, deficient control processes are frequently reported in obese and binge eating people (Pelchat, 2009b, Volkow et al., 2011, Yanovski, 2003). The combination of loss of control in combination with higher food cravings – especially cravings for palatable or high caloric food, may lead to loss of control over food intake and therefore weight gain. Consistent with this, higher craving for food has been related to higher weight and lack of success in weight loss programmes (Lafay et al., 2001, Vander Wal et al., 2007, Wurtman and Wurtman, 1986).
The neurobiological correlates of craving are hypothesized to be shared between substance dependent patients and people who are craving for high palatable food (Volkow et al., 2013). In fact, there is considerable evidence from human neuroimaging studies implicating the same neural structures in both food and drug craving. The orbitofrontal cortex (OFC) is related to salience attribution to potentially rewarding stimuli, such as food or drugs (Volkow et al., 2013). Increased salience attribution to drugs is an important aspect of addiction (Dom et al., 2005). Increased OFC activity has also been linked to increased food craving in lean healthy controls (Wang et al., 2004). Other studies have also shown that dopamine is related to the desire for both drugs and food (Blum et al., 2011, Volkow et al., 2002). Furthermore, brain activations in amygdala, insula, bilateral orbitofrontal cortex and striatum overlap for food and smoking cues in normal weight individuals (Tang et al., 2012). Moreover, D2-dopamine receptor density in the striatum has been negatively correlated with BMI of obese people (Wang et al., 2001). Lower D2-dopamine receptor density in the striatum is also related cocaine dependence, heavy nicotine and alcohol use (Connor et al., 2007); nicotine craving (Connor et al., 2007, Erblich et al., 2005, Heinz et al., 2004, Volkow et al., 1993); and reduced frontal metabolism in cocaine dependence (Volkow et al., 1993).
Reduced (pre)frontal activation has been reported in obese patients, with and without binges, in reaction to food and food cues. Hypo-activation of the (pre)frontal cortex has been implicated in deficient inhibitory control and hyper-activation of DLPFC in reaction to food stimuli was related to craving for food (Karhunen et al., 2000, Wang et al., 2004). Obese patients show less activation in DLPFC compared to healthy controls after a meal, indicating reduced reactivity to ingestion of food, which may be related to satiation (Le et al., 2006). Also, decreased blood flow in the prefrontal cortex has been associated with higher weight in healthy subjects (Willeumier et al., 2011, Willeumier et al., 2012). Impaired executive control has been reported in obese women (Kishinevsky et al., 2012) whereas successful dieters activate their DLPFC/OFC while eating (DelParigi et al., 2007). Together, these findings implicate the presence of disrupted motivational neural processes and impulse control in obesity (Nijs et al., 2009).
Addiction and obesity are among the biggest health problems of the western world today (Hedley et al., 2004, WHO, 2010). Substance dependence is known for its high relapse rates (Dutra et al., 2008) and as noted before, craving is an important risk factor for relapse (Oslin et al., 2009, Sinha et al., 2006). In a review, McLellan et al. (2000) concluded that only 40–60% of all treatment seeking substance dependent patients were still abstinent at 1 year follow-up. Relapse rates for nicotine dependence are estimated to be around 85% for counselling therapy alone and 78% for counselling combined with medication (Fiore et al., 2008). Furthermore, weight loss programmes are often ineffective for obese patients, as 33% to 66% of patients regain all weight that was lost, or gain even more (Bacon and Aphramor, 2011, Mann et al., 2007). Therefore, the available treatment options are ineffective for a substantial proportion of these patients and new treatment options are clearly needed. Non-invasive neurostimulation such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are new intervention methods that may target the reduction of craving levels in substance dependence and obese or binge eating groups. By reducing craving levels, it would become easier for people with addictive disorders, obesity, or binge eating groups, to maintain control over intake or to remain abstinent.
Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have proven to be effective techniques for altering brain activity (Barr et al., 2008, George and Aston-Jones, 2010). Both techniques induce small electrical currents in the brain that cause alterations in neuronal firing [for a more detailed description, see George and Aston-Jones (2010)]. These techniques can exert both inhibitory and excitatory effects on the brain, depending on the stimulation frequency. In general, low frequency stimulation (<1 Hz) is considered to exert inhibitory effects, whereas high frequency stimulation (>5 Hz) is considered to exert excitatory effects on the brain (Hoffman, 2002, Ziemann et al., 2008). The effects of repeated stimulation (repetitive TMS or rTMS and tDCS), have been proven to last beyond the actual time of stimulation, enabling altered brain activity for an extended period of time (Ziemann et al., 2008). These prolonged effects have potential in the treatment of a variety of disorders. Previous randomized controlled trials of rTMS in depression have indeed shown a decrease in depressive symptoms following repeated high frequency stimulation (Dell’Osso et al., 2011, Lam et al., 2008, Pascual-Leone et al., 1996). The Food and Drug Administration has therefore approved rTMS stimulation as a treatment option for depression (FDA, 2008). Furthermore, recent studies show that stimulation of the DLPFC can acutely decrease craving levels after a single administration of rTMS in samples with nicotine dependence (Amiaz et al., 2009, Eichhammer et al., 2003, Johann et al., 2003), alcohol dependence (Mishra et al., 2010), marijuana dependence (Boggio et al., 2010), cocaine dependence (Politi et al., 2008) and food craving (Montenegro et al., 2012). Although these results seem promising, other studies have failed to show significant decreases in craving in similar populations (Barth et al., 2011, Herremans et al., 2012).
The mechanisms through which tDCS and rTMS exert their effects on the brain are only partly understood, but may involve increased cognitive control, decreased craving, or both. Most studies have used the DLPFC as stimulation site with the aim to reduce craving. Two possible mechanisms through which stimulation may decrease craving levels have been proposed by Diana (2011). Firstly, interconnections of the DLPFC with the ventral tegmental area (VTA) may increase dopamine excretion from the VTA to the ventral striatum, an area that plays a major role in reward processing. Secondly, stimulation of the DLPFC stimulates glutamate containing cortico-fugal fibres, which end on dopamine containing terminals in the ventral striatum (Strafella et al., 2001), potentially increasing dopamine excretion. Both proposed neural mechanisms are supported to some extent by studies in rodents (Carr and Sesack, 2000, Keck et al., 2002) and primates (Frankle and Haber, 2006). There is evidence for anatomical connections between DLPFC and VTA, as Carr and Sesack (2000) labelled retrograde projections from VTA to DLPFC, showing both GABA-containing meso-accumbens neurons and dopamine-containing mesocortical neurons in the rodent brain. Furthermore, Frankle and Haber (2006) reported evidence for anatomical connections between DLPFC and VTA structures in primates by anterograde labelling. Keck et al. (2002) showed that high-frequency rTMS stimulation of the prefrontal rat brain increased dopamine levels in the dorsal hippocampus and the shell of the nucleus accumbens, and increased extracellular dopamine concentrations in the dorsal striatum.
As previously mentioned, neurostimulation may also increase cognitive control and cognitive functioning in general, which is important for preventing relapse (Garavan, 2007). Another mechanism through which non-invasive neurostimulation may reduce craving is through enhancement of DLPFC activity and its connections to the striatum. Cognitive deficiencies related to decreased prefrontal functioning have been reported in substance dependence and might be related to reduced effectiveness of cognitive behavioural therapy (Carroll et al., 2011, Vik et al., 2004). Additionally, the DLPFC is important for actively reducing negative affect by reappraisal, defined as; ‘reinterpreting the meaning of a stimulus to change one's emotional response to it’ (Ochsner and Gross, 2005). For example, changes in craving levels can be achieved by instructing nicotine dependent subjects to think about either the immediate positive effects (rewarding) or delayed negative consequences (like development of lung cancer) of smoking (Kober et al., 2010a). In this study, subjects reported significantly lower craving levels in the ‘delayed negative consequences’ condition, suggesting a possible role for cognitive (reappraisal) strategies in reducing craving levels. Kober et al. (2010b) showed that increased activation of the DLPFC during regulation of craving for nicotine resulted in a decrease in ventral striatum activity and a subsequent decrease in craving levels, pointing towards a potential working mechanism for neurostimulation of the DLPFC. Furthermore, a neuro-stimulation induced increase in dopamine secretion could also increase dopamine concentrations in DLPFC and therefore possibly enhance cognitive control (Volkow et al., 2009). Additionally, there is an increased interest for cognitive enhancers for the treatment of substance dependence (Brady et al., 2011). Cognitive enhancers may improve the cognitive impairments in attention, working memory and response inhibition, which have been frequently reported in substance dependence (Schmaal et al., 2011, Sofuoglu, 2010, Sofuoglu et al., 2013). The effects of rTMS on cognitive functioning in patients suffering from psychiatric or neurological conditions have been reviewed by Guse et al. (2010) and include improvement in executive functioning, response inhibition and selective attention. Impairments in these cognitive functions have been reported in addictive disorders (Fernández-Serrano et al., 2010, Koob and Volkow, 2010, van Holst and Schilt, 2011), but little attention has been given to the application of non-invasive neurostimulation to improve cognitive functions in substance dependence.
The meta-analysis presented in this paper therefore evaluates the available evidence regarding effects of non-invasive neurostimulation (rTMS and tDCS) compared to sham stimulation, in substance dependence and in craving related to high-palatable food. With this review, the potential of these neuro-modulation techniques for the treatment of substance dependence and excessive craving for food in obese or binge-eating groups can be assessed. Furthermore, several additional comparisons were made. Firstly, the choice for the DLPFC as stimulation target is very consistent across studies, but selecting either the left or the right DLPFC is not. Therefore, this meta-analysis also evaluates whether differences exist between the effects of left- or right-DLPFC stimulation. Secondly, to investigate the applicability of neurostimulation across substances, effects of neuro-modulation studies in specific substances are compared. Thirdly, food craving studies are compared to studies that focus on craving in substance dependence, to assess differences in effectiveness. Finally, tDCS and rTMS were compared in order to assess whether these different stimulation techniques differ in effectiveness.
Section snippets
Inclusion criteria for the selection of studies
In order to prevent information bias and to control for placebo effects, only double-blind RCTs comparing the effect of rTMS or tDCS stimulation with sham stimulation of the DLPFC on craving levels were included in the meta-analysis. All studies included in this meta-analysis had craving reduction as a primary outcome measure. The selected studies only concerned high frequency stimulation studies. All studies assessed craving levels in alcohol, nicotine, cocaine and marijuana dependent
Search results
The initial search resulted in 76 potentially eligible studies, which were then subjected to closer inspection. For several reasons, 59 studies were excluded from the meta-analysis (see Fig. 1). Exclusion criteria included: studies assessing the effects of other stimulation techniques than tDCS or rTMS (such as nervus vagus stimulation and electro convulsive therapy) or studies assessing the effect of DLPFC stimulation on other topics than craving (e.g. Parkinson's disease, chronic pain,
Discussion
This random effects meta-analysis of 17 studies revealed a significant medium effect size (Hedge's g = 0.476) favouring non-invasive DLPFC neurostimulation over sham stimulation in the reduction of substance or food craving. No significant differences were found between rTMS and tDCS, between the different substances or food, or between left and right DLPFC stimulation. Both rTMS and tDCS were administered without anaesthetics and did not cause significant side effects.
It should be noted that
Acknowledgement
The research was funded by The European Foundation for Alcohol Research (ERAB), EA 10 27 “Changing the vulnerable brain: a neuromodulation study in alcohol dependence”
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