The neurobiology of addiction: the perspective from magnetic resonance imaging present and future.

BACKGROUND AND AIMS: Addiction is associated with severe economic and social consequences and personal tragedies, the scientific exploration of which draws upon investigations at the molecular, cellular and systems levels with a wide variety of technologies. Magnetic resonance imaging (MRI) has been key to mapping effects observed at the microscopic and mesoscopic scales. The range of measurements from this apparatus has opened new avenues linking neurobiology to behaviour. This review considers the role of MRI in addiction research, and what future technological improvements might offer. METHODS: A hermeneutic strategy supplemented by an expansive, systematic search of PubMed, Scopus and Web of Science databases, covering from database inception to October 2015, with a conjunction of search terms relevant to addiction and MRI. Formal meta-analyses were prioritized. RESULTS: Results from methods that probe brain structure and function suggest frontostriatal circuitry disturbances within specific cognitive domains, some of which predict drug relapse and treatment response. New methods of processing imaging data are opening opportunities for understanding the role of cerebral vasculature, a global view of brain communication and the complex topology of the cortical surface and drug action. Future technological advances include increases in MRI field strength, with concomitant improvements in image quality. CONCLUSIONS: The magnetic resonance imaging literature provides a limited but convergent picture of the neurobiology of addiction as global changes to brain structure and functional disturbances to frontostriatal circuitry, accompanied by changes in anterior white matter.The authors receive support from the Behavioural and Clinical Neuroscience Institute, jointly funded by the Medical Research Council and the Wellcome Trust, and the National Institute for Health Research Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Wiley via https://doi.org doi:10.1111/add.1347

Relationship between white matter changes and aggression in methamphetamine dependence

Background: Methamphetamine (MA) abuse is a growing problem in the world and especially in South Africa’s Western Cape. Amphetamine-type stimulants have become the second most widely abused illicit drugs worldwide. Admission data from substance abuse treatment centres in the Western Cape show the fastest increase for any drug ever noted in the country in MA related admissions. MA has neurotoxic effects on the brain leading, amongst other effects, to white matter (WM) changes. Moreover, increased levels of aggression are commonly found in individuals with MA abuse. Although behavioural deficits are well described, the underlying mechanisms are still poorly understood. While previous studies have examined WM abnormalities relating to cognitive impairment, none have investigated associations between WM integrity in individuals with MA dependence and aggression. Methods: Diffusion Tensor Imaging (DTI) was used to investigate WM changes in 40 individuals with MA dependence and 40 matched healthy control subjects. Aggression was measured with the Buss & Perry Questionnaire in 40 MA users and 36 controls. Two approaches to assess WM integrity in the brain were employed. First, whole brain voxel wise comparison across subjects using tract based spatial statistics (TBSS) in FSL was used. Fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (λ║) and perpendicular diffusivity (λ┴) were compared between the two groups. Second, a region of interest (ROI) approach was used, which focused on three WM tracts in the frontal brain, commonly found to play a role in aggressive behaviour: (1) the genu of the corpus callosum (CC), (2) the cingulum and (3) the uncinate fasciculus

The neurostructural effects of prenatal exposure to methamphetamine in an infant population in the Western Cape

Prenatal methamphetamine exposure is associated with functional and neurostructural alterations, but neuroimaging investigations of these effects in infants are almost non-existent. Studies in neonates permit a degree of separation of drug exposure effects from potential confounders in the postnatal environment. Magnetic resonance imaging (MRI) was used to investigate the neurostructural effects of prenatal methamphetamine exposure on neonates recruited from a Cape Town community. Mothers were recruited during pregnancy and interviewed regarding methamphetamine use. Women in the exposure group used methamphetamine at least twice per month during pregnancy, while control mothers did not use methamphetamine. MRI scans were acquired within the first postnatal month. Anatomical images were processed using FreeSurfer and subcortical and cerebellar structures manually segmented with Freeview. Volumes were regressed with methamphetamine exposure (days/month of pregnancy) and related confounding variables, including total brain volume, gestational age at scan, exposure to cigarette smoking and infant sex. Diffusion data were processed with FSL, and diffusion tensors and tensor parameters determined using AFNI. Probabilistic tractography defined white matter connections between target regions. For the first analysis, five major white matter networks (commissural, and bilateral projection and association networks) were defined between spherical targets. For the second analysis, regions traced in the anatomical study were used as targets. Averaged DTI parameters were then calculated for each connection, and multiple regression analysis determined associations between DTI parameters and methamphetamine exposure at network level and in the individual connections. Methamphetamine exposure was associated with reduced caudate nucleus volume bilaterally, and in the right caudate following adjustment for confounders. Exposure was associated with reduced fractional anisotropy in all major white matter networks, and in individual connections within the limbic meso-cortico-striatal circuit. Exposure was associated with increased radial diffusivity in a subset of these. These results support findings in older children of methamphetamine-induced neurostructural damage, and demonstrate that such effects are already measurable in neonates. Corticostriatal circuit changes may underlie the impaired executive function observed in prenatally exposed children, and suggest a specific mechanism of damage in dopaminergic-related circuits that is consistent with the neurotoxic actions of methamphetamine

Impact of FAAH Genotype and Marijuana Use on Brain Structure and Neuropsychological Performance in Emerging Adults

Introduction: Chronic MJ use may be associated with higher cognitive ability impairments (see Lisdahl et al., 2013). Regions undergoing later maturation (Gogtay 2004), may be at increased risk for MJ-induced alterations. Endogenous cannabinoid signaling (ECS) is modulated by the function the enzyme Fatty Acid Amide Hydrolase (see Ho & Hilard, 2005), thus the gene encoding for this enzyme (FAAH) impacts ECS (Sipe et al., 2002). Here, we examine the impact of MJ use and FAAH genotype on PFC complexity and underlying frontal white matter (WM) integrity in young adults. Methods: Participants included 37 MJ users and 37 non-using young adults (ages 18-25). Of those, 27 were FAAH A carriers and 47 were homozygous (C/C) carriers. Exclusion criteria included co-morbid psychiatric and neurologic disorders and excessive other drug use. Brain complexity and WM integrity was measured using local gyrification index and Tracula programs. The Letter Number Sequencing, PASAT and D-Kefs c/w interference measured complex attention and inhibition. Multiple regressions and Pearson r correlations were used to predict LGI, WM integrity and cognitive performance indices from MJ use status, FAAH status, and MJ*FAAH interactions controlling for demographic variables and comorbid drug use. Results: MJ users demonstrated decreased LGI in bilateral vmPFC (RH: [beta=-.54, p\u3c.001] and LH: [beta=-.55, p\u3c.001]); bilateral mPFC (RH: [beta=-.48, p=.001] and LH: [beta=-.51, p\u3c.001]); and bilateral frontal poles (RH: [beta=-.31, p=.02]; LH: [beta=-.43, p=.004]), with increased LGI in LH DLPFC [beta=.40, p=.004]. Controlling for the same variables, reduced WM integrity was found in bilateral UCF (RH: [beta=.32, p=.03] and LH: [beta=.31, p=.03]) and fMinor [beta=.27, p=.05] tracts of MJ users. Significant interactions between MJ*FAAH were seen predicting LGI in LH OFC [beta=-.24, p=.04] and WM integrity in fMinor [beta=.26, p=.04] and LH ATR [beta=.36, p=.003]. In MJ users, increased gyrification was associated with better LNS performance in RH mPFC [r=.51, p=.001], RH vmPFC [r=.41, p=.01], and RH frontal pole [r=.45, p=.005] and a negative correlation with gyrification and color-word completion time in LH vmPFC [r=-.32, p=.05]. In MJ users, decreased WM integrity was associated with greater PASAT performance in the RH UNC [r=.38, p=.02]. Discussion: MJ use was associated with reduced LGI in several PFC regions with one region showing an opposite relationship. These results are consistent with Mata and colleagues (2010). We also found reduced WM integrity in fronto-temporal tracts, which may have important emotion regulation implications. These brain characteristics were also moderated by FAAH genotype. Additional implications of ECS and brain health will be discussed

Lithium, magnetic resonance and the human brain

PhD ThesisThis thesis explores the effects of lithium on the human brain using structural, functional and spectroscopic magnetic resonance techniques. Contemporary issues surrounding the pharmacological effects of lithium are investigated and aspects of its pharmacokinetics examined. Bipolar disorder is known to be associated with dysfunction of themonoaminergic neurotransmitter systems of the brain. It is proposed that the antimanic properties of lithium derive from its attenuation of the actions of dopamine. In a randomised, placebo-controlled study of lithium involving 24 healthymen, mania was modelled by the administration of methamphetamine. Sustained attention, known to be disturbed in mania, was assessed during functional magnetic resonance imaging. Within the lithium group, response times were slowed and the effects of methamphetamine on functional magnetic resonance imaging contrast diminished. These findings are discussed in the context of current theories and contrasted with existent data. Lithium has been reported to increase the volume of grey matter in the brain in numerous magnetic resonance imaging studies. This observation was replicated in a longitudinal, voxel-based morphometry study of 31 healthy men. Combining quantitative imaging with various structural analysis techniques, it is argued that the grey matter change may be better accounted for by lithium altering the relaxation characteristics of protons; that is to say, signal change not true volume expansion. The biophysical basis of this theory is discussed, together with its implications. The pharmacokinetic properties of lithium in man are incompletely characterised, in particular its distribution in various tissues of the brain. The development of a magnetic resonance spectroscopy tool is described; its purpose was to determine the concentration of lithium in grey and white matter in a time-scale suited to clinical practice. Lithium was found to be evenly distributed in the brain regions examined, with total acquisition times constrained to less than óþ minutes. The applications and future developments of in vivo lithium spectroscopy are considered. It is concluded that variousmagnetic resonance techniquesmay be usefully applied to the investigation of the interactions between lithium and the human brain.The Medical Research Council, Clinical Research Training Fellowship

Cocaine addiction in the rat: alterations in brain functions and novel medications

Cocaine addiction is a chronic mental illness affecting a small subgroup of cocaine users (approx. 18%). Little efforts have been taken so far to understand individual differences in the vulnerability to cocaine addiction; i.e. it is unclear why some users become addicted whereas the majority of them are able to maintain the control over drug-taking and -seeking. Most preclinical studies have not considered the possibility to study individual differences in addiction vulnerability and furthermore may explain the high failure rates of drugs that reach Phase III-IV of clinical trials. Hence, a translational animal model is fundamental to produce meaningful results to the clinic. In this thesis, a DSM-IV/5-based preclinical model of cocaine addiction was used to identify pre-existing vulnerability differences and the changes produced by pathological state of addiction. The so-called 0/3crit animal model consists of training rats for intravenous cocaine self-administration for at least 45 sessions. Thereafter, three main DSM-based addiction behavioral criteria were tested, (1) motivation to take the drug, (2) persistence to seek the drug, and (3) persistence of self-administration despite negative consequences (i.e., application of an electric foot-shock). For each of the three criteria, a score of either 1 or 0 was given to animals performing above or below 60th percentile of the population distribution, respectively. Animals positive for all criteria (3crit) were classified as addicted-like, whereas animals negative for all criteria (0crit) were classified as non-addicted-like/resilient rats. This thesis had three aims: (i) Neuroimaging studies in cocaine addicts revealed various structural and functional changes but findings are inconclusive and this may be due to pre-existing features in the function or structure in brains of vulnerable subjects and different drug intake patterns. Based on this, longitudinal studies, particularly in controlled animal models, are warranted. Here a longitudinal translational multimodal neuroimaging study was performed using the 0/3crit animal model of cocaine addiction to investigate pre-existing differences and changes in brains of cocaine addicted-like and non-addicted-like rats. (ii) Conditioned cocaine cues can trigger craving and relapse. Pavlovian conditioned stimuli can also impact ongoing instrumental behavior, even if the instrumental behavior is acquired independently of Pavlovian conditioning. This process is called Pavlovian-to-Instrumental transfer (PIT). A hypothesis in drug addiction posits that Pavlovian conditioned cues can bias instrumental behavior towards drug seeking and intake and that a more pronounced PIT response occurs in vulnerable subjects. The second aim was therefore to test this hypothesis and to ask whether 3crit rats show a more pronounced PIT response than 0crit rats. (iii) Pharmacological treatments in cocaine addiction are still lacking. In previous preclinical studies different glutamate receptor antagonists and GABAB agonists such as baclofen, have been tested but either failed in clinical studies or reported severe side effects in pharmacovigilance. Here, different pharmacological approaches were taken: First, the novel GABAB positive allosteric modulator CMPPE was tested in comparison to baclofen in order to produce lesser side effects. Second the NR3A subunit was selectively targeted as an alternative to NMDAR antagonists. Finally, melatonin was tested for normalizing altered circadian rhythmicity in cocaine addiction. The longitudinal MRI results revealed structural changes in the brains of 3crit and 0crit rats. Grey matter (GM) volume was found to have increased in prelimbic (Prl) and cingulate (Cg) cortices, nucleus accumbens (NAc), caudate putamen (CPu), substantia nigra, and ventral and globus pallidum in the 3crit group, whereas 0crit rats showed no changes in GM volume, except for the CPu, compared to control. Diffusion tensor imaging (DTI) analysis revealed a higher fractional anisotropy in the zona incerta in the 0crit rats compared to 3crit rats. PET results showed higher activity of mPFC and right CPu in the 0crit group compared to controls. Arc expression was significantly reduced in the infralimbic (IFL) cortex in the 3crit group. Salience of conditioned-cues was found similar in 0crit and 3crit rats in the PIT paradigm. Positive allosteric modulator of GABAB receptors and melatonin abolished cue-elicited cocaine-seeking behavior. In summary, cocaine addiction produced structural changes in brain regions central for motivation and drug rewarding effects in 3crit rats, whereas the addiction resilient rats showed increased volume in brain regions involved in habit behavior as well as an increased in microstructural integrity in a brain area that regulates adaptive behavior. Functional assessments indicated the relevance of the mPFC (Prl and IFL) activity for both controlled or compulsive drug-seeking and –taking. These results agree with clinical studies, where mPFC function negatively correlates with impulsive behavior in psychostimulant abusers as well as changes were found in brain regions, such as Prl, Cg, CPu, and NAc, that are known to play a role in drug addiction. Moreover, other factors, such as structural and functional changes, instead of Pavlovian or instrumental conditioning may lead to addiction behaviors because salience to conditioned stimuli and learning ability were similar between the groups. And finally, positive allosteric modulator of GABAB receptors and melatonin appears to be promising candidates for medication development in cocaine addiction. The 0/3crit model of cocaine addiction has excellent face validity and can be used to study the underpinning mechanisms that lead to compulsive drug use

Harm reduction for alcohol and other drug use in young people: The seductive allure of neuroscience

A predominance of mental disorders, including substance use disorders, arise during adolescence and track into adulthood. Protracted neurodevelopment may promote the onset and escalation of substance use and increase the vulnerability to harm, however to date there has been no comprehensive review of neurobiological and cognitive risk factors and consequences of illicit substance use. Effective public health efforts to reduce the harms of substance use among young people are critically important. Senior secondary school represents an optimal developmental period to effect change, however age-appropriate interventions targeting this older age group are extremely limited. Moreover, neuroscience-based preventive interventions are virtually non-existent. This thesis aims to first, investigate the impact of substance use on neurodevelopment and second, to develop and evaluate neuroscience-based resources that reduce substance-use related harms in late adolescents. Study 1 is a comprehensive, quantitative systematic review of the neurobiological and cognitive precursory risks and consequential harms of illicit substance use in young people. The review reports few neurodevelopmental risk factors and many structural, functional and cognitive consequences following frequent illicit substance use, which demonstrate some degree of recovery following abstinence. Study 2 evaluates neuroscience-based animations and neuroscience-literacy levels among young people. The findings support the use of neuroscience in substance use education, however, indicates the belief in neuromyths continue to persist. Studies 3-5 outline the development and evaluation of a neuroscience-based, harm reduction program known as The Illicit Project, in secondary schools across New South Wales, Australia. The results from a cluster randomised controlled trial indicate the intervention is feasible and effective in reducing the likelihood of risky alcohol, cannabis, MDMA and tobacco use, as well as reducing alcohol-related harms, and improving drug literacy levels among late adolescents. Overall, this body of studies makes a substantial contribution to the fields of substance use and prevention science through the development and translation of new knowledge into effective resources for young people

Neuropharmacology and toxicology of novel amphetamine-type stimulants

In recent years there has been a large increase in the use of a new kind of amphetamine- type stimulants known as substituted cathinones. These compounds have a short history of human use, and little is known about their potential neurotoxicity. Two of the most popular substituted cathinones, 4-methylmethcathinone (4-MMC, mephedrone) and 3,4- methylenedioxymethcathinone (MDMC, methylone} are, aside from their β-ketone group, close structural analogues of potentially neurotoxic amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). This has led to concern about the potential neurotoxicity of these novel compounds, and warrants a closer investigation into their possible long-term neurotoxic effects. METHODS The long-term effects of METH and MDMA as well as 4-MMC and MDMC were assessed using a range of biochemical assays, including assessment of monoamine levels and their transporters. The effects on brain activity were investigated using manganese-enhanced magnetic resonance imaging. Furthermore, behavioral experiments assessing cognition and neuropsychiatric function were performed. Finally, in vitro experiments in a neuroblastoma cell line were performed to identify mechanisms responsible for the observed differences in toxicity between the amphetamines and cathinones. RESULTS Unlike METH and MDMA, which produced strong reductions in dopamine and serotonin levels or brain activation, 4-MMC produced few notable effects on monoamine levels and had only minor effects on brain activation, although MDMC produced a reduction in 5-HT levels similar to MDMA. No clear effects on behavioral tests of memory function were observed as both increases and decreases in test performance were seen following 4- MMC and MDMC. In vitro experiments revealed that cathinones differ from amphetamines in their redox properties, and 4-MMC produced different effects than METH on the mitochondrial electron transport chain. CONCLUSIONS The substituted cathinones 4-MMC and MDMC do not appear to be more neurotoxic than METH and MDMA. If anything, they show a more favorable safety profile. Therefore, these substances do not appear to present an imminent and severe threat to public health. From a harm reduction perspective, these compounds may be good alternatives toMETH and MDMA. However, future work is needed to assess with certainty the long- term effects of amphetamine-type stimulants in humans.Miten myrkyllisiä muuntohuumeet ovat? Viime vuosina on tullut saataville uusia huumaavasti vaikuttavia aineita, jotka on hieman muutettu aikaisemmin tunnetuista laittomista huumeista. Näitä muuntohuumeita olivat mm. mefedroni, metyloni, MDPV ja alfa-PVP. Niitä myytiin aluksi internetin kautta, kunnes viranomaiset saivat ne luokitelluksi huumausaineiksi. Suurena huolena näiden uusien aineiden käytössä oli se, ettei niiden myrkyllisyydestä tai pitkäaikaisista haitoista ollut tutkimustuloksia. Käyttäjät ottivatkin suuren riskin kokeillessaan näitä laillisia huumeita (legal highs) heti niiden tullessa saataville. Koska em. aineiden rakenteet muistuttavat metamfetamiinin ja ekstaasin rakenteita, niillä otaksuttiin olevan samanlaisia toksisia vaikutuksia aivoihin ja elimistöön. Tässä työssä tutkittiin kokeellisesti mefedronin ja metylonin mahdollisia haittavaikutuksia aivojen välittäjäaineiden vaikutuksiin ja aivojen aktivaatioon, joiden tiedetään olevan herkkiä huumeiden runsaalle käytölle. Metylonin vaikutukset olivat aivojen hippokampuksessa ja otsalohkossa samankaltaisia kuin ekstaasin, jota se rakenteellisesti muistuttaa. Mefedronilla oli vain vähän pitkäaikaisvaikutuksia verrattuna rakenteellisesti läheiseen tunnetusti myrkylliseen metamfetamiiniin. Mm. sen vaikutus aivojen pitkäaikaiseen aktivaatioon oli erilainen kuin metamfetamiinin, joka vähensi useiden aivoalueiden aktivaatiotilaa vielä kaksi viikkoa 4-päivän annostelun jälkeen. Tulostemme perusteella näyttävät pienet erot stimulanttihuumeiden rakenteissa vaikuttavan käytön aiheuttamiin pitkäaikaishaittoihin, vaikka aineet edelleen omaavat riippuvuutta ylläpitävän päihdevaikutuksensa. Jatkotutkimuksia näistä aineista tarvitaan, ja jatkossakin saataville tulevien uusien muuntohuumeiden haittoja tulisi pystyä aktiivisesti selvittämään. Terveyspolitiikan ja haittojen minimointiin pyrkivän päihdepolitiikan tulisi tähdätä sekä käytön minimointiin ja sen suuntaamiseen mahdollisimman vähän haitallisiin päihteisiin