Opioid dependence: brain structure and function : a magnetic resonance imaging, neuropsychological, and electromagnetic study

Background: Opiod dependence is a chronic severe brain disorder associated with enormous health and social problems. The relapse back to opioid abuse is very high especially in early abstinence, but neuropsychological and neurophysiological deficits during opioid abuse or soon after cessation of opioids are scarcely investigated. Also the structural brain changes and their correlations with the length of opioid abuse or abuse onset age are not known. In this study the cognitive functions, neural basis of cognitive dysfunction, and brain structural changes was studied in opioid-dependent patients and in age and sex matched healthy controls. Materials and methods: All subjects participating in the study, 23 opioid dependents of whom, 15 were also benzodiazepine and five cannabis co-dependent and 18 healthy age and sex matched controls went through Structured Clinical Interviews (SCID) to obtain DSM-IV axis I and II diagnosis and to exclude psychiatric illness not related to opioid dependence or personality disorders. Simultaneous magnetoencephalography (MEG) and electroencephalography (EEG) measurements were done on 21 opioid-dependent individuals on the day of hospitalization for withdrawal therapy. The neural basis of auditory processing was studied and pre-attentive attention and sensory memory were investigated. During the withdrawal 15 opioid-dependent patients participated in neuropsychological tests, measuring fluid intelligence, attention and working memory, verbal and visual memory, and executive functions. Fifteen healthy subjects served as controls for the MEG-EEG measurements and neuropsychological assessment. The brain magnetic resonance imaging (MRI) was obtained from 17 patients after approximately two weeks abstinence, and from 17 controls. The areas of different brain structures and the absolute and relative volumes of cerebrum, cerebral white and gray matter, and cerebrospinal fluid (CSF) spaces were measured and the Sylvian fissure ratio (SFR) and bifrontal ratio were calculated. Also correlation between the cerebral measures and neuropsychological performance was done. Results: MEG-EEG measurements showed that compared to controls the opioid-dependent patients had delayed mismatch negativity (MMN) response to novel sounds in the EEG and P3am on the contralateral hemisphere to the stimulated ear in MEG. The equivalent current dipole (ECD) of N1m response was stronger in patients with benzodiazepine co-dependence than those without benzodiazepine co-dependence or controls. In early abstinence the opioid dependents performed poorer than the controls in tests measuring attention and working memory, executive function and fluid intelligence. Test results of the Culture Fair Intelligence Test (CFIT), testing fluid intelligence, and Paced Auditory Serial Addition Test (PASAT), measuring attention and working memory correlated positively with the days of abstinence. MRI measurements showed that the relative volume of CSF was significantly larger in opioid dependents, which could also be seen in visual analysis. Also Sylvian fissures, expressed by SFR were wider in patients, which correlated negatively with the age of opioid abuse onset. In controls the relative gray matter volume had a positive correlation with composite cognitive performance, but this correlation was not found in opioid dependents in early abstinence. Conclusions: Opioid dependents had wide Sylvian fissures and CSF spaces indicating frontotemporal atrophy. Dilatation of Sylvian fissures correlated with the abuse onset age. During early withdrawal cognitive performance of opioid dependents was impaired. While intoxicated the pre-attentive attention to novel stimulus was delayed and benzodiazepine co-dependence impaired sound detection. All these changes point to disturbances on frontotemporal areas.Huumeriippuvuus on krooninen aivosairaus, joka johtaa aineen jatkuvaan käyttöön huolimatta käytön aiheuttamista vakavista haitoista kaikilla elämän alueilla. Huumeriippuvuuteen liittyy myös huomattava huumeidenkäytön uusiutumisriski erityisesti varhaisen vieroituksen aikana, mutta vielä pitkänkin päihteettömän ajanjakson jälkeen. Tutkimuksen tavoitteena oli selvittää pitkäaikaisen opioidien (heroiini ja buprenorfiini) väärinkäytön vaikutusta aivojen rakenteeseen magneettikuvauksella ja toimintaan aivojen sähköisiä vasteita mittaavilla elektroenkefalografia (EEG) - ja magnetoenkefalografiatutkimuksilla (MEG). Lisäksi kognitiivista suoriutumista selvitettiin varhaisen vieroitushoidon aikana neuropsykologisilla testeillä. Tutkimukseen osallistui 23 opioidiriippuvaista henkilöä, joista 15 oli myös bentsodiatsepiiniriippuvaisia. Tutkittavilla oli vakava pitkäaikainen opioidiriippuvuus. Tutkittavien tuloksia verrattiin iältään ja sukupuoleltaan vastaavien terveiden henkilöiden tutkimustuloksiin. Kaikille tutkittaville tehtiin strukturoidut psykiatriset haastattelut, joilla pois suljettiin sellaiset psykiatriset sairaudet, jotka eivät liity päihteiden käyttöön tai persoonallisuushäiriöihin. Kaikilla opioidiriippuvaisilla oli persoonallisuushäiriöitä, mutta verro-keilla ei niitä todettu. Vieroitushoitoon tulopäivänä opioidiriippuvaisille tehtiin samanaikainen EEG-MEG mittaus, jossa tutkittiin kuulovasteita. Tahatonta tarkkavaisuutta tutkittiin ns. poikkeavuusnegatiivisuus vasteella (mismatch negativity, MMN) ja P3a vasteella. MEG-EEG mittauksessa potilailla olivat MMN vaste EEG mittauksessa ja P3a vaste MEG mittauksessa viivästyneet viitaten tahattoman tarkkaavaisuuden muutokseen. Näitä vasteita pidetään kognitiivisina, alkeellista työmuistia edustavina vasteina. Potilailla, joilla oli myös bentsodiatsepiiniriippuvuus, oli kuuloärsykkeen aiheuttama vaste voimistunut. Aineiden sekakäyttö siis lisäsi kuulovasteen muutoksia. Vieroitushoidon aikana 15 opioidiriippuvaiselle tehtiin laaja neuropsykologinen tutkimus, jolla selvitettiin joustavaa älykkyyttä, muistin eri osa-alueita ja toiminnan ohjausta. Neuro-psykologisessa testissä potilaat menestyivät verrokeita huonommin tarkkavaisuutta ja työmuistia (PASAT) sekä toiminnan ohjausta (RFFT) ja joustavaa älykkyyttä mittaavissa tes-teissä (CFIT). PASAT ja CFIT testien tulokset korreloivat positiivisesti vieroitushoidon kestoon. Opioidiriipuvaisten kokonaissuoriutuminen neuropsykologisissa testeissä vieroitusvaiheessa oli verrokeita vaatimattomampi. Kahden viikon vieroitushoitojakson lopussa 17 opioidiriippuvaista kävi aivojen 1,5 T magneettiikuvauksessa. Kuvista analysoitiin valkean ja harmaan aineen sekä aivoselkäydin-nestetilojen tilavuudet sekä tehtiin aivorakenteiden pinta-ala mittauksia ja laskettiin rakenteiden suhteita. Myös korrelaatiot eri tutkimustulosten ja päihdehistorian välille laskettiin. Aivojen magneettiikuvauksessa todettiin, että aivojen sivukammiot olivat laajemmat kuin verrokeilla. Opioidiriipuvaisilla Sylvian uurteet oli leveämmät suhteessa aivojen poikkimittaan kuin verrokeilla ja tämä suhde korreloi opioidien käytön aloitusikään. Löydös viittaa aivojen otsa- ja ohimolohkojen surkastumiseen. Aivojen tilavuusmittauksissa todettiin aivojen kokonaisvolyymin olevan verrokeita pienempi ja suhteellisen aivoselkäydinnestemäärän olevan tutkittavilla merkittävästi verrokeita suurempi. Verrokeilla neuropsykologinen kokonaissuoriutuminen korreloi positiivisesti harmaan aineen määrään, mutta opioidirippuvaisilla henkilöillä tällaista korrelaatiota ei havaittu, voidaan siis ajatella vieroitusvaiheen muutosten heikentävän opioidiriippuvaisten suoriutumista ehkä pysyvämpiä muutoksia enemmän. Kaikissa eri tutkimuksissa saadut tulokset viittaavat pääosin otsa- ja ohimolohkojen toiminnan ja rakenteen muutoksiin opioidiriippuvaisilla

Using machine-learning approach to distinguish patients with methamphetamine dependence from healthy subjects in a virtual reality environment

Background: The aim of this study was to evaluate whether machine learning (ML) can be used to distinguish patients with methamphetamine dependence from healthy controls by using their surface electroencephalography (EEG) and galvanic skin response (GSR) in a drug-simulated virtual reality (VR) environment. Methods: A total of 333 participants with methamphetamine (METH) dependence and 332 healthy control subjects were recruited between January 2018 and January 2019. EEG (five electrodes) and GSR signals were collected under four VR environments: one neutral scenario and three METH-simulated scenarios. Three ML classification techniques were evaluated: random forest (RF), support vector machine (SVM), and logistic regression (LR). Results: The MANOVA showed no interaction effects among the two subject groups and the 4 VR scenarios. Taking patient groups as the main effect, the METH user group had significantly lower GSR, lower EEG power in delta (p < .001), and alpha bands (p < .001) than healthy subjects. The EEG power of beta band (p < .001) and gamma band (p < .001) was significantly higher in METH group than the control group. Taking the VR scenarios (Neutral versus METH‐VR) as the main effects, the GSR, EEG power in delta, theta, and alpha bands in neutral scenario were significantly higher than in the METH‐VR scenario (p < .001). The LR algorithm showed the highest specificity and sensitivity in distinguishing methamphetamine‐dependent patients from healthy controls. Conclusion: The study shows the potential of using machine learning to distinguish methamphetamine-dependent patients from healthy subjects by using EEG and GSR data. The LR algorithm shows the best performance comparing with SVM and RF algorithm

Development of EEG gama indicies of cue reactivity to assess functional outcomes of neurofeedback training in substance use disorder.

In 2006 it was estimated by the Substance Abuse and Mental Health Service Administration (SAMHSA, 2007) that 19.9 million Americans used illicit drugs, computing to roughly 8.0 % of the United States population. In 2007, there were 2.1 million active cocaine users, comprising 0.8 percent of the population. The National Institute on Drug Abuse (NIDA) estimates that the total expenditure of drug-related complications is greater than 500 billion dollars when healthcare, legal procedures and job loss are considered. Research has shown that prolonged drug use has a profound effect on the EEG recordings of drug addicts when compared to controls during cue reactivity tests. Cue reactivity refers to a phenomenon in where individuals with a history of drug abuse exhibit excessive psychophysiological responses to cues associated with their drug of choice. The goal of this research is to develop gamma band EEG indices to determine the effectiveness of neurofeedback therapies which are thought to offer a non-invasive method of mediating EEG abnormalities resulting from prolonged substance abuse. Method: Ten current cocaine abusers were treated using neurofeedback protocol to simultaneously increase SMR and decrease Theta activity, combined with Motivational Interviewing sessions. Eight of them completed all planned pre and post-neurofeedback cue reactivity tests with event-related EEG recording and clinical evaluations. Cue reactivity tests consisted of a visual oddball task with images from the International Affective Picture System and drug-related pictures. Evoked and induced gamma responses to target and non-target drug cues were analyzed using wavelet analysis and coherence protocols via custom algorithms implemented in MatLab. Results: Outpatient subjects with cocaine addiction completed the bio-behavioral intervention and successfully increased SMR while keeping theta practically unchanged in 12 sessions of neurofeedback training. Neurofeedback treatment resulted in a lower EEG gamma reactivity to drug-related images in a post-neurofeedback cue reactivity test. In particular, evoked gamma showed decreases in power to non-target and target drugrelated cues at all topographies (left, right, frontal, parietal, medial, inferior); while induced gamma power decreased globally to both target and non-target drug cues. Also, long range coherence was found to increase in specified electrode pairings post neurofeedback. Our findings supported our hypothesis that gamma band cue reactivity measures are sufficiently sensitive to functional outcomes of neurofeedback treatment. Both evoked and induced gamma measures were found capable of detecting changes in EEG responses to both target and non-target drug cues. Conclusion: Our study emphasizes the utility of cognitive neuroscience methods based on EEG gamma band measures for the assessment of the functional outcomes of neurofeedback-based bio-behavioral interventions for addictive disorders. This approach may have significant potential for identifying both physiological and clinical markers of treatment progress. These methodologies can also be adapted and used in additional pathologies to provide fast and reproducible evidence of treatment outcomes

High-performance detection of alcoholism by unfolding the amalgamated EEG spectra using the Random Forests method

We show that by unfolding the outdated EEG standard bandwidths in a fine-grade equidistant 99-point spectrum we can precisely detect alcoholism. Using this novel pre-processing step prior to entering a random forests classifier, our method substantially outperforms all previous results with a balanced accuracy of 97.4 percent. Our machine learning work contributes to healthcare and information systems. Due to its drastic and protracted consequences, alcohol consumption is always a critical issue in our society. Consequences of alcoholism in the brain can be recorded using electroencephalography (EEG). Our work can be used to automatically detect alcoholism in EEG mass data within milliseconds. In addition, our results challenge the medically outdated EEG standard bandwidths

The effects of prolonged abstinence on the processing of smoking cues: an ERP study among smokers, ex-smokers and never-smokers

Abstract Processing bias is an important feature of substance abuse. The issue whether processing bias is a more or less permanent feature of nicotine addiction remains to be resolved. The present study addresses the role of smoking status on smoking-related processing bias. We employed Event-Related Brain Potentials (ERPs) as measure of processing bias to investigate this issue. Further, self-report measures of nicotine craving and pleasantness ratings of smoking stimuli were obtained. Three groups, smokers, ex-smokers and never-smokers, were compared on their electrophysiological brain response to smoking-related and neutral pictures. The present study shows that both the P300 and SPW amplitudes in response to smoking-related pictures are significantly more enhanced for smokers than for ex-smokers and never-smokers at frontal and central sites, whereas the magnitude of the P300 and SPW amplitudes in response to neutral pictures does not differ between the three groups. Accordingly, it can be concluded that smokers show more bias for smoking-related pictures than ex-smokers and smokers. Because there is no significant difference between the P300 and SPW amplitudes of ex-smokers and never-smokers, it can also be concluded that ex-smokers display the same (low) level of processing bias as never-smokers. In addition, nicotine-craving ratings and pleasantness ratings of smoking stimuli were higher in smokers compared to ex-smokers. It can be concluded that the smoking-related craving, pleasantness rating, and processing bias decreases after a period of prolonged abstinence

Multimodal neurocognitive markers of interoceptive tuning in smoked cocaine

Contemporary neurocognitive models of drug addiction have associated this condition with changes in interoception —namely, the sensing and processing of body signals that fulfill homeostatic functions relevant for the onset and maintenance of addictive behavior. However, most previous evidence is inconsistent, behaviorally unspecific, and virtually null in terms of direct electrophysiological and multimodal markers. To circumvent these limitations, we conducted the first assessment of the relation between cardiac interoception and smoked cocaine dependence (SCD) in a sample of (a) 25 participants who fulfilled criteria for dependence on such a drug, (b) 22 participants addicted to insufflated clorhidrate cocaine (only for behavioral assessment), and (c) 25 healthy controls matched by age, gender, education, and socioeconomic status. We use a validated heartbeat-detection (HBD) task and measured modulations of the heart-evoked potential (HEP) during interoceptive accuracy and interoceptive learning conditions. We complemented this behavioral and electrophysiological data with offline structural (MRI) and functional connectivity (fMRI) analysis of the main interoceptive hubs. HBD and HEP results convergently showed that SCD subjects presented ongoing psychophysiological measures of enhanced interoceptive accuracy. This pattern was associated with a structural and functional tuning of interoceptive networks (reduced volume and specialized network segregation). Taken together, our findings provide the first evidence of an association between cardiac interoception and smoked cocaine, partially supporting models that propose hyper-interoception as a key aspect of addiction. More generally, our study shows that multimodal assessments of interoception could substantially inform the clinical and neurocognitive characterization of psychophysiological and neurocognitive adaptations triggered by addiction.Fil: de la Fuente de la Torre, Laura Alethia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Sedeño, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Schurmann Vignaga, Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Ellmann, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Sonzogni, Silvina Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Belluscio, Laura María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Castagnaro, Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Boano, Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Cetkovich Bakmas, Marcelo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Torralva, Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Cánepa, Eduardo César. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Tagliazucchi, Enzo Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Universidad Nacional de Cuyo; ArgentinaFil: Ibañez, Agustin Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Universidad Autónoma del Caribe; Colombia. Universidad Adolfo Ibañez; Chil

Executive Dysfunction and Reward Dysregulation: Interactions in Drug Addiction

Cocaine addiction is a serious public health hazard, and contributes to disastrous outcomes for individuals who suffer from it. Addiction is accompanied by an inability to control one\u27s own behavior, and a preoccupation with cocaine at the expense of other rewarding pursuits. Previous research has suggested that difficulties with executive function and reward processing may underlie these problems, but the extent to which each contributes to addiction severity, or how these two factors may interact, remains to be elucidated. By using event related potential (ERP) measures in combination with information about self-reported anhedonia over three experiments, we set out to more clearly define the phenotype of cocaine addiction and to investigate the extent to which executive dysfunction and reward dysregulation are associated with addiction severity. A model was designed to examine these factors. In addition, in a fourth study we investigated the integrity of executive functioning in both neutral and emotional contexts in abstinent cocaine users. We found that cocaine users show much more anhedonia than controls, and this anhedonia is associated with addiction severity. In addition, anhedonia is associated with poorer ability to monitor behavior when working toward reward, with increased reward motivation in both controls and cocaine users, and also with reduced consummatory reward response in cocaine users. Intriguingly, however, anhedonia is not associated with executive function deficits that are found in cocaine users, and these same executive function deficits are not associated with addiction severity. Finally, we show these executive function deficits to be normalized in abstinent cocaine abusers, and show that abstinent cocaine abusers do not modulate inhibitory response in response to emotional stimuli. Combined, these findings suggest that addiction is a phenotype defined by the presence of both reward dysregulation and executive dysfunction, and that reward dysregulation especially is associated with increased severity of the syndrome. These findings are then discussed in terms of a possible mechanistic model

Evidence of Neurotoxicity of Ecstasy: Sustained Effects on Electroencephalographic Activity in Polydrug Users

According to previous EEG reports of indicative disturbances in Alpha and Beta activities, a systematic search for distinct EEG abnormalities in a broader population of Ecstasy users may especially corroborate the presumed specific neurotoxicity of Ecstasy in humans.105 poly-drug consumers with former Ecstasy use and 41 persons with comparable drug history without Ecstasy use, and 11 drug naives were investigated for EEG features. Conventional EEG derivations of 19 electrodes according to the 10-20-system were conducted. Besides standard EEG bands, quantitative EEG analyses of 1-Hz-subdivided power ranges of Alpha, Theta and Beta bands have been considered.Ecstasy users with medium and high cumulative Ecstasy doses revealed an increase in Theta and lower Alpha activities, significant increases in Beta activities, and a reduction of background activity. Ecstasy users with low cumulative Ecstasy doses showed a significant Alpha activity at 11 Hz. Interestingly, the spectral power of low frequencies in medium and high Ecstasy users was already significantly increased in the early phase of EEG recording. Statistical analyses suggested the main effect of Ecstasy to EEG results.Our data from a major sample of Ecstasy users support previous data revealing alterations of EEG frequency spectrum due rather to neurotoxic effects of Ecstasy on serotonergic systems in more detail. Accordingly, our data may be in line with the observation of attentional and memory impairments in Ecstasy users with moderate to high misuse. Despite the methodological problem of polydrug use also in our approach, our EEG results may be indicative of the neuropathophysiological background of the reported memory and attentional deficits in Ecstasy abusers. Overall, our findings may suggest the usefulness of EEG in diagnostic approaches in assessing neurotoxic sequela of this common drug abuse