Proof-of-concept trial of Goal Management Training+ to improve executive functions and treatment outcomes in methamphetamine use disorder.

BACKGROUND: Deficits in executive function are common in methamphetamine use disorder (MUD), likely contributing to difficulties in sustained treatment success. Cognitive remediation interventions are designed to treat such deficits but have not been adapted to the needs of people with MUD. This study presents a proof-of-concept trial to evaluate a new cognitive remediation program for MUD, Goal Management Training+ (GMT+). METHODS: This was a cluster-randomised crossover trial comparing GMT+ with a psychoeducation-based control (Brain Health Workshop; BHW). GMT+ is a therapist-administered group-based cognitive remediation for executive dysfunction comprising four 90-minute weekly sessions and daily journal activities. BHW is a lifestyle psychoeducation program matched to GMT+ for therapist involvement, format, and duration. Participants (n = 36; GMT n = 17; BHW n = 19) were recruited from therapeutic communities in Victoria, Australia. Primary outcomes included intervention acceptability, feasibility, and improvements in self-reported executive function. Secondary outcomes included cognitive tests of executive function, severity of methamphetamine dependence, craving, and quality of life. We performed mixed linear modelling and calculated Hedges' g effect sizes. RESULTS: GMT+ participant ratings and program retention indicated high acceptability. There was no difference between GMT+ and BHW on self-reported executive function (g = 0.06). Cognitive tasks suggested benefits of GMT+ on information gathering (g = 0.88) and delay-discounting (g = 0.80). Severity of methamphetamine dependence decreased more in GMT+ (g = 1.47). CONCLUSIONS: GMT+ was well-accepted but did not improve self-reported executive functioning. Secondary outcomes suggested GMT+ was beneficial for objective cognitive performance and severity of dependence.

Neural network modelling reveals changes in directional connectivity between cortical and hypothalamic regions with increased BMI.

BACKGROUND/OBJECTIVES: Obesity has been ascribed to corticostriatal regions taking control over homeostatic areas. To test this assumption, we applied an effective connectivity approach to reveal the direction of information flow between brain regions and the valence of connections (excitatory versus inhibitory) as a function of increased BMI and homeostatic state. SUBJECTS/METHODS: Forty-one participants (21 overweight/obese) underwent two resting-state fMRI scans: after overnight fasting (hunger) and following a standardised meal (satiety). We used spectral dynamic causal modelling to unravel hunger and increased BMI-related changes in directed connectivity between cortical, insular, striatal and hypothalamic regions. RESULTS: During hunger, as compared to satiety, we found increased excitation of the ventromedial prefrontal cortex over the ventral striatum and hypothalamus, suggesting enhanced top-down modulation compensating energy depletion. Increased BMI was associated with increased excitation of the anterior insula over the hypothalamus across the hunger and satiety conditions. The interaction of hunger and increased BMI yielded decreased intra-cortical excitation from the dorso-lateral to the ventromedial prefrontal cortex. CONCLUSIONS: Our findings suggest that excess weight and obesity is associated with persistent top-down excitation of the hypothalamus, regardless of homeostatic state, and hunger-related reductions of dorso-lateral to ventromedial prefrontal inputs. These findings are compatible with eating without hunger and reduced self-regulation views of obesity.

Lack of longitudinal changes in cognition in individuals with methamphetamine use disorder during the first 6 weeks after commencing treatment.

Background: Methamphetamine use disorder (MUD) associates with cognitive impulsivity deficits. However, few studies have examined longitudinal changes in cognition, and it remains unclear if deficits resolve during early recovery.Objectives: To compare: (1) cognitive function of individuals with MUD at treatment onset and six-weeks later with controls tested over the same period; (2) cognitive changes in MUD-individuals who remained abstinent versus relapsed.Method: We recruited 108 participants meeting DSM-IV-TR criteria for methamphetamine dependence (81 males) and 50 demographically matched controls (38 males); 77 methamphetamine- dependent participants (59 males) and 48 controls (36 males) were retained at follow-up. We administered response inhibition, delay discounting and uncertainty-based decision-making tests at both endpoints. Relapse was defined as methamphetamine concentrations >0.4 ng/mg at follow-up in hair toxicology.Results: We found a significant time-by-group interaction on uncertainty-based decision-making (effect size: η2 = .05), although post-hoc tests to disentangle this interaction yielded inconclusive results (p-range = .14-.40; BF10-range = 0.43-1.67). There were no significant time-by-group interactions on response inhibition or delay discounting, with the former likely a null effect (η2-interaction = .003 and .02; BFincl = 0.23 and 0.71). There were no significant differences in cognitive recovery between individuals who maintained abstinence (n = 12) versus relapsed (n = 65) (η2-range = .003-.04), although evidence was inconclusive toward whether findings reflected true null effects (BFincl-range = 0.33-0.75).Conclusion: We did not find evidence that MUD-related cognitive impulsivity deficits improve beyond practice effects over 6 weeks. Findings do not support previous, albeit conflicting, evidence of early recovery of cognitive deficits in MUD.

Hypothalamic Networks in Adolescents With Excess Weight: Stress-Related Connectivity and Associations With Emotional Eating.

OBJECTIVE: Adolescents with excess weight are particularly sensitive to stress, which may contribute to the presence of emotional eating behaviors. It is proposed that this may be due to alterations in the connectivity between hypothalamic networks and regions of the "emotional nervous system," involved in the regulation of energy balance and stress processing. However, this remains to be clarified in adolescents with excess weight. METHOD: We investigated whole-brain differences in the functional connectivity of the medial and lateral hypothalamus (MH and LH) between adolescents with excess weight (EW, n = 53; mean age = 14.64 years, SD = 1.78) and normal weight (NW, n = 51; mean age = 15.29 years, SD = 1.75) using seed-based resting-state analyses. Then, in a subset of 22 adolescents with EW (mean age = 15.75 years, SD = 1.70) and 32 with NW (mean age = 15.27, SD = 2.03), we explored for group interactions between the MH/LH networks and stress response in the Trier Social Stress Task (TSST) and emotional eating, assessed with the Dutch Eating Behavior Questionnaire (DEB-Q). RESULTS: Compared to NW, EW showed higher functional connectivity in the LH-orbitofrontal cortex, ventral striatum, anterior insula, and in the MH-middle temporal cortex networks. EW also showed lower connectivity in the LH-cerebellum, and in the MH-middle prefrontal, pre-, and postcentral gyri networks. In EW, higher connectivity of the LH-nucleus accumbens and LH-midbrain networks were associated with stress response. Higher connectivity in the LH-midbrain was also associated with a greater presence of emotional eating behaviors in EW. CONCLUSION: Adolescents with EW showed functional connectivity alterations within both MH/LH networks. Alterations in the LH network were linked with higher levels of stress response and emotional-driven eating patterns.

The role of corticostriatal-hypothalamic neural circuits in feeding behaviour: implications for obesity.

Emerging evidence from human imaging studies suggests that obese individuals have altered connectivity between the hypothalamus, the key brain region controlling energy homeostasis, and cortical regions involved in decision-making and reward processing. Historically, animal studies have demonstrated that the lateral hypothalamus is the key hypothalamic region involved in feeding and reward. The lateral hypothalamus is a heterogeneous structure comprised of several distinct types of neurons which are scattered throughout. In addition, the lateral hypothalamus receives inputs from a number of cortical brain regions suggesting that it is uniquely positioned to be a key integrator of cortical information and metabolic feedback. In this review, we summarize how human brain imaging can inform detailed animal studies to investigate neural pathways connecting cortical regions and the hypothalamus. Here, we discuss key cortical brain regions that are reciprocally connected to the lateral hypothalamus and are implicated in decision-making processes surrounding food.

Cognitive and neuromodulation strategies for unhealthy eating and obesity: Systematic review and discussion of neurocognitive mechanisms.

We systematically reviewed research on cognitive training and neuromodulation interventions for reducing food craving/intake, unhealthy diet and weight, and discussed their mechanisms of action. We reviewed 50 studies involving six cognitive trainings: Approach and Attentional Bias Modification, Implementation Intentions, Response Inhibition, Episodic Future Thinking and Working Memory; and four neuromodulation approaches: Transcranial Magnetic Stimulation (TMS), transcranial Direct Current Stimulation (tDCS), Deep Brain Stimulation (DBS) and Neurofeedback. Response Inhibition and Implementation Intentions have shown to reduce unhealthy diet and weight in people with overweight/obesity. Attentional Bias Modification has shown promising results in healthy-weight participants. Brain stimulation of the Dorsolateral Prefrontal Cortex via tDCS and the Hypothalamus via DBS showed benefits for reducing food craving and weight in people with overweight/obesity. Studies quality was generally high, but most trials were short-term and many conducted in healthy-weight samples. Modification of cognitive control and motivational processes/circuits are common mechanisms of beneficial training and neuromodulation interventions, and thus a promising approach for overweight/obesity treatment. Longer duration trials in clinical populations are needed to confirm benefits.

Impulsivity predicts poorer improvement in quality of life during early treatment for people with methamphetamine dependence.

BACKGROUND AND AIMS: Methamphetamine dependence is associated with heightened impulsivity and diminished quality of life, but the link between impulsivity and changes in quality of life during treatment has not been examined. We aimed to investigate how different elements of impulsivity predict change in quality of life in the 6 weeks after engaging in treatment. DESIGN: Longitudinal, observational cohort study. SETTING: Public and private detoxification and rehabilitation facilities in metropolitan Melbourne, Australia. PARTICIPANTS: One hundred and eight individuals with methamphetamine dependence (81 male) tested within 3 weeks of commencing treatment; 80 (74%) were followed-up at 6 weeks. MEASUREMENTS: The Continuous Performance Test-2 measured impulsive action (cognitive and motor impulsivity); the Delay Discounting Task measured impulsive choice. Quality of life was measured with the World Health Organization Quality of Life Scale-Brief, which includes social, psychological, physical and environment domains. Control variables included age, gender, estimated IQ, depression severity score, methamphetamine dependence severity score, cannabis dependence severity score and treatment modality. FINDINGS: We found that all three forms of impulsivity were significant predictors of change in the social domain: motor impulsivity (ß = -0.54, P = 0.013), cognitive impulsivity (ß = -0.46, P = 0.029) and impulsive choice (ß = -0.26, P = 0.019). Change in the psychological domain was predicted significantly by motor impulsivity (ß = -0.45, P = 0.046). Control variables of age and depression were associated significantly with changes in the physical domain. CONCLUSIONS: In Australian methamphetamine-dependent individuals, elevated impulsivity predicts lower improvement of social and psychological quality of life in the first 6-9 weeks of treatment.

Altered cross-talk between the hypothalamus and non-homeostatic regions linked to obesity and difficulty to lose weight.

Interactions between the hypothalamus and non-homeostatic regions may contribute to explain the difficulty to lose weight in obesity, an assumption never tested in human longitudinal studies. We investigated whether the functional connectivity between the medial and lateral hypothalamus (MH and LH) and corticostriatal regions differs between individuals with excess weight (n = 42) and normal weight (n = 39) using a seed-based resting-state approach. In addition, we examined the longitudinal association between functional connectivity and weight loss in a 3-month follow-up diet. Results showed that participants with excess weight had increased connectivity between the MH and the striatum and subgenual anterior cingulate cortex, and decreased connectivity with the middle frontal gyrus, and the bed nucleus of the stria terminalis (BNST), as well as a decreased connectivity between the LH and the cerebellum. Decreased connectivity between the MH and the posterior part of the BNST, and between the LH and the cerebellar cortex, predicted a greater percentage of weight loss. Functional connectivity measures explained 36% of the 3-month weight change among individuals with excess weight. We conclude that altered functional connectivity between homeostatic-hypothalamic regions and non-homeostatic corticostriatal and cerebellar regions is linked to obesity and difficulty to lose weight.

Goal Management Training and Mindfulness Meditation improve executive functions and transfer to ecological tasks of daily life in polysubstance users enrolled in therapeutic community treatment.

BACKGROUND: We have previously shown that Goal Management Training+Mindfulness Meditation (GMT+MM) improves executive functions in polysubstance users enrolled in outpatient treatment. The aim of this study was to establish if GMT+MM has similar positive effects on executive functions in polysubstance users in residential treatment, and if executive functions' gains transfer to more ecologically valid goal-oriented tasks. METHODS: Thirty-two polysbustance users were randomly allocated to eight weeks of GMT+MM (n=16) or control, i.e., no-intervention (n=16); both groups received treatment as usual. Outcome measures included performance in laboratory tasks of basic and complex executive functions (i.e., basic: working memory and inhibition; complex: planning and self-regulation) and in an ecological task of goal-directed behavior (the Multiple Errands Test - contextualized version, MET-CV) measured post-interventions. RESULTS: Results showed that GMT+MM was superior to control in improving basic measures of working memory (Letter-number sequencing; F=4.516, p=0.049) and reflection impulsivity (Information Sampling Test; F=6.217, p=0.018), along with initial thinking times during planning (Zoo Map Test; F=8.143, p=0.008). In addition, GMT+MM was superior to control in improving performance in the MET-CV (task failures; F=8.485, p=0.007). CONCLUSION: Our findings demonstrate that GMT+MM increases reflective processes and the achievement of goals in daily activities, furthermore ecological test can detects changes easily than laboratory tasks.

Profiles of substance use disorders in patients of therapeutic communities: link to social, medical and psychiatric characteristics.

BACKGROUND: Therapeutic community (TC) clients frequently display a pattern of multiple substance use disorders (SUDs) which is associated with poorer treatment outcomes. This study aimed to characterize multiple SUD profiles in patients enrolled in TCs, and examine the association of these profiles with social, medical and psychiatric outcomes. METHODS: Observational study. We acquired substance use diagnoses and sociodemographic, medical and psychiatric comorbidity data for 4102 patients who had been admitted to six public TCs in Andalusia (Spain) from 2004 to 2012. Latent class analysis was applied to participants' substance use diagnoses, and the resulting classes were associated with social (i.e., education, employment, criminality), medical (i.e., infectious diseases) and psychiatric comorbidity. RESULTS: We found four differentiated profiles of substance use diagnoses among TC patients: cocaine/opiates (Class 1: 37% of participants); cocaine/opiates/benzodiazepines (Class 2: 25.3%); alcohol (Class 3: 24.7%); and cocaine/cannabis/alcohol (Class 4: 12.9%). Classes 1 and 2 were associated with poorer social and medical characteristics. Class 2 was also associated with greater prevalence of impulsive spectrum mental disorders. Class 3 was associated with greater prevalence of mood and anxiety disorders and cognitive dysfunction, and Class 4 was associated with higher prevalence of psychotic illness. CONCLUSIONS: Patients admitted to TCs have heterogeneous substance use diagnostic profiles. Profiles involving multiple use of heroin, cocaine, alcohol and benzodiazepines are associated with poorer social and medical function and impulse control disorders. Profiles involving alcohol use and cannabis/cocaine use are associated with cognitive dysfunction and psychotic illness respectively.

Cingulate biochemistry in heroin users on substitution pharmacotherapy.

OBJECTIVE: High doses of opiate substitution pharmacotherapy are associated with greater treatment retention and lower illicit drug consumption, although the neurobiological bases of these benefits are poorly understood. Dysfunction of the anterior cingulate cortex (ACC) is associated with greater addiction severity and mood dysregulation in opiate users, such that the beneficial effects of substitution pharmacotherapy may relate to normalisation of ACC function. This study aimed to investigate the differential impact of methadone compared with buprenorphine on dorsal ACC biochemistry. A secondary aim was to explore the differential effects of methadone and buprenorphine on dorsal ACC biochemistry in relation to depressive symptoms. METHODS: Twenty-four heroin-dependent individuals stabilised on methadone (n=10) or buprenorphine (n=14) and 24 healthy controls were scanned using proton Magnetic Resonance Spectroscopy and compared for metabolite concentrations of N-acetylaspartate, glutamate/glutamine, and myo-inositol. RESULTS: (1) Methadone was associated with normalisation of dorsal ACC biochemistry (increased N-acetylaspartate and glutamate/glutamine levels, and decreased myo-inositol levels) in a dose-dependent manner; (2) buprenorphine-treated individuals had higher myo-inositol and glutamate/glutamine levels than methadone-treated patients in the right dorsal ACC; and (3) myo-inositol levels were positively correlated with depressive symptoms in participants stabilised on buprenorphine. CONCLUSIONS: These findings point to a beneficial role of high-dose methadone on dorsal ACC biochemistry, and suggest a link between elevated myo-inositol levels and depressive symptoms in the context of buprenorphine treatment.

Combined Goal Management Training and Mindfulness meditation improve executive functions and decision-making performance in abstinent polysubstance abusers.

The clinical relevance of neuropsychological deficits in addicted individuals has fostered interest in treatment strategies aimed to effectively target executive and decision-making dysfunction. One of the best-validated interventions for executive dysfunction is Goal Management Training (GMT) (Robertson et al., 2005), an interactive program aimed at improving participants' organization and ability to achieve goals. Mindfulness-based meditation can complement GMT training in order to improve attentional scanning and "reading" of emotional signals involved in adaptive decision-making. In this pilot study we investigated the efficacy of a 7-week program including GMT+Mindfulness (GMT+MF), as compared to standard treatment alone (STx), for reducing executive and decision-making deficits in an outpatient sample of alcohol and polysubstance abusers. Eighteen participants were enrolled in the GMT+MF group, whereas 16 participants formed the STx group; both groups were matched for relevant demographic and clinical variables, and pre-treatment degree of executive dysfunction. Results showed that the individuals enrolled in GMT+MF significantly improved their performance on neuropsychological measures of working memory (Letter Number Sequencing), response inhibition (Stroop) and decision-making (Iowa Gambling Task) after the treatment; whereas individuals enrolled in STx alone failed to show significant changes. These preliminary results indicate that the GMT+MF intervention may be effective in reducing executive and decision-making deficits in polysubstance abusers, and they support future randomized controlled studies aimed at examining the extent to which these improvements may generalize to every day functioning and may affect the capacity of addicted individuals to achieve and maintain abstinence.