Profiles of visuospatial memory dysfunction in opioid exposed and dependent populations

Background . Chronic opioid exposure is common world-wide, but behavioural performance remains under-investigated. This study aimed to investigate visuospatial memory performance in opioid-exposed and dependent clinical populations and its associations with measures of intelligence and cognitive impulsivity. Methods . We recruited 109 participants: (i) patients with a history of opioid dependence due to chronic heroin use (n = 24), (ii) heroin users stabilised on methadone maintenance treatment (n = 29), (iii) participants with a history of chronic pain and prescribed tramadol and codeine (n = 28) and (iv) healthy controls (n = 28). The neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery included the Delayed Matching to Sample (DMS), Pattern Recognition Memory, Spatial Recognition Memory, Paired Associate Learning, Spatial Span Task, Spatial Working Memory and Cambridge Gambling Task. Pre-morbid general intelligence was assessed using the National Adult Reading Test. Results . As hypothesised, this study identified the differential effects of chronic heroin and methadone exposures on neuropsychological measures of visuospatial memory (p < 0.01) that were independent of injecting behaviour and dependence status. The study also identified an improvement in DMS performance (specifically at longer delays) when the methadone group was compared with the heroin group and also when the heroin group was stabilised onto methadone. Results identified differential effects of chronic heroin and methadone exposures on various neuropsychological measures of visuospatial memory independently from addiction severity measures, such as injecting behaviour and dependence status.PostprintPeer reviewe

Protracted abstinence in males with an opioid use disorder : partial recovery of nucleus accumbens function

Opioid use disorder (OUD) affects more than 27 million people globally accounting for more than 300,000 deaths annually. Protracted abstinence among individuals with OUD is rare due to a high relapse rate among those not receiving medications for OUD. Extensive preclinical studies form the basis of the allostasis theory, which proposes long lasting functional brain abnormalities that persist after opioid withdrawal and contribute to relapse. Few studies have tested the allostasis theory in humans using neuroimaging. Here we used fMRI and an instrumental learning task to test allostasis theory predictions (ATP) of functional abnormalities in both positive valence (PVS) and negative valence (NVS) accumbens systems in OUD patients with protracted abstinence (n=15), comparing them with OUD patients receiving methadone treatment (MT) (n=33), and with healthy controls (n=23). As hypothesized, protracted abstinence OUD patients showed incomplete recovery of nucleus accumbens function, as evidenced by blunted response to aversive events (NVS) during negative reinforcement, as observed in MT patients. In contrast, their accumbens response to rewarding events (PVS) during positive reinforcement was similar to that of controls and different to that in MT patients whose response was blunted. Protracted abstinence OUD patients also showed improvements in depression symptoms compared to MT patients. Residual depressive symptoms and pre-MT intravenous drug measures were associated with worse accumbens function in protracted abstinence. These results support the ATP of long lasting dysfunction of NVS after withdrawal and show preliminary evidence of recovery of PVS function with protracted withdrawal. Therapeutic strategies that target NVS may facilitate recovery.Publisher PDFPeer reviewe

Compulsivity in opioid dependence

This study was part funded by an unrestricted educational grant provided by Schering-Plough and a grant by an Anonymous Trust. Study support was also provided by the Scottish Mental Health Research Network. AB has received educational grants from Schering Plough and he has received research project funding from Schering-Plough, Merck Serono, and Indivior.Objective: This study aimed to investigate the relationship between compulsivity versus impulsivity and structural MRI abnormalities in opioid dependence. Method: We recruited 146 participants: i) patients with a history of opioid dependence due to chronic heroin use (n=24), ii) heroin users stabilised on methadone maintenance treatment (n=48), iii) abstinent participants with ahistory of opioid dependence due to heroin use (n=24) and iv) healthy controls(n=50). Compulsivity was measured using Intra/Extra-Dimensional (IED) Task and impulsivity was measured using the Cambridge Gambling Task (CGT).Structural Magnetic Resonance Imaging (MRI) data were also obtained. Results: As hypothesised, compulsivity was negatively associated with impulsivity (p<0.02). Testing for the neural substrates of compulsivity versus impulsivity, we found a higher compulsivity/impulsivity ratio associated with significantly decreased white matter adjacent to the nucleus accumbens, bed nucleus of stria terminalis and rostral cingulate in the abstinent group,compared to the other opioid dependent groups. In addition, self-reported duration of opioid exposure correlated negatively with bilateral globus pallidus grey matter reductions. Conclusion: Our findings are consistent with Volkow & Koob’s addiction models and underline the important role of compulsivity versus impulsivity inopioid dependence. Our results have implications for the treatment of opioid dependence supporting the assertion of different behavioural and biological phenotypes in the opioid dependence and abstinence syndromes.PostprintPeer reviewe

Chronic heroin use disorder and the brain:current evidence and future implications

The incidence of chronic heroin use disorder, including overdose deaths, has reached epidemic proportions. Here we summarise and evaluate our knowledge of the relationship between chronic heroin use disorder and the brain through a narrative review. A broad range of areas was considered including causal mechanisms, cognitive and neurological consequences of chronic heroin use and novel neuroscience-based clinical interventions. Chronic heroin use is associated with limited or very limited evidence of impairments in memory, cognitive impulsivity, non-planning impulsivity, compulsivity and decision-making. Additionally, there is some evidence for certain neurological disorders being caused by chronic heroin use, including toxic leukoencephalopathy and neurodegeneration. However, there is insufficient evidence on whether these impairments and disorders recover after abstinence. Whilst there is a high prevalence of comorbid psychiatric disorders, there is no clear evidence that chronic heroin use per se causes depression, bipolar disorder, PTSD and/or psychosis. Despite the growing burden on society from heroin use, knowledge of the long-term effects of chronic heroin use disorder on the brain remains limited. Nevertheless, there is evidence for progress in neuroscience-based interventions being made in two areas: assessment (cognitive assessment and neuroimaging) and interventions (cognitive training/remediation and neuromodulation). Longitudinal studies are needed to unravel addiction and neurotoxic mechanisms and clarify the role of pre-existing psychiatric symptoms and cognitive impairments.PostprintPeer reviewe

Blunted midbrain reward activation during smoking withdrawal : a preliminary study

This research has been supported by a self-funded PhD scholarship and by a University of St. Andrews endowment fund.Introduction: Tobacco smoking is the leading preventable cause of death, causing more than six million deaths annually worldwide, mainly due to cardiovascular disease and cancer. Many habitual smokers try to stop smoking but only about 7% are successful, despite widespread knowledge of the risks. Development of addiction to a range of substances is associated with progressive blunting of brain reward responses and sensitisation of stress responses, as described by the allostasis theory of addiction. There is pre-clinical evidence from rodents for a dramatic decrease in brain reward function during nicotine withdrawal. Methods: Here we tested the hypothesis that habitual smokers would also exhibit blunted reward function during nicotine withdrawal using a decision-making task and fMRI. Results: Our findings supported this hypothesis, with midbrain reward-related responses particularly blunted. We also tested the hypothesis that smokers with a longer duration of smoking would have more pronounced abnormalities. Contrary to expectations, we found that a shorter duration of smoking in younger smokers was associated with the most marked abnormalities, with blunted midbrain reward related activation including the dopaminergic ventral tegmental area. Discussion: Given the substantial mortality associated with smoking, and the small percent of people who manage to achieve sustained abstinence, further translational studies on nicotine addiction mechanisms are indicated.Peer reviewe

High-Throughput, Time-Resolved Mechanical Phenotyping of Prostate Cancer Cells

Abstract Worldwide, prostate cancer sits only behind lung cancer as the most commonly diagnosed form of the disease in men. Even the best diagnostic standards lack precision, presenting issues with false positives and unneeded surgical intervention for patients. This lack of clear cut early diagnostic tools is a significant problem. We present a microfluidic platform, the Time-Resolved Hydrodynamic Stretcher (TR-HS), which allows the investigation of the dynamic mechanical response of thousands of cells per second to a non-destructive stress. The TR-HS integrates high-speed imaging and computer vision to automatically detect and track single cells suspended in a fluid and enables cell classification based on their mechanical properties. We demonstrate the discrimination of healthy and cancerous prostate cell lines based on the whole-cell, time-resolved mechanical response to a hydrodynamic load. Additionally, we implement a finite element method (FEM) model to characterise the forces responsible for the cell deformation in our device. Finally, we report the classification of the two different cell groups based on their time-resolved roundness using a decision tree classifier. This approach introduces a modality for high-throughput assessments of cellular suspensions and may represent a viable application for the development of innovative diagnostic devices

A causal role for the anterior mid-cingulate cortex in negative affect and cognitive control

Converging evidence has linked the anterior mid-cingulate cortex to negative affect, pain and cognitive control. Shackman and colleagues proposed this region uses information about punishment to control aversively motivated actions. Studies on the effects of lesions allow causal inferences about brain function; however, naturally occurring lesions in the anterior mid-cingulate cortex are rare. In two studies we therefore recruited 94 volunteers, comprising 15 patients with treatment-resistant depression who had received bilateral Anterior Cingulotomy, which consists of lesions made within the anterior mid-cingulate cortex, 20 patients with treatment-resistant depression who had not received surgery and 59 healthy controls. Using the Ekman 60 Faces paradigm and two Stroop paradigms, we tested the hypothesis that patients who received Anterior Cingulotomy were impaired in recognising negative facial affect expressions but not positive or neutral facial expressions, and impaired in Stroop cognitive control, with larger lesions being associated with more impairment. Consistent with hypotheses, we found that larger volume lesions predicted more impairment in recognising fear, disgust and anger, and no impairment in recognising facial expressions of surprise or happiness. However we found no impairment in recognising expressions of sadness. Also consistent with hypotheses, we found that larger volume lesions predicted impaired Stroop cognitive control. Notably, this relationship was only present when anterior mid-cingulate cortex lesion volume was defined as the overlap between cingulotomy lesion volume and Shackman and colleague’s meta-analysis derived binary masks for negative affect and cognitive control. Given substantial evidence from healthy subjects that the anterior mid-cingulate cortex is part of a network associated with the experience of negative affect and pain, engaging cognitive control processes for optimising behaviour in the presence of such stimuli, our findings support the assertion that this region has a causal role in these processes. Whilst the clinical justification for cingulotomy is empirical and not theoretical, it is plausible that lesions within a brain region associated with the subjective experience of negative affect and pain may be therapeutic for patients with otherwise intractable mood, anxiety and pain syndromes.PostprintPeer reviewe

International perspectives on opioid use disorder and treatment : results from an online convenience sample

Funding: M.F. is an employee of the US Federal Government and is supported by National Institutes of Health (NIH) intramural funding (ZIA-DA000635 and ZIA-AA000218).Opioid use disorder (OUD) is a chronic disease characterised by periods of abstinence and episodic return to use, that is associated with enormous socioeconomic burden and great risk for morbidity and mortality. Implementation of national opioid agonist treatment programs (OAT) has been an important strategy to respond to the opioid crisis tailored to each region. Heterogeneity across such programs and policies introduces a challenge in terms of harmonisation but also an opportunity for mutual learning and improvement. In this study, a convenience sample of 15 addiction medicine professionals were invited to complete an online questionnaire focused on challenges and strategies in delivering OAT in different countries and regions. Although national opioid treatment programs (OTP) were available in all but one country, important barriers were identified, and treatment coverage was overall low. In some countries, political and legislative changes are needed to improve public health responses and community attitudes towards persons with opioid use disorder (PWOUD). Providing evidence-based information to clinicians and individuals, strengthening the education of health professionals, and minimising stigma at different levels are seen as important steps that national and international institutions must take to address the opioid crisisPublisher PDFPeer reviewe