Neurobiology of pathological gambling. Brain imaging and epidemiological studies

Pathological gambling, a form of behavioral addiction, refers to maladaptive, compulsive gambling behavior severely interfering with an individual’s normal life. The prevalence of pathological gambling has been estimated to be 1–2% in western societies. The reward deficiency hypothesis of addiction assumes that individuals that have, or are prone, to addictions have blunted mesolimbic dopamine reward signaling, which leads to compulsive reward seeking in an attempt to compensate for the malfunctioning brain reward network. In this research project, the effects of gambling were measured using brain [11C] raclopride PET during slot machine gambling and possible brain structural changes associated with pathological gambling using MRI. The subjects included pathological gamblers and healthy volunteers. In addition, impulse control disorders associated with Parkinson’s disease were investigated by using brain [18F]fluorodopa PET and conducting an epidemiological survey. The results demonstrate mesolimbic dopamine release during gambling in both pathological gamblers and healthy volunteers. Striatal dopamine was released irrespective of the gambling outcome, whether the subjects won or not. There was no difference in gambling induced dopamine release between pathological gamblers and control subjects, although the magnitude of the dopamine release correlated with gambling related symptom severity in pathological gamblers. The results also show that pathological gambling is associated with extensive abnormality of brain white matter integrity, as measured with diffusion tensor imaging, similar to substance-addictions. In Parkinson’s disease patients with impulse control disorders, enhanced brain [18F] fluorodopa uptake in the medial orbitofrontal cortex was observed, indicating increased presynaptic monoamine function in this region, which is known to influence signaling in the mesolimbic system and reward processing. Finally, a large epidemiological survey in Finnish Parkinson’s disease patients showed that compulsive behaviors are very common in Parkinson disease and they are strongly associated with depression. These findings demonstrate the role of dopamine in pathological gambling, without support for the concept of reward deficiency syndrome.Siirretty Doriast

Functional organisation of behavioural inhibitory control mechanisms in cortico-basal ganglia circuitry: implications for stimulant use disorder.

The neural and psychological mechanisms of inhibitory control processes were investigated, focusing on the cortico-basal ganglia circuits in rats and humans. These included behavioural flexibility, ‘waiting’ and ‘stopping’ impulsivity and involved serial spatial reversal learning task in rodents, and in humans, premature responses in the Monetary Incentive Delay (MID) task and the stop-signal reaction time task. Chapter 2 and Chapter 3 focus on individual differences in behavioural flexibility in rats while Chapter 4, Chapter 5 and Chapter 6 consider how inhibitory control mechanisms are affected by the psychostimulant drug cocaine in both rats and humans. As reported in Chapter 2, systemic modulation of monoaminergic transmission by monoamine oxidase A (MAO-A) inhibitors enhanced reversal learning performance, selectively by decreasing the lose-shift probability, thereby implicating a role for dopamine, serotonin and noradrenaline in facilitating learning from negative feedback. Resting state functional magnetic resonance imaging (fMRI) revealed enhanced functional connectivity of the orbitofrontal and motor cortices as a correlate of flexible reversal learning performance, consistent with elevated levels of monoamines in these region (Chapter 3). Having clarified the mechanisms underlying behavioural flexibility in rats, Chapter 4 reports that escalation of intravenous cocaine self-administration induces behavioural inflexibility in rats even after a relatively short period of cocaine intake. Computational models, including a reinforced and Bayesian learner, revealed a lack of exploitation of the learned response-outcome relationships in cocaine-exposed rats. Chapter 5 focused on impulse control in human volunteers, identifying the striatal and cingulo-opercular networks as substrates of impulsive, premature responding in healthy 4 volunteers, stimulant-dependent individuals and their unaffected siblings. Loss of impulse control was elicited by different incentives for drug-free participants as opposed to drug users. Drug cues elicited striatal activation and increased premature responses in the stimulant-dependent group compared with the control group. In contrast, the ventral striatum was linked to incentive specific activation to reward anticipation. Task-based fMRI demonstrated that interactions between dorsal striatum and cingulo-opercular “cold cognition” networks underlie failures of impulse control in the control, at-risk and stimulant-dependent groups. However, whereas the cingulo-opercular networks were associated with premature responding in all groups, the reward system was activated specifically by the drug incentive cues in the stimulant group, and by monetary incentive cues in the drug-free groups. Chapter 6 presents evidence that corticostriatal functional and effective connectivity in an overlapping network that includes the anterior cingulate and inferior frontal cortices as well as motor cortex, the subthalamic nucleus and dorsal striatum, is critical to stopping impulse control in both control and cocaine individuals. No stopping efficiency impairments were observed in the cocaine-dependent group. Nevertheless, lower structural corticostriatal connectivity measured using diffusion MRI was associated with response execution impairments in cocaine participants performing a stop-signal reaction time task. Further, response execution was rescued by the selective noradrenaline reuptake inhibitor atomoxetine, which also increased corticostriatal effective connectivity. Finally, increased impulsivity and behavioural inflexibility seen in stimulant use disorder in Chapter 5 and Chapter 4, respectively, were not observed in the endophenotype at risk for developing stimulant abuse but were rather a consequence of stimulant abuse. These results further clarify the monoaminergic substrates of behavioural flexibility and specify the neural and computational impairments in inhibitory control induced by stimulant dependence.Pinsent Darwin Studentship from the Dept of Physiology, Development and Neuroscienc

Human subjective homologues of established basic emotion correlations in lower mammals: a neuro-psychoanalytic study

Early separation experiences predispose people to depression and depressive episodes are triggered by experiences of social loss. The normal separation response entails a 'protest' phase followed by a 'despair' phase. The affective neuroscience paradigm of Jaak Panksepp identifies two basic emotion systems as being centrally involved in this normal separation response, namely, PANIC/GRIEF and SEEKING, and it conceptualises the despair phase of the cascade as the normal prototype for depression. In affective terms, major depression is seen as a disorder characterised by an overactive PANIC/GRIEF system and an underactive SEEKING system. There is considerable pre-clinical research that underwrites this conclusion, but the evidence in humans is limited. The general aim of this thesis was to investigate the claim that the feelings associated with depression represent an abnormal variant of the normal mammalian separation response in human subjects. The PANIC/GRIEF and SEEKING systems were artificially stimulated and dampened in a sample of healthy volunteers (N=16) via the administration of opioid and dopamine antagonists and agonists. This was an exploratory study, with a double-blind, placebo-controlled, repeated-measures design. The effects of the medications on SEEKING, PANIC/GRIEF, positive and negative affect and mood were investigated using both quantitative and qualitative measures. The results provided suggestive rather than strongly confirmatory evidence for the central hypotheses of this study. Naltrexone (a mu-opioid antagonist) did not increase PANIC/GRIEF and negative affect as predicted but there was some evidence that it led to the worsening of mood, a significant reduction in positive affect and feelings of social and affective disconnection. Morphine (a mu-opioid agonist) reduced PANIC/GRIEF as predicted, but contrary to predictions, positive affect was reduced. There was some evidence to show that Morphine led to an increase in the expression of feelings of contentment, relaxation, happiness and reduced concern. Haloperidol (a dopamine antagonist) reduced SEEKING as predicted but did not increase negative affect as expected. There was some evidence to show that it led to a worsening of mood and positive affect and produced depressive affects such as low drive,low energy, loss of motivation and interest. Madopar (a dopamine agonist) did not increase SEEKING or improve mood as predicted, but there was some evidence that it generated positive affects and reduced the sadness associated with experiences of loss. On Haloperidol, participants with lower 'despair’ had significantly reduced SEEKING and positive affect and higher depression scores, compared to participants with higher 'despair’. On Madopar, participants with lower 'despair’ experienced a greater improvement in positive affect and mood, compared to those with higher 'despair’. On Morphine, measures of avoidant attachment rather than anxious attachment were comparatively more effective in differentiating between Low and High 'protest’, and that those with higher 'protest’ experienced comparatively more PANIC GRIEF, negative and depressive affect. These results provide some 'proof of concept’ for the conceptualization of depression as pathological 'despair’ and that depression feels bad because a dampened SEEKING system and a stimulated PANIC/GRIEF system produce the type of feelings that are characteristic of depression. The results also draw attention to factors that potentially contribute to the limited success of purely drug-focused interventions in depression

Seasonality in trauma admissions - Are daylight and weather variables better predictors than general cyclic effects?

Trauma is a leading global cause of death, and predicting the burden of trauma admissions is vital for good planning of trauma care. Seasonality in trauma admissions has been found in several studies. Seasonal fluctuations in daylight hours, temperature and weather affect social and cultural practices but also individual neuroendocrine rhythms that may ultimately modify behaviour and potentially predispose to trauma. The aim of the present study was to explore to what extent the observed seasonality in daily trauma admissions could be explained by changes in daylight and weather variables throughout the year.publishedVersio

Dopaminergic mechanisms underlying psychosis

Schizophrenia is a potentially devastating mental illness with a complex aetiology, in which the odds ratios for environmental risk factors for the disorder are greater than the odds ratios of any single gene hitherto identified. Within schizophrenia, striatal dopamine dysfunction has been proposed to underlie the development of psychosis. The Aberrant Salience hypothesis provides an explanatory model based on empirical findings to explain how psychotic symptoms may arise from striatal hyperdopaminergia, whereby multiple risk factors converge to elevate striatal dopamine synthesis capacity as the Final Common Pathway to psychosis. Two important epidemiological risk factors for the disorder are chronic cannabis use and longterm psychosocial stress, both of which have evidence supporting effects on the dopamine system. Environmental risk factors are by their very nature modifiable, and so this thesis examined whether these environmental risk factors were associated with the same dopaminergic abnormalities that have been observed in schizophrenia with 3,4-dihydroxy-6- [18F]-fluoro-l-phenylalanine Positron Emission Tomography. This thesis also examined whether cannabis users exhibit aberrant salience processing using a behavioural task, the Salience Attribution Task. This thesis found that long-term cannabis use was associated with reduced dopamine synthesis capacity and no relationship was found between striatal dopamine synthesis capacity and cannabis-induced psychotic-like symptoms. Whilst cannabis use was not associated with increased aberrant salience processing, there was a relationship between cannabis-induced psychotic-like symptoms and aberrant salience processing. This thesis found that long-term psychosocial stress is associated with reduced dopamine synthesis capacity, although this finding may be due confounding factors. However, a positive relationship was observed between childhood and recent adult stressors and dopamine synthesis capacity. These findings call into question the hypothesis that cannabis increases the risk of psychosis by inducing the same changes observed in schizophrenia, although there some evidence to support the hypothesis that psychosocial stressors do increase risk via this mechanism.Open Acces

Uma dose de criatividade : uma revisão integrativa dos efeitos dos psicadélicos na criatividade

Background: Creativity is an important asset in the modern world. It can be defined as the ability to come up with ideas or artefacts that are original and valuable. Classic psychedelic drugs (i.e., dimethyltryptamine, psilocybin, lysergic acid diethylamide, and mescaline) have long been hailed as substances that can enhance creativity in their users. The recent resurgence in psychedelic research has brought with it the opportunity to understand the psychological, cognitive, and behavioural effects that these drugs exert in humans. This integrative review was conducted in order to summarize the knowledge pertaining to the effects that psychedelics can have on creativity by analyzing every study to date that assessed creativity through psychometric measures. Methods: A search was conducted on the MEDLINE, Web of Science, and PsycINFO databases for studies published until 17 November 2020, alongside other relevant sources, that assessed changes in creativity alongside psychedelic administration. Results: Out of the 314 studies identified, a total of 10 studies were included and analyzed, of which 5 were quasi-experiments, 4 were observational/naturalistic, and only 1 was a randomized controlled trial. All four of the main psychedelic compounds were represented. Every study assessed components and subcomponents of divergent and convergent thinking, with only one instance of product assessment. In most studies, divergent thinking increased during the acute stage of the drug intake and convergent thinking increased in the long-term. Conclusions: Psychedelics may be able to enhance divergent thinking in the acute phase and convergent thinking in later phases. However, evidence is limited due to the low number of studies available, small sample sizes, lack of randomized controlled trials, and significant methodological limitations throughout most studies. Potential mechanisms underlying these effects are discussed, along with suggestions for future studies.Introdução: A criatividade é um ativo valioso no mundo moderno que pode ser definida como a capacidade de criar ideias ou artefactos que são originais e valiosos. Os psicadélicos clássicos (i.e., dimetiltriptamina, psilocibina, dietilamida do ácido lisérgico e mescalina) são desde há muito valorizados como substâncias que podem aumentar a criatividade nos seus utilizadores. O ressurgimento recente na investigação psicadélica representa uma oportunidade de compreender os efeitos psicológicos, cognitivos e comportamentais que estas substâncias exercem no ser humano. Esta revisão integrativa teve como objetivo sumarizar o conhecimento relativo aos efeitos que os psicadélicos podem ter na criatividade, analisando todos os estudos realizados à data que avaliassem a relação entre psicadélicos e criatividade através de medidas psicométricos. Métodos: Foi realizada uma pesquisa nas bases de dados MEDLINE, Web of Science e PsycINFO por estudos publicados até 17 de novembro de 2020, bem como em outras fontes relevantes, que avaliassem mudanças na criatividade relacionadas com administração de psicadélicos. Resultados: Dos 314 estudos identificados, um total de 10 estudos foram incluídos e analisados, dos quais 5 eram quasi-experiências, 4 eram observacionais/naturalísticos e apenas 1 era um ensaio randomizado controlado. Todas as quatro principais substâncias psicadélicas estiveram representadas. Todos os estudos avaliaram componentes e subcomponentes de pensamento divergente e/ou convergente, enquanto que apenas um avaliou produção criativa. Na maioria dos estudos, o pensamento divergente aumentou durante a fase aguda da toma da substância e o pensamento convergente aumentou a longo-prazo. Conclusões: Os psicadélicos aparentam ser substâncias capazes de elevar o pensamento divergente na fase aguda e o pensamento convergente nas fases posteriores. No entanto, esta evidência é ainda limitada tendo em conta o baixo número de estudos disponíveis, o reduzido tamanho da amostra, a ausência de ensaios randomizados controlados e limitações metodológicas significativas na maioria dos estudos. São discutidos possíveis mecanismos na base destes efeitos e sugestões para estudos futuros