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

Cortical - Basal Ganglia Circuits: Control of Behaviour and Alcohol Misuse

Highly organised and differentiated neural circuits form and unite to link the cortex with the basal ganglia and thalamus to mediate movement, cognition and behaviour. Previous assertions that the basal ganglia primarily acted to filter cortical information to facilitate motor outputs only have since given way to an understanding of the basal ganglia as a relay and gating structure with functionally and structurally segregated inputs, functions and outputs. Thus, cortical – basal ganglia circuits can be segregated into three broadly separable functional domains mediating motor (primary and supplementary motor cortex (SMA) and putamen), cognitive (dorsolateral prefrontal cortex (dlPFC) and caudate), and limbic (ventromedial prefrontal cortex and ventral striatum (VS)) processes. In addition, cognitive and behavioural programs that pass through the cortical – basal ganglia circuitry can be subject to filtering by the subthalamic nucleus (STN), which receives direct projections from the cortex. This work first demonstrated the functional organisation of segregated intrinsic cortical – basal ganglia circuits in humans, alongside a detailed map of functional subzones within STN, a small and technically inaccessible midbrain structure. The behavioural relevance of the defined cortical – basal ganglia circuits was investigated by examining the cognitive constructs of impulsivity and compulsivity. Waiting impulsivity, a tendency towards rapid premature responses that has been associated with compulsive drug use, was associated with connectivity between limbic regions including subgenual anterior cingulate cortex, VS and STN. However, motor impulsivity, in the form of stopping ability, was associated with motoric regions including pre-SMA and STN. Compulsivity was captured as deficits in: reversal learning, implicating lateral orbitofrontal cortex; attentional shifting, implicating dlPFC; and habit learning, implicating SMA. Neural circuit changes were also examined in individuals with alcohol dependence and binge drinkers. Waiting impulsivity was elevated in both groups and the functional connectivity, microstructural integrity and anatomical connectivity of the neural circuit underlying waiting impulsivity were associated with problematic drinking behaviours in both groups. Together, this work establishes that discrete functional subzones of small subcortical regions can be differentiated in humans and that their behavioural correlates can be similarly mapped. The definition of intrinsic network architecture underlying a particular behaviour and the demonstration its disturbance in psychiatric groups will crucially inform the development of future diagnostic and therapeutic models

Decision Making: The Neuroethological Turn

Neuroeconomics applies models from economics and psychology to inform neurobiological studies of choice. This approach has revealed neural signatures of concepts like value, risk, and ambiguity, which are known to influence decision making. Such observations have led theorists to hypothesize a single, unified decision process that mediates choice behavior via a common neural currency for outcomes like food, money, or social praise. In parallel, recent neuroethological studies of decision making have focused on natural behaviors like foraging, mate choice, and social interactions. These decisions strongly impact evolutionary fitness and thus are likely to have played a key role in shaping the neural circuits that mediate decision making. This approach has revealed a suite of computational motifs that appear to be shared across a wide variety of organisms. We argue that the existence of deep homologies in the neural circuits mediating choice may have profound implications for understanding human decision making in health and disease

The role of dopamine in learning, movement & motivation

The primary aim of the research I have undertaken is to better understand the influence of dopamine on behavior and to build on knowledge of the various roles of dopamine in the healthy brain but also to improve understanding of the deficits affecting patients with Parkinson’s disease (PD), the hallmark of which is dopamine depletion. By testing PD patients on cognitive and motor tasks, we are able to probe the effects of dopamine depletion in humans. Testing PD patients in different medication states also provides a method with which to attempt to tease apart the various roles of dopamine from each other. My first two experiments use the PD model to this end whereas the third experiment utilises a pharmacological manipulation in healthy individuals. The aim of my first experiment was to tease apart the relative contribution of dopamine to learning from its influence on action performance, and by doing this to better understand the deficits which have been observed in PD patients in reinforcement learning tasks. The second experiment focuses on the motor deficits observed in PD. The aim of this study was to test whether these motor deficits can at least in part explained by the deficits in reward sensitivity. The third and final experiment in this thesis uses a pharmacological manipulation in healthy individuals to isolate the role of dopamine in set shifting in the context of a response to cues with negative hedonic valence, with the hope of better understanding the neurobiology underlying pathological behaviours associated with the hyperdopaminergic state

Different Types of Decision Making Impairments in Anorexia Nervosa

Research on neurocognitive aspects in Anorexia Nervosa (AN) has outlined a cognitive profile characterized by deficiency in the ability to set-shifting (cognitive flexibility) and weak central coherence. A smaller agreement emerges in relation to the compromission of decisional profiles frequently observed in patients with AN since both the complexity of the pathology and the executive function itself make it unclear the nature of these alterations and its relationships with specific or independent clinical and enviornmental variables. The aim of this study was: to investigate different types of decision-making (DM) ability, veridical and adaptive, in a sample of patients with AN using the Iowa Gambling Task and the Cognitive Bias Task; to analyze test performance using a specific cognitive model for the Iowa Gambling Task (Expectancy Valence Learning Model), and to study the relationship with clinical features, focusing on their relationship with neuropsychological profiles and clinical variables; to explore the neural correlations of the two tasks with functional connectivity; to observe the the impact of the genetic profile on different types of DM. Materials and Methods: The sample, consisting of 310 female subjects with AN lifetime and 301 female subjects without diagnosis of lifetime eating disorders, was tested in relation to DM abilities through the Iowa Gambling Task and cognitive Bias Task. All of the participants completed a baseline assessment including the Structured Clinical Interview (SCID) for the DSM-IV, section for eating disorders, and neuropsychological tests including the Wisconsin Card Sorting Test, and Trail Making Test for assessing abilities of abstraction and cognitive flexibility; 10 "and 30" interference memory test for evaluation of working memory, Stop Signal Task for evaluation of inibitory control. The Expectancy Valence Model (EVM) was used to analyze the results obtained in IGT. A genotyping was performed to evaluate the impact of the major polymorphisms implicated in decision-making (158 Val → Met) of the COMT gene and single nucleotide A / G polymorphism (SNP rs25531) of the serotonin carrier gene 5 - HTTLPR. In a smaller subgroup of 35 AN and 34 Healthy control seed based resting state Functional connectivity was explored. Compared to the group of healthy subjects, the decision-making profile of patients suffering from AN was worse in both Iowa Gambling Task (IGT), which evaluates veridical DM, and Cognitive Bias Task (Cbias), which evaluates adaptive DM, regardless of the diagnostic subtype (restrictive vs. binging/purging), psychopathology severity, scholarity, manual 3 dominance or outcome specific treatment. However in IGT the affective decision-making seems to be independent of IMC, conversely in Cbias the adaptive decisional profile was influenced by underweight. Both types of decision-making in patients were not affected by neurocognitive or clinical variables considered. The unfavorable geotype in AN resulted the homozygous for the met allele of the Comt gene and for the short variant of the serotonin transporter gene. The resting functional connectivity explored on the seeds of interest (executive network, orbitofrontal cortex, accumbens and amygdala) in a subgroup of patients and controls showed significantly different patterns of correlation with the scores of IGt and Cbias. In addition, different resting neural patterns appear to be involved in the two different tasks considered. Only in the AN group a positive correlation between the scores on IGT and the activity of the amygdala resulted. In AN group an higher coactivation within the executive, accumbens and orbitofrontal networks was linked to higher context-independency decisional style assessed with CBias, whereas for the executive network the opposite was true for healthy women. In summary our results confirm an impairment of different types of decision making in AN and highlitght the importance of assessing decisional processes with different specific tasks in clinical sample. In particular different maladaptative strategies are associated with ineffective decisional profiles in AN, consisting in a “myopia for the future” and “anxiety inhibition” in veridical situations and in a difficulty to update/review one’s own mindset according to new environmental stimuli (context indipendent reasoning strategies) in adaptive decisional framework. The severity of malnurishment seems to influence adaptive decisional style conferring a bias toward a context indipent reasoning, suggesting the need of metacognitive approach to help patients to be more aware of their tendency to automatically use selection bias in DM contexts. Genetic polimorphysms may in part account for the impaired decision making observed in AN patients, with a negative impact of met Comt allele and the short variant of 5HTTLPR polymorphism. Functional connectivity suggests the presence of different dysfunctional decision making networks in AN patients in the two decisional framework, confirming the importance of emotion and anxiety on decisional performance in AN. Since the cross sectional design of our study, further and longitudinal studies with recovered and at risk subjects are necessary to confirm our results

Neuronale und psychologische Korrelate sozialer Präferenzen

Prosoziale Entscheidung sind Entscheidungen, die die Auswirkung auf andere Personen berücksichtigen und von denen andere Personen profitieren. Aktuelle Erkenntnisse der sozialen Neurowissenschaften sowie der Neuroökonomie legen nahe, dass prosoziale Entscheidungen Hirnareale aktivieren, die im Kontext individueller Entscheidungen mit Belohnung assoziiert sind (u.a. ventromedialer prefrontaler Cortex, medialer orbitofrontaler Cortex, Nucleus Accumbens; Ruff & Fehr, 2014). Dies eröffnet die allgemeine Frage, ob prosoziale Handlungen für den Akteur „belohnend“ sind und folglich neuronale Indikatoren eines Belohnungsempfindens beobachtet werden können. Darüber hinaus stellt sich die spezifischere Frage, ob soziale und individuelle (die eigene Person betreffende) Entscheidungen von Aktivität in den gleichen Hirnarealen begleitet werden. Zur Beantwortung dieser Forschungsfragen tragen die Erkenntnisse der vorliegenden drei Studien, mit Hilfe der Methode der funktionellen Magnetresonanztomografie (fMRT), bei. Es handelt sich bei den drei Studien um die SVO-Studie, die Charity-Studie und die Effort-Studie. Die SVO- und die Charity-Studie untersuchten neuronale Korrelate prosozialer Entscheidungen in einem ökonomischen Paradigma mit unterschiedlichen Rezipienten (in der SVO-Studie war ein anderer Studienteilnehmer der Rezipient (Kuss et al., 2015), in der Charity-Studie eine Spendenorganisation (Kuss et al., 2013)). Die Effort-Studie (Hernandez Lallement, J.*, Kuss, K.*, Trautner, P., Weber, B., Falk, A., Fliessbach, 2014) erweiterte diese Erkenntnisse um den Aspekt der Leistung bei prosozialen Entscheidungen und ging der Frage nach, ob „verdientes“ Geld neuronal anders verarbeitet wird als „geschenktes“ Geld. Sowohl die SVO- als auch die Charity-Studie verwendeten ein Entscheidungsparadigma, welches der Ökonomie angelehnt ist (sog. modifiziertes Diktatorspiel). Dieses ermöglichte die einzelnen Phasen prosozialer Entscheidungen (vor, während, nach der Entscheidung) zu untersuchen, wobei der Fokus auf die Belohnungsareale des menschlichen Gehirns gelegt wurde. In der SVO-Studie (Kuss et al., 2015) fanden sich während prosozialer Entscheidungen für eine andere Person Aktivierung in belohnungsassoziierten Arealen (ventromedialer prefrontaler Cortex, medialer orbitofrontaler Cortex), sowie Aktivierungen in Arealen, die mit kognitiver Kontrolle und Deliberation assoziiert sind (dorsomedialer prefrontaler Cortex). Somit zeigten sich, neben den belohnungsassoziierten Aktivierungen, neuronale Indikatoren weiterer kognitiver Prozesse, im Sinne der Kontrolle über primär eigensinnige Motive. Zudem liefert die Studie Erkenntnisse bezüglich interindividueller Unterschiede von Probanden mit unterschiedlicher sozialer Wertorientierung (social value orientation: prosoziale versus egoistische Wertorientierung; Van Lange, 1999). Wir fanden behaviorale und neuronale Indikatoren automatisierten prosozialen Verhaltens von prosozialen Probanden, sowie verstärkter deliberativer Prozesse von egoistischen Probanden während prosozialer Entscheidungen. Diese Ergebnisse legen nahe, dass prosoziales Verhalten je nach Ausprägung des Persönlichkeitsmerkmals social value orientation (SVO) entweder eher intuitiv ist, oder einer Unterdrückung eigensinniger Impulse und somit kognitiver Ressourcen bedarf. Im Anschluss an die Entscheidung induzierten wir Belohnungsvorhersagefehler (Englisch: Reward Prediction Error, RPE). Belohnungsvorhersagefehler für den eigenen Geldgewinn sind durch neuronale Aktivität im Nucleus accumbens (NAcc) – einem Teil des mediostriatalen Belohnungssystems – repräsentiert (Pagnoni, Zink, Montague, & Berns, 2002; Schultz, 1998). In der Charity-Studie (Kuss et al., 2013) konnten wir durch unsere experimentelle Manipulation erstmals ein äquivalentes RPE-Signal für einen Spenden-Geldbetrag – und somit einen für das materielle Selbstinteresse der Person völlig irrelevanten Geldbetrag – in der gleichen Hirnregion nachweisen. Dies traf nur für Probanden zu, die bereit waren auf den eigenen Gewinn zugunsten der Spendenorganisation zu verzichten und somit auch behavioral demonstrierten, dass sie der Spendenorganisation einen hohen Wert beimessen. Die Effort-Studie (Hernandez Lallement, J.*, Kuss, K.*, Trautner, P., Weber, B., Falk, A., Fliessbach, 2014) knüpfte an diese Ergebnisse an und erweiterte diese um den Aspekt der Leistungserbringung bei prosozialen Entscheidungen, d.h. konkret inwieweit die Tatsache, ob jemand für einen Geldbetrag eine Leistung erbracht hat, oder nicht (Windfall-Money), die neuronalen Reaktionen auf diese Geldbeträge verändert. Die Ergebnisse verdeutlichen, dass das menschliche Gehirn Kontextfaktoren, bzw. die Umstände des Erhalts einer Belohnung, kodiert: Es zeigte sich eine stärkere Assoziation der Aktivierung in Belohnungsarealen (NAcc) mit der Höhe des „verdienten“ Geldes, wenn das Geld durch das Lösen einer anstrengenden Aufgabe geschah. In ähnlicher Weise zeigte sich eine Assoziation mit der Höhe des Verlustes dieses Geldes in der anterioren Insel. Diese Ergebnisse sprechen dafür, dass das Gehirn den subjektiven Belohnungswert kodiert und neben dem absoluten Wert einer Belohnung Kontextfaktoren berücksichtigt. Die Studien zeigen, dass soziale und nicht-soziale Kognition die gleichen Hirnareale aktivieren und ebenso Belohnungszentren des Gehirns während prosozialer Entscheidungen aktiviert sind, wie es während individueller Entscheidungen der Fall ist. Diese Aktivierungen in klassischen Belohnungsarealen des Gehirns können als neuronaler Indikator für den Belohnungswert prosozialen Verhaltens gedeutet werden und legen den verlockenden, jedoch mit Vorsicht zu ziehenden Schluss nahe, dass prosoziales Verhalten belohnend ist. Zudem werden komplexe Kontextinformationen (Umstand des Erhalts einer Belohnung) durch das menschliche Gehirn kodiert. Dies könnte ein neuronaler Indikator der erhöhten Sensitivität bezüglich Belohnungen und Verlust nach starker Anstrengung sein – ein aus ökologischer Perspektive adaptiver Mechanismus. Zudem bieten die Paradigmen der SVO- und der Charity-Studie mit der Einführung des Belohnungsvorhersagefehlers (RPE) eine geeignete Methode, zwei Ereignisse getrennt zu beobachten, die per se miteinander verknüpft sind: Neuronale Reaktionen in Zusammenhang mit der Belohnung und der Entscheidung, die zur Belohnung führt