Neuroscience makes use of many metaphors in its attempt to explain the relationship between our brain and our behaviour. In this thesis I contrast the most commonly used metaphor - that of computation driven by neuron action potentials - with an alternative view which seeks to understand the brain in terms of an agent learning from the reward signalled by neuromodulators. To explore this reinforcement learning model I construct computational models to assess one of its key claims — that the neurotransmitter dopamine signals unexpected reward, and that this signal is used by the brain to learn control of our movements and drive goal-directed behaviour. In this thesis I develop a selection of computational models that are motivated by either theoretical concepts or experimental data relating to the effects of dopamine. The first model implements a published dopamine-modulated spike timing-dependent plasticity mechanism but is unable to correctly solve the distal reward problem. I analyse why this model fails and suggest solutions. The second model, more closely linked to the empirical data attempts to investigate the relative contributions of firing rate and synaptic conductances to synaptic plasticity. I use experimental data to estimate how model neurons will be affected by dopamine modulation, and use the resulting computational model to predict the effect of dopamine on synaptic plasticity. The results suggest that dopamine modulation of synaptic conductances is more significant than modulation of excitability. The third model demonstrates how simple assumptions about the anatomy of the basal ganglia, and the electrophysiological effects of dopamine modulation can lead to reinforcement learning like behaviour. The model makes the novel prediction that working memory is an emergent feature of a reinforcement learning process. In the course of producing these models I find that both theoretically and empirically based models suffer from methodological problems that make it difficult to adequately support such fundamental claims as the reinforcement learning hypothesis. The conclusion that I draw from the modelling work is that it is neither possible, nor desirable to falsify the theoretical models used in neuroscience. Instead I argue that models and metaphors can be valued by how useful they are, independently of their truth. As a result I suggest that we ought to encourage a plurality of models and metaphors in neuroscience. In Chapter 7 I attempt to put this into practice by reviewing the other transmitter systems that modulate dopamine release, and use this as a basis for exploring the context of dopamine modulation and reward-driven behaviour. I draw on evidence to suggest that dopamine modulation can be seen as part of an extended stress response, and that the function of dopamine is to encourage the individual to engage in behaviours that take it away from homeostasis. I also propose that the function of dopamine can be interpreted in terms of behaviourally defining self and non-self, much in the same way as inflammation and antibody responses are said to do in immunology.

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Binge eating disorder (BED) is the most prevalent of all eating disorders and is characterized by recurrent episodes of eating a large amount of food in the absence of control. There have been various kinds of research of BED, but the phenomenon remains poorly understood. This thesis reviews the results of research on BED to provide a synthetic view of the current general understanding on BED, as well as the neural correlates of the disorder and treatments. Research has so far identified several risk factors that may underlie the onset and maintenance of the disorder, such as emotion regulation deficits and body shape and weight concerns. However, neuroscientific research suggests that BED may characterize as an impulsive/compulsive disorder, with altered reward sensitivity and increased attentional biases towards food cues, as well as cognitive dysfunctions due to alterations in prefrontal, insular, and orbitofrontal cortices and the striatum. The same alterations as in addictive disorders. Genetic and animal studies have found changes in dopaminergic and opioidergic systems, which may contribute to the severities of the disorder. Research investigating neuroimaging and neuromodulation approaches as neural treatment, suggests that these are innovative tools that may modulate food-related reward processes and thereby suppress the binges. In order to predict treatment outcomes of BED, future studies need to further examine emotion regulation and the genetics of BED, the altered neurocircuitry of the disorder, as well as the role of neurotransmission networks relatedness to binge eating behavior.

abstract: Sleep is an essential human function. Modern day society has made it so that sleep is prioritized less and less. Professionals in critical positions such as doctors, nurses, and emergency medical technicians can often have hectic schedules that are unforgiving toward sleep due to the increase in shift work that dominates these fields. Sleep deficits can have detrimental effects on one’s psyche and mood. Depression and anxiety both have high comorbidity rates with insomnia because of sleeping deficits. Transdermal Electrical Nerve Stimulation (TENS) offers a potential solution to improving sleep quality and mood by modulating the ascending reticular activating system (RAS). This system starts in the anterior portion of the head with trigeminal nerve branches and is stimulated using a 500-550 Hz waveform. In this experiment Positive Affect and Negative Affect Schedule (PANAS) scores are recorded daily to monitor mood differences between pre and post treatment (TENS vs Sham). PANAS scores were found to be insignificant between groups. Pittsburgh Sleep Quality Index (PSQI), and Fitbit were chosen to study perceived sleep, and objective sleep. Both PSQI, and Fitbit found insignificant differences between TENS and Sham. Finally, the Beck Depression and Beck Anxiety Inventories were administered weekly to determine if there are immediate changes to depressive and anxiety symptom, after a week of treatment (TENS vs Sham). A significant difference was found between the pre and post of the TENS treatment group. The TENS group was not found to be significantly different from Sham, potentially the result of a placebo effect. These results were found with n=10 participants in the TENS treatment group and n=6 in the sham group. / Dissertation/Thesis / Masters Thesis Engineering 2018

abstract: Vagus nerve stimulation (VNS) has shown benefits beyond its original therapeutic application, though there is a lack of research into these benefits in healthy and athletic populations. To address this gap in the VNS literature, the present study addresses the feasibility and possible efficacy of transcutaneous VNS (tVNS) in improving performance and various biometrics during two athletic tasks: golf tee shots and baseball pitching. Performance, cortical dynamics, anxiety measures, muscle excitation, and heart rate characteristics were assessed before and after stimulation using electroencephalography (EEG), the State-Trait Anxiety Inventory (STAI), and electrocardiography (ECG) during the baseball and golf tasks as well as electromyography (EMG) for muscle excitation in the golf participants. Golfers exhibited increased perceived quality of each repetition (independent from outcome) and an improvement in state and trait anxiety after stimulation. Golfers in the active stimulation group also showed a greater reduction in right upper trapezius muscle excitation when compared to the sham stimulation group. Baseball pitchers exhibited an increase in perceived quality of each repetition (independent from outcome) after active stimulation but not an improvement of state and trait anxiety. No significant effects of stimulation Priming, stimulation Type, or the Priming×Type interaction were seen in heart rate, EEG, or performance in the golf or baseball tasks. The present study supports the feasibility of tVNS in sports and athletic tasks and suggests the need for future research to investigate further into the effects of tVNS on the performance, psychologic, and physiologic attributes of athletes during competition. / Dissertation/Thesis / Masters Thesis Biomedical Engineering 2019

L'agressivité est un comportement fréquemment observé chez les animaux et qui est notamment modulé par la sérotonine (5-HT) et les hormones stéroïdes. Cependant, même si des hypothèses évoquent une interaction possible entre ces molécules dans la régulation des comportements agressifs, peu d’études permettent de les confirmer. De plus les mécanismes neuronaux sous-tendant ces comportements agressifs sont encore peu connus. En utilisant comme modèle l'écrevisse de Louisiane, très étudiée pour son comportement agressif et ses hiérarchies sociales, ce travail montre comment la 5-HT et les hormones stéroïdes modifient les réseaux neuronaux et contrôlent ainsi l'agressivité de ces animaux. La mue des écrevisses est contrôlée par une hormone stéroïde appelée 20-hydroxyecdysone (20E), dont la concentration augmente pendant la prémue. Durant cette période, la 20E diminue à la fois l’agressivité des écrevisses et la locomotion. L’activité du réseau locomoteur, un des supports essentiels de l'agressivité (permettant les approches, les attaques… ou les fuites) et son intégration sensori-motrice sont fortement inhibés également. Cette inhibition passe par une réduction de la réactivité des réseaux, notamment via la baisse de résistance d’entrée (Rin) des motoneurones. En présence de 20E, la concentration de 5-HT augmente fortement dans l’organisme par l’inhibition présumée de la voie de dégradation de la 5-HT. Nous supposons comme déjà décrit sur d’autres réseaux que cette augmentation bloquerait les réseaux dans un état inhibée. Cet état inhibée serait maintenu par la baisse de Rin, causée par la libération de 5-HT sur la partie périphérique des MN principalement inhibitrice. / In animal kingdom, aggressivity is a very frequent behavior obvious. Serotonin (5-HT) and steroid hormones modulate this behavior. However, even if several hypothesis raise that one interaction is possible between these molecules to control aggressivity, no study can confirm it. Moreover, neuronal actions behind this behavior stay unclear. In this study, we show how 5-HT and steroid hormones can regulate neural networks and aggressivity. Crayfish molting is regulated by a steroid hormone, called 20-hydroxyecdysone (20E) and its concentration increases during pre-molt period. 20E decreases crayfish aggressivity and locomotion. Locomotors activities and sensory-motor integration are also inhibited during pre-molt. This inhibition is caused by a drop of neural reactivity because input resistance of motoneurons decreases. After injection of 20E or during pre-molt period, 5-HT concentration increase. We think this increase would block networks in inhibition state during pre-molt.

Activation of muscarinic acetylcholine receptors (mAChRs) has pronounced effects on GABAergic interneurons, including depolarization of their resting membrane potential, and increasing their action potential and vesicular release frequency. Moreover, postsynaptic mAChR activation in hippocampal pyramidal neurons reduces the expression of the K+-Cl- cotransporter (KCC2). However, whether mAChR activation modulates the expression of disinhibition-mediated synaptic plasticity has not been examined. I induced inhibitory long-term potentiation (LTP) by applying coincident pre/postsynaptic stimulation in the hippocampus. This plasticity was characterized by an increase in the postsynaptic potential (PSP) amplitude and a depolarization in the inhibitory postsynaptic potential (IPSP) reversal potential; characteristics of disinhibition-mediated LTP (dmLTP). Activation of mAChRs during this plasticity induction protocol prevented the expression of dmLTP via a presynaptic downregulation of transmitter release. This was concluded from evidence that the PSP amplitude and IPSP reversal potential were unaltered, and paired-pulse depression occurred following plasticity induction in the presence of mAChR activation.

Activation of muscarinic acetylcholine receptors (mAChRs) has pronounced effects on GABAergic interneurons, including depolarization of their resting membrane potential, and increasing their action potential and vesicular release frequency. Moreover, postsynaptic mAChR activation in hippocampal pyramidal neurons reduces the expression of the K+-Cl- cotransporter (KCC2). However, whether mAChR activation modulates the expression of disinhibition-mediated synaptic plasticity has not been examined. I induced inhibitory long-term potentiation (LTP) by applying coincident pre/postsynaptic stimulation in the hippocampus. This plasticity was characterized by an increase in the postsynaptic potential (PSP) amplitude and a depolarization in the inhibitory postsynaptic potential (IPSP) reversal potential; characteristics of disinhibition-mediated LTP (dmLTP). Activation of mAChRs during this plasticity induction protocol prevented the expression of dmLTP via a presynaptic downregulation of transmitter release. This was concluded from evidence that the PSP amplitude and IPSP reversal potential were unaltered, and paired-pulse depression occurred following plasticity induction in the presence of mAChR activation.

abstract: Noninvasive neuromodulation could help treat many neurological disorders, but existing techniques have low resolution and weak penetration. Ultrasound (US) shows promise for stimulation of smaller areas and subcortical structures. However, the mechanism and parameter design are not understood. US can stimulate tail and hindlimb movements in rats, but not forelimb, for unknown reasons. Potentially, US could also stimulate peripheral or enteric neurons for control of blood glucose. To better understand the inconsistent effects across rat motor cortex, US modulation of electrically-evoked movements was tested. A stimulation array was implanted on the cortical surface and US (200 kHz, 30-60 W/cm2 peak) was applied while measuring changes in the evoked forelimb and hindlimb movements. Direct US stimulation of the hindlimb was also studied. To test peripheral effects, rat blood glucose levels were measured while applying US near the liver. No short-term motor modulation was visible (95% confidence interval: -3.5% to +5.1% forelimb, -3.8% to +5.5% hindlimb). There was significant long-term (minutes-order) suppression (95% confidence interval: -3.7% to -10.8% forelimb, -3.8% to -11.9% hindlimb). This suppression may be due to the considerable heating (+1.8°C between US/non-US conditions); effects of heat and US were not separable in this experiment. US directly evoked hindlimb and scrotum movements in some sessions. This required a long interval, at least 3 seconds between US bursts. Movement could be evoked with much shorter pulses than used in literature (3 ms). The EMG latency (10 ms) was compatible with activation of corticospinal neurons. The glucose modulation test showed a strong increase in a few trials, but across all trials found no significant effect. The single motor response and the long refractory period together suggest that only the beginning of the US burst had a stimulatory effect. This would explain the lack of short-term modulation, and suggests future work with shorter pulses could better explore the missing forelimb response. During the refractory period there was no change in the electrically-evoked response, which suggests the US stimulation mechanism is independent of normal brain activity. These results challenge the literature-standard protocols and provide new insights on the unknown mechanism. / Dissertation/Thesis / Doctoral Dissertation Bioengineering 2015

abstract: The use of a non-invasive form of energy to modulate neural structures has gained wide spread attention because of its ability to remotely control neural excitation. This study investigates the ability of focused high frequency ultrasound to modulate the excitability the peripheral nerve of an amphibian. A 5MHz ultrasound transducer is used for the study with the pulse characteristics of 57msec long train burst and duty cycle of 8% followed by an interrogative electrical stimulus varying from 30μsecs to 2msecs in pulse duration. The nerve excitability is determined by the compound action potential (CAP) amplitude evoked by a constant electrical stimulus. We observe that ultrasound's immediate effect on axons is to reduce the electrically evoked CAP amplitude and thereby suppressive in effect. However, a subsequent time delayed increased excitability was observed as reflected in the CAP amplitude of the nerve several tens of milliseconds later. This subsequent change from ultrasound induced nerve inhibition to increased excitability as a function of delay from ultrasound pulse application is unexpected and not predicted by typical nerve ion channel kinetic models. The recruitment curve of the sciatic nerve modified by ultrasound suggests the possibility of a fiber specific response where the ultrasound inhibits the faster fibers more than the slower ones. Also, changes in the shape of the CAP waveform when the nerve is under the inhibitive effect of ultrasound was observed. It is postulated that these effects can be a result of activation of stretch activation channels, mechanical sensitivity of the nerve to acoustic radiation pressure and modulation of ion channels by ultrasound. The neuromodulatory capabilities of ultrasound in tandem with electrical stimulation has a significant potential for development of neural interfaces to peripheral nerve. / Dissertation/Thesis / Masters Thesis Bioengineering 2016