The dopaminergic system and human spatial working memory : a behavioural, eletrophysiological and cerebral blood flow investigation

Dopamine appears to play a critical role in regulating spatial working memory (SWM) in non-human primates, and SWM deficits are observed in patients with Parkinson's disease and schizophrenia. Unfortunately, the current experimental literature in humans is marred by inconsistent behavioural findings, and there is a void in neuroimaging studies examining dopaminergic manipulation of SWM-related brain activity. The present thesis used a combination of behavioural neurocognitive testing and brain imaging to further examine dopaminergic manipulation of SWM in healthy humans, using two pharmacological challenges: 1) acute tyrosine depletion (TPD) (to acutely deplete tonic dopamine), and 2) D1/D2 receptor activation using the dopamine receptor agonist pergolide (to stimulate dopamine neurotransmission) under conditions of TPD. The effects of TPD on behavioural performance were examined using three SWM tasks: 1) a delayed-recognition task previously impaired by TPD (Experiment 1) and 2) two delayed-response tasks designed to vary only in response requirements (Experiment 2). The findings demonstrated an apparent failure of TPD to impair performance on any of the tasks. Further, the effects of TPD on SWM-related brain activity during a SWM n-back task were examined using regional Cerebral Blood Flow (rCBF) measured by H2 150 Positron Emission Tomography (Experiment 2), and Steady State Visually Evoked Potentials (SSVEP) measured by Steady State Probe Topography (Experiment 4). TPD failed to produce discernable effects on either neural networks (task-related rCBF) or temporal electrophysiological activity (SSVEP) associated with the SWM n-back task. In contrast, D1/D2 receptor stimulation under dopamine depleted conditions impaired performance on both a SWM delayed-response task (Experiment 1) and SWM n-back task (Experiment 2), and resulted in task-related increases in fronto-temporal SSVEP latency (suggestive of increased inhibition) and decreases in parieto-occipital SSVEP amplitude (suggestive of increased activation) during the early delay period of the SWM n-back task (Experiment 4). These changes are consistent with the undisputed role of frontal and parietal regions in n-back task performance, and with previous evidence of dopaminergic modulation of these regions in animals and humans. In summary, TPD did not modulate SWM behavioural performance on four different SWM tasks with differing task demands, and failed to produce measurable changes to either SWM-related neural networks (task-related rCBF) or cortical electrophysiological activity (SSVEP) associated with the SWM n-back task. The implication of these findings, when taken together with previous studies, is that the degree of dopaminergic depletion achieved with TPD may be insufficient to consistently and robustly modulate SWM networks in healthy humans, questioning the utility of TPD as a probe of dopaminergic function. In addition, these findings demonstrate the complexity of stimulating D1/D2 receptors under dopamine depleted conditions, and highlight the critical importance of baseline dopamine levels in influencing the effects of acute dopamine challenge on SWM performance