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.
| Identifer | oai:union.ndltd.org:ADTP/216546 |
| Date | January 2005 |
| Creators | Ellis, Kathryn Anne, kellis@unimelb.edu.au |
| Publisher | Swinburne University of Technology. Brain Sciences Institute |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://www.swin.edu.au/), Copyright Kathryn Anne Ellis |
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