To survive in a complex changing environment humans frequently need to adapt their behaviour incidentally from normal interactions in the environment without any specific intention to learn. Whilst there is a considerable body of research into incidental learning of sequential information there is still fundamental debate regarding its cognitive basis, the associated neural mechanisms and the way in which it is affected by neurological disease. These issues were explored, in normal participants and neurological patients, using manipulations of the Serial Reaction Task [SRT] in which participants gradually learn a stimulus sequence (usually screen locations) after responding to each item by pressing corresponding response buttons. The first two experiments (chapter 3) demonstrate that the specific metric used to quantify learning and the occurrence of highly salient repeat locations may inflate estimates of learning in tasks with increased motor demands. The next three experiments (chapter 4) examine whether a secondary (not directly behaviourally relevant) information source during the SRT facilitates chunking in memory and overall learning. In a spatial SRT task (specified by horizontal location), additional spatial information (vertical location) enhanced learning but a secondary perceptual property (colour) produced a cost. However, in a perceptual SRT a secondary perceptual property (colour) had no effect. The next study demonstrates that impairments of incidental learning in Parkinson’s disease are partially reduced by administration of l-Dopa. Implications for models of striatal function and studies suggesting implicit learning is impaired by l-Dopa are discussed. Finally, the impact of Deep Brain Stimulation of the GPi is investigated in a population known to have only limited cognitive deficits relating to their illness (dystonia). Despite previous reports of impaired intentional learning in participants with a high genetic risk of Dystonia, there was no evidence for any impairment before or after stimulation. Implications across studies and future research directions are also discussed.

Due to the common belief that language is unique to humans, great emphasis has been placed on the neocortex, while the role of the subcortical areas has been minimized. This project used event-related functional magnetic resonance imaging (fMRI) to study the linguistic involvement of the basal ganglia (BG). Previous research has demonstrated that the BG are implicated in building up sequences of behavior into meaningful, goal-directed repertoires This study developed the idea of motor sequencing into linguistic sequencing to test the BG's involvement in the abstract sequencing of language. Since past imaging studies failed to present a coherent picture of the BG laterality, which might be due to the absence of the control for subjects' familial handedness background, this subject factor was also investigated.Twenty-four right-handed, neurologically healthy English speakers were recruited. Half of them had left-handed blood relatives (FS+); the other half did not (FS-). Their tasks included 1) linguistic sequencing--reordering phrases into a sentence or reordering words along the general-specific dimension, 2) non-linguistic sequencing--swapping designated phrases/words and 3) repeat--repeating words in their original sequence. Voxel-wise analysis showed that both the BG and cortical areas were activated when subjects performed a reordering task. Region of interest (ROI) analysis demonstrated that the BG were involved in linguistic sequencing (reorder - repeat) and that Broca's area and the caudate head were co-opted in computing hierarchical structure (reorder - swap). Although familial sinistrality did not alter the activation pattern of Broca's area and the caudate head, it played a role in their activation asymmetry: both subject groups had left-lateralization in the inferior frontal gyrus, but they failed to show identical laterality in the BG. A possible explanation based on the direct and indirect pathways in the BG was offered and the laterality discrepancy was attributed to these two groups' different time course of language acquisition.To summarize, this study suggested that the BG, especially the head of the caudate nucleus, were involved in the abstract sequencing of language and that the distinct brain asymmetry associated with different familial sinistrality background might be rooted in the BG.

Parkinson’s disease (PD) is a movement disorder that is of basal ganglia origin. It is characterized by a severe loss of dopaminergic input to the striatum and symptoms such as bradykinesia, rigidity and tremor. There is growing evidence that PD is associated with pathological synchronous oscillatory activity in the basal ganglia, which primarily occurs in the 11-30 Hz range, the so-called beta band. The aim of this project was to better understand the oscillatory activity recorded from the basal ganglia of PD patients and to elucidate the significance of this activity in PD. To do this, neuronal firing and local field potentials (LFPs) were recorded from the subthalamic nucleus (STN) and globus pallidus internus (GPi) of PD patients undergoing stereotactic neurosurgery for implantation of therapeutic deep brain stimulation electrodes. Beta oscillatory LFP activity in the STN and GPi was found to be coherent with, and reflect to a certain degree, rhythmic activity in a population of local neurons. I have demonstrated for the first time that the degree of beta oscillatory firing in the STN, which is maximal in the motor portion, correlates with the patients’ benefit from dopaminergic medications, but not with baseline motor deficits. My study has also established that beta oscillatory firing in the STN does not positively correlate with the patients’ tremor scores and that during periods of tremor patients tend to have less beta oscillatory firing and increased neuronal oscillatory firing at the tremor frequency. Temporal examination of the LFPs recorded during periods of intermittent resting tremor revealed that stronger tremor is associated with increased LFP power in the low gamma range (35-55 Hz) and there is a decrease in the ratio of beta to gamma coherence. Similarly, a change in balance between oscillatory activities was observed during levodopa-induced dyskinesias. Finally, when the oscillatory activity in the GPi of PD patients was compared to that in dystonia I found that in dystonia, oscillatory LFP activity is less likely to reflect the neuronal firing. These findings indicate that beta oscillatory activity in the basal ganglia might reflect the degree of dopamine deficiency in the striatum and that the relative strength of oscillatory rhythms may play an important role in mediating the pathological features in PD.

Many studies of ‘executive control’ have focused on the prefrontal cortex (PFC), which contains the neuronal functional properties, modulatory neurotransmitters, and network connections with sensory and motor regions to make this large brain area a candidate region to provide all the necessary elements to voluntarily control behavior. However, like the motor and premotor cortex, the PFC is integrated with the basal ganglia (BG) in such a similar fashion, that it is impossible not to consider that the PFC might depend on the BG to implement executive control effectively. This thesis draws on knowledge of PFC and BG function, and combines studies that require the instantaneous top-down control over motor behavior with a neurological patient group with primarily BG dysfunction (Parkinson’s disease), to provide for a new understanding of prefrontal-BG networks sub-serving executive control. The tasks performed by subjects consist of antisaccades (generate a voluntary eye-movement away from a visual stimulus) and those dealing with task switching (change behavior after an alternate was previously required). Numerous neural and functional imaging studies have identified key areas of the prefrontal cortex and BG that are critical to antisaccade generation, and studies in task switching have implicated similar neural mechanisms that are involved in overriding one behavior with another. By combining task switching with antisaccades, this thesis specifically examines the neural mechanisms related to suddenly changing behavior, under conditions where one behavior is easier to perform than the other. The methods utilize on-line eye-tracking in healthy young adults and older adults with, and without, Parkinson’s disease, to develop theories of a role of the BG in executive control, and to search for specific neural correlates of executive control signals in the PFC, premotor cortex and BG using functional magnetic resonance imaging (fMRI). Together, the conclusions drawn from this thesis point to an important role of the BG in overriding more automatic behavior with behavior that is more difficult to perform. This thesis also suggests that this overriding mechanism occurs through the boosting of cortical executive control signals via net excitatory feedback from the BG. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2010-09-09 12:17:46.904

Background: Multiple sclerosis (MS) is a chronic, neurological disease characterized by targeted destruction on central nervous system (CNS) myelin. The autoimmune theory is the most widely accepted explanation of disease pathology. Circulating Th-1 cells become activated by exposure to CNS-specific antigens such as myelin basic protein. The activated Th-1 cells secrete inflammatory cytokines, which are pivotal for inflammatory responses. We hypothesize that enhanced production of inflammatory cytokines triggers cellular events within the dorsal root ganglia (DRG) and/or spinal cord, facilitating the development of neuropathic pain (NPP) in MS. NPP, the second worst disease-induced symptom suffered by patients with MS, is normally regulated by DRG and/or spinal cord. Objective: To determine gene and protein expression levels of tumor necrosis factor-alpha (TNF ) within DRG and/or spinal cord in an animal model of MS. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in adolescent female Lewis rats. Animals were sacrificed every 3 days post-disease induction. DRG and spinal cords were harvested for protein and gene expression analysis. Results: We show significant increases in TNF expression in the DRG and of EAE animals at peak disease stage, as assessed by clinical symptoms. Conclusion: Antigen-induced production of inflammatory cytokines such as TNF within the DRG identifies a potential noel mechanism for MS-induced NPP.

Parkinson’s disease (PD) is a movement disorder that is of basal ganglia origin. It is characterized by a severe loss of dopaminergic input to the striatum and symptoms such as bradykinesia, rigidity and tremor. There is growing evidence that PD is associated with pathological synchronous oscillatory activity in the basal ganglia, which primarily occurs in the 11-30 Hz range, the so-called beta band. The aim of this project was to better understand the oscillatory activity recorded from the basal ganglia of PD patients and to elucidate the significance of this activity in PD. To do this, neuronal firing and local field potentials (LFPs) were recorded from the subthalamic nucleus (STN) and globus pallidus internus (GPi) of PD patients undergoing stereotactic neurosurgery for implantation of therapeutic deep brain stimulation electrodes. Beta oscillatory LFP activity in the STN and GPi was found to be coherent with, and reflect to a certain degree, rhythmic activity in a population of local neurons. I have demonstrated for the first time that the degree of beta oscillatory firing in the STN, which is maximal in the motor portion, correlates with the patients’ benefit from dopaminergic medications, but not with baseline motor deficits. My study has also established that beta oscillatory firing in the STN does not positively correlate with the patients’ tremor scores and that during periods of tremor patients tend to have less beta oscillatory firing and increased neuronal oscillatory firing at the tremor frequency. Temporal examination of the LFPs recorded during periods of intermittent resting tremor revealed that stronger tremor is associated with increased LFP power in the low gamma range (35-55 Hz) and there is a decrease in the ratio of beta to gamma coherence. Similarly, a change in balance between oscillatory activities was observed during levodopa-induced dyskinesias. Finally, when the oscillatory activity in the GPi of PD patients was compared to that in dystonia I found that in dystonia, oscillatory LFP activity is less likely to reflect the neuronal firing. These findings indicate that beta oscillatory activity in the basal ganglia might reflect the degree of dopamine deficiency in the striatum and that the relative strength of oscillatory rhythms may play an important role in mediating the pathological features in PD.

Background: Multiple sclerosis (MS) is a chronic, neurological disease characterized by targeted destruction on central nervous system (CNS) myelin. The autoimmune theory is the most widely accepted explanation of disease pathology. Circulating Th-1 cells become activated by exposure to CNS-specific antigens such as myelin basic protein. The activated Th-1 cells secrete inflammatory cytokines, which are pivotal for inflammatory responses. We hypothesize that enhanced production of inflammatory cytokines triggers cellular events within the dorsal root ganglia (DRG) and/or spinal cord, facilitating the development of neuropathic pain (NPP) in MS. NPP, the second worst disease-induced symptom suffered by patients with MS, is normally regulated by DRG and/or spinal cord. Objective: To determine gene and protein expression levels of tumor necrosis factor-alpha (TNF ) within DRG and/or spinal cord in an animal model of MS. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in adolescent female Lewis rats. Animals were sacrificed every 3 days post-disease induction. DRG and spinal cords were harvested for protein and gene expression analysis. Results: We show significant increases in TNF expression in the DRG and of EAE animals at peak disease stage, as assessed by clinical symptoms. Conclusion: Antigen-induced production of inflammatory cytokines such as TNF within the DRG identifies a potential noel mechanism for MS-induced NPP.

Parkinson’s disease (PD) is characterized by the loss of dopamine in the basal ganglia and leads to paucity of movements, rigidity of the limbs, and rest tremor. Synaptic plasticity was characterized in the substantia nigra pars reticulata (SNr), a basal ganglia output structure, in 18 PD patients undergoing implantation of deep brain stimulating electrodes. Field evoked potentials (fEPs) in SNr were measured with one microelectrode using single pulses from a second microelectrode ~ 1 mm away. High frequency stimulation (HFS – 4 trains of 2s at 100Hz) in the SNr failed to induce a lasting change in test fEPs amplitudes in patients OFF medication. Following L-Dopa, HFS induced a potentiation of the fEPs that lasted more than 150s. Our findings suggest that extrastriatal dopamine modulates activity dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of PD.

Parkinson’s disease (PD) is accompanied by a significant amount of beta β-band (11Hz-30Hz) neuronal and local field potential (LFP) oscillatory activity in the subthalamic nucleus (STN). The aim of this study was to measure the spatial extent of β coherent activity in the STN and coherence between STN-SNr in PD patients OFF levodopa by systematically varying the vertical distance between two microelectrodes. We found significant β-LFP coherence across the dorsoventral extent of STN. Spatially extended beta LFP was positively correlated with the mUPDRS scores of the PD patients in the OFF state. Additionally, a significant coherence was found between β-LFPs in dorsal STN and dorsal SNr. These data suggest that the whole STN may be entrained within the β band in PD patients OFF meds. The finding of coherence between STN and SNr suggests that β oscillations synchronize both the input and output nuclei of the basal ganglia.

Parkinson’s disease (PD) is characterized by the loss of dopamine in the basal ganglia and leads to paucity of movements, rigidity of the limbs, and rest tremor. Synaptic plasticity was characterized in the substantia nigra pars reticulata (SNr), a basal ganglia output structure, in 18 PD patients undergoing implantation of deep brain stimulating electrodes. Field evoked potentials (fEPs) in SNr were measured with one microelectrode using single pulses from a second microelectrode ~ 1 mm away. High frequency stimulation (HFS – 4 trains of 2s at 100Hz) in the SNr failed to induce a lasting change in test fEPs amplitudes in patients OFF medication. Following L-Dopa, HFS induced a potentiation of the fEPs that lasted more than 150s. Our findings suggest that extrastriatal dopamine modulates activity dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of PD.