The basal ganglia are a group of subcortical nuclei that contain about 100 million neurons in humans. Different modes of basal ganglia dysfunction lead to Parkinson's disease and Huntington's disease, which have debilitating motor and cognitive symptoms. However, despite intensive study, both the internal computational mechanisms of the basal ganglia, and their contribution to normal brain function, have been elusive. The goal of this thesis is to identify basic principles that underlie basal ganglia function, with a focus on signal representation, computation, dynamics, and plasticity. This process begins with a review of two current hypotheses of normal basal ganglia function, one being that they automatically select actions on the basis of past reinforcement, and the other that they compress cortical signals that tend to occur in conjunction with reinforcement. It is argued that a wide range of experimental data are consistent with these mechanisms operating in series, and that in this configuration, compression makes selection practical in natural environments. Although experimental work is outside the present scope, an experimental means of testing this proposal in the future is suggested. The remainder of the thesis builds on Eliasmith & Anderson's Neural Engineering Framework (NEF), which provides an integrated theoretical account of computation, representation, and dynamics in large neural circuits. The NEF provides considerable insight into basal ganglia function, but its explanatory power is potentially limited by two assumptions that the basal ganglia violate. First, like most large-network models, the NEF assumes that neurons integrate multiple synaptic inputs in a linear manner. However, synaptic integration in the basal ganglia is nonlinear in several respects. Three modes of nonlinearity are examined, including nonlinear interactions between dendritic branches, nonlinear integration within terminal branches, and nonlinear conductance-current relationships. The first mode is shown to affect neuron tuning. The other two modes are shown to enable alternative computational mechanisms that facilitate learning, and make computation more flexible, respectively. Secondly, while the NEF assumes that the feedforward dynamics of individual neurons are dominated by the dynamics of post-synaptic current, many basal ganglia neurons also exhibit prominent spike-generation dynamics, including adaptation, bursting, and hysterses. Of these, it is shown that the NEF theory of network dynamics applies fairly directly to certain cases of firing-rate adaptation. However, more complex dynamics, including nonlinear dynamics that are diverse across a population, can be described using the NEF equations for representation. In particular, a neuron's response can be characterized in terms of a more complex function that extends over both present and past inputs. It is therefore straightforward to apply NEF methods to interpret the effects of complex cell dynamics at the network level. The role of spike timing in basal ganglia function is also examined. Although the basal ganglia have been interpreted in the past to perform computations on the basis of mean firing rates (over windows of tens or hundreds of milliseconds) it has recently become clear that patterns of spikes on finer timescales are also functionally relevant. Past work has shown that precise spike times in sensory systems contain stimulus-related information, but there has been little study of how post-synaptic neurons might use this information. It is shown that essentially any neuron can use this information to perform flexible computations, and that these computations do not require spike timing that is very precise. As a consequence, irregular and highly-variable firing patterns can drive behaviour with which they have no detectable correlation. Most of the projection neurons in the basal ganglia are inhibitory, and the effect of one nucleus on another is classically interpreted as subtractive or divisive. Theoretically, very flexible computations can be performed within a projection if each presynaptic neuron can both excite and inhibit its targets, but this is hardly ever the case physiologically. However, it is shown here that equivalent computational flexibility is supported by inhibitory projections in the basal ganglia, as a simple consequence of inhibitory collaterals in the target nuclei. Finally, the relationship between population coding and synaptic plasticity is discussed. It is shown that Hebbian plasticity, in conjunction with lateral connections, determines both the dimension of the population code and the tuning of neuron responses within the coded space. These results permit a straightforward interpretation of the effects of synaptic plasticity on information processing at the network level. Together with the NEF, these new results provide a rich set of theoretical principles through which the dominant physiological factors that affect basal ganglia function can be more clearly understood.

The neural mechanisms underlying vocal motor control are poorly understood in mammalian systems. Particularly lacking are details pertaining to the mechanisms and neuroanatomical basis of sensory-motor integration and vocal plasticity, both of which are thought to be essential for evolutionarily advanced vocal behaviors like birdsong or human speech. Based on clinical evidence and imaging studies in humans, as well as its known significance for motor control in general, the basal ganglia (BG) have been hypothesized as a key site for audio-vocal integration, but direct evidence of this is lacking. In this dissertation, I will fill this gap by providing experimental evidence that the basal ganglia are an important component of the forebrain vocal motor pathway. First, I present two examples of vocal plasticity in Tadarida brasiliensis that can serve as powerful behavioral assays of audio-vocal integration. Secondly I provide evidence of BG functions in audio-vocal integration by knocking down striatal dopamine levels with the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyrridine (MPTP). Finally, I will utilize the D1-type receptor specific agonist SKF82958 and antagonist SCH23390 to examine how the direct pathway of the BG regulates vocal production and sensorymotor integration. The behavioral results of these experiments indicate that the bats have a complex and context depended vocal response to noise stimuli that can be used to examine the neurological control of vocal plasticity. Further, the pharmacological evidence demonstrated that the BG was necessary for maintaining and modulating normal muscle force during vocal production. Finally, the mechanism of action in the basal ganglia was found to depend at least partly on activity at D1-type dopamine receptors. The results of this dissertation support the hypothesis that the BG is a critical structure in the modulation of vocal commands in the forebrain vocal-motor pathway. Pathological or pharmacological disruption of dopamine signaling severely degraded the bats abilities to produce natural sounding calls or make adaptive changes to the acoustic environment. These results have implications for research into the treatment of basal ganglia disorders such as Parkinson’s disease, providing an animal model for the study of hypokinetic dysarthria.

Thesis (Ph. D.)--University of Toledo, 2009. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences (Cancer Biology)." Title at OhioLINK ETD site: Investigation of common bases of sympathetic nervous system and neuroblastoma development. Title from title page of PDF document. Includes bibliographical references (p. 72-75, 119-125, 152-192).

Thesis (Ph. D.)--York University, 2000. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 209-273). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://wwwlib.umi.com/cr/yorku/fullcit?pNQ59157.

Optimal decision making requires one to determine the best action among available alternatives as well as the most appropriate level of engagement for performance. While current research and models of decision making have largely focused on the former problem, or action selection, less is known about the latter problem of the selection of motivational drive. Thus, I designed a self-paced decision-making paradigm that aimed to dissociate both facets of selection in rats. First, I showed that the expected net value of potential options influenced rats' general motivation to perform: rats globally exhibited shorter latency to initiate trials in states of high net return than in states of low net return. In contrast, the relative value of options biased choice direction. To study the neural substrates underlying either process, I examined the role of the striatum, which is closely connected with cortex and dopamine neurons, acting as a major hub for reward-related information. In chapter 1, I show that selective lesions of the dorsomedial (DMS) but not ventral striatum (VS) impaired net value-dependent motivational drive but largely spared choice biases. Specifically, DMS lesions rendered animals' latency to initiate trials dependent on the absolute value of immediately preceding trial outcomes rather than on the net value of options. Accordingly, tetrode recordings in Chapter 2 showed that the DMS rather than VS predominantly encodes net value. In fact, net value representation in the DMS was stronger than either absolute or relative value representations during early trial epochs. Thus, the DMS flexibly encodes net expected return, which can guide the selection of motivational drive.

Schizophrenia is among the most debilitating mental disorders, yet the pathophysiology remains unclear. The basal ganglia, a region of the brain involved in motor, cognitive, and sensory processes, may be involved in the pathophysiology of schizophrenia. Some, but not all, neuroimaging studies suggest abnormalities of the basal ganglia in schizophrenia. However, previous studies have examined whole basal ganglia nuclei as opposed to using a unified basal ganglia complex that incorporates anterior-posterior divisions, dorsal-ventral divisions, and gray-white matter segmentation. The hypothesis for the present study was that basal ganglia sub-regions forming functionally relevant subdivisions might be different in schizophrenia. Magnetic resonance imaging scans were acquired from 25 first-episode schizophrenia subjects and 24 healthy subjects. Using manual and automated neuroimaging techniques, total and segmented (gray-white matter) volumes were obtained for the caudate, putamen, and globus pallidus. For the striatum (caudate and putamen), total and segmented volumes were obtained for their respective sub-regions. These sub-regions were restructured into associative, limbic, and sensorimotor subdivisions. Schizophrenia subjects had 6% smaller gray matter volumes for the caudate and 8% smaller gray matter volumes for the associative striatum relative to healthy subjects. Basal ganglia function was studied by examining performance on a neuropsychological test that assesses frontostriatal functioning. For male subjects there was a significant negative correlation between volume of the associative striatum and performance on the neuropsychological test (r=-0.57, p=0.03). Smaller volumes of the associative striatum were associated with more errors on the neuropsychological test. This test was specific to the associative striatum, as another neuropsychological test did not reveal any correlation. In schizophrenia subjects, the relationship between basal ganglia volumes and motor symptoms severity was examined. For antipsychotic-naive subjects there was a significant negative correlation between volume of the motor striatum and severity of Parkinsonism (r=-0.65, p=0.03). The present study suggests that total basal ganglia nuclei volumes are not different in schizophrenia, but gray matter volumes of total basal ganglia nuclei and subdivisions forming functional units may be different in schizophrenia. Structural abnormalities involving the basal ganglia may lead to disrupted functional circuits in schizophrenia.

Individuals with Parkinson’s disease (PD) display deficits in voluntary saccade generation but improved automatic, visually-triggered saccade performance. This can be tested using prosaccades, saccades to visual stimuli, and antisaccades, saccades in the opposite direction from the visual stimuli. Voluntary saccade impairments resulting in antisaccade direction errors and longer saccadic reaction times (SRTs) are thought to be due to insufficient presetting of neural circuitry during saccade preparation in complex tasks involving suppression and selection. The basal ganglia, a major site of PD pathology, might be the cause of abnormalities in preparing for action selection in PD patients. Recently, microsaccade rates have been hypothesized to reflect the dual preparatory signals of saccade facilitation and suppression. In this thesis, we investigated the microsaccade behaviour of PD patients as they performed prosaccades and antisaccades. We hypothesized that deficits in voluntary movements in PD would result in impaired suppression of involuntary movements as reflected by increased microsaccade rates. Our findings demonstrate consistently elevated microsaccade rates in PD subjects compared to age-matched controls. Furthermore, positive correlations were found between antisaccade direction error rate and microsaccade rate as well as microsaccade rate and Hoehn-Yahr score, an indicator of disease severity in PD patients. We conclude that microsaccades reflect the impaired suppression of involuntary movements caused by voluntary movement deficits in PD pathology. Our findings indicate that microsaccades provide insight into action preparatory mechanisms and BG dysfunction. Therefore, measuring microsaccades in PD may provide a useful biomarker to follow disease progression and effectiveness of treatment therapies. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2014-01-09 23:31:21.78

No description available.

The difficulty with movement initiation, or akinesia, is a cardinal symptom of Parkinson�s disease (PD) and the loss of dopaminergic cells, affecting the function of the basal ganglia, the thalamus and the motor cortex, has long been documented. From a broader perspective, it has been proposed that akinesia is caused by impaired function in different brain areas, inside and outside the basal ganglia, operating as a �behavioural arrest control system� (Klemm, 2001). Several neurotransmitters seem to modulate the activity of this system and, contrasting the well-known effects of dopamine, the involvement of adenosine has only recently emerged, particularly via A2A receptors. Adenosine plays an opposite role to dopamine in the brain: adenosine stimulation at A2A receptors inhibits movement (Ferre et al., 1991a; Hauber and Munkle, 1995; Rimondini et al., 1997), whereas A2A antagonists seem to promote movement (Kanda et al., 2000; Bara-Jimenez et al., 2003; Pinna et al., 2005). Although specific adenosine A2A and dopamine D2 receptors are known to antagonistically interact (Ferre et al., 1997; Fuxe et al., 1998; Ferre et al., 2001), little is known of the involvement of A2A receptors in regulating neural activity in the basal ganglia, a crucial point for the future use of A2A antagonists as adjuvant therapy in Parkinson�s disease. In fact, although it is generally accepted that akinesia results from altered function in the cortico-basal ganglia-cortical loop, as confirmed in several studies reporting changes in basal ganglia activity following dopamine depletion (Blandini et al., 2000; Bevan et al., 2002; Boraud et al., 2002), no study to date has systematically investigated electrophysiological changes in the basal ganglia during akinesia induced by adenosine receptor stimulation. Starting from a common behavioural effect, this study tries to bridge this gap by investigating and comparing, in two basal ganglia structures, the neural substrate of akinesia after acute dopamine D2 receptor blockade and adenosine A2A receptor stimulation. The external segment of the globus pallidus (GP, or simply globus pallidus in the rat) and the substantia nigra pars reticulata (SNr) were chosen as the recording sites because both nuclei are included into the �behavioural arrest control system� and seem to express somewhat complementary functions, as a respective key integrative station and main output of the basal ganglia. Dopamine function was manipulated by acute decrease in availability of dopamine binding sites in the brain, through specific dopamine D2 receptor blockade with systemic injections (1.0 and 1.5 mg/kg) of raclopride(3,5-dichloro-N-[(1-ethylpyrrolidin-2-y)methyl]-2-hydroxy-6-methoxy-benzamide), resulting in akinesia. Conversely, movement was inhibited by specific adenosine A2A receptor stimulation with systemic injections (2.5 and 5.0 mg/kg) of the drug CGS21680 (sodium-2-p-carboxyethylphenylamino-5-N-carboxamidoadenosine). In both situations, behaviour was assessed through specific akinesia tests. Single neuron activity before injection and changes in the firing frequency and firing pattern occurring after injection have been analysed and compared for each cell recorded from GP and SNr, during periods of behavioural rest. Synchronised firing between cell pairs has also been assessed. However, the small number of cell pairs showing correlated firing in each structure after systemic injection of drugs was not statistically relevant for further analysis and interpretation of synchronised firing during drug induced akinesia. In our experiments, both drugs inhibited movement, albeit somewhat differently, with lack of rigidity and �flat� body position after adenosine stimulation. Dopamine blockade decreased mean firing rate and dramatically altered the firing pattern in both investigated structures, generally increasing burst activity (increased percentage of spikes in bursts, mean number of bursts, mean number of spikes per burst, mean intra-burst firing frequency) and decreasing regularity of firing (increased coefficient of variation of the inter-spike intervals). Increased burst activity in the rat basal ganglia in an acute model of parkinsonian akinesia, following systemic raclopride injections, confirmed the importance of changes in the firing pattern in PD. The only electrophysiological effect of systemic A2A stimulation was decreased mean firing rate in the GP, a weak effect that could not propagate towards output stations of the basal ganglia. The lack of changes in the firing pattern, at both input and output levels of the basal ganglia, suggests a correlation with the lack of rigidity in adenosine-stimulation-induced akinesia.

The role of the basal ganglia in human language function remains unknown, despite a corpus of literature documenting the association between vascular lesions of the dominant nonthalamic subcortical (NS) region and disordered language. Theories of subcortical language function have been postulated (e.g., Crosson, 1985; Wallesch & Papagno, 1988), however, research in this field has remained largely data-driven, providing limited descriptions of individuals with vascular NS lesions in terms of performance on standard off-line language measures. This approach has failed to reveal the underlying nature of these language deficits “locally” in terms of various dynamic and temporally constrained linguistic and nonlinguistic component processes. The current series of studies are based largely on the premise that such empirical data has the potential to speak more directly to the cogency of current theories proposing a subcortical role in language or related cognitive functions. The present thesis investigated the performance of individuals with dominant chronic vascular NS lesions, compared to matched control subjects, individuals with Parkinson’s disease (PD) (also assumed to have NS dysfunction) and subjects with cortical lesions (CL), on a series of experiments which allowed for the real-time examination of language processing, manipulating the degree to which automatic and attentional/strategic processing is invoked. The theoretical underpinning of these experiments hinges primarily on the proposed role of frontal-subcortical systems in mediating aspects of language via attentional/strategic mechanisms. Accordingly, it was hypothesised that the locus of impairment for individuals with NS lesions would be centred selectively on those facets of language processing which require increased recourse to these proposed frontal-subcortical cognitive capacities. The language abilities of 15 subjects with chronic dominant NS lesions, 15 matched control subjects, 14 matched subjects with CL, and 12 matched individuals with PD were examined initially on the Western Aphasia Battery (WAB) and the Boston Naming Test (BNT). Most NS subjects were classified as non-aphasic according to the WAB, however, circumscribed deficits were evidenced, typically in generative and confrontation naming. In contrast, the CL group showed significant deficits on most aspects of the WAB compared to matched normal control subjects, and presented with a more severe impairment than NS subjects overall on the WAB and in confrontation naming and repetition. The PD group performance was not significantly different from the matched control group, while PD subjects performed better than the NS group overall on the WAB. The same cohort of NS, CL, PD, and control subjects undertook a battery of complex language measures designed to place a range of higher-order cognitive demands on the language processing system. This battery included subtests from the Test of Language Competence-Expanded Edition (TLC-E), the Test of Word Knowledge (TOWK), and The Word Test-Revised (TWT-R). The NS, CL, and PD subjects presented with marked disturbances in those tasks involving cognitive-linguistic flexibility, sentence formulation, indeterminacy of meaning, and metalinguistic manipulation of the lexical-semantic system. Collectively, the off-line results suggest that those aspects of language processing which are more heavily reliant on higher-order cognitive capacities are selectively compromised in subjects with NS lesions and PD. This assumption was further examined and substantiated in a series of on-line lexical ambiguity priming experiments performed by a subset of the original NS subjects (n = 10), matched control subjects (n = 10), matched CL subjects (n=10), and matched PD subjects (n = 10). When lexical ambiguities were presented in a single word context as word triplets, NS subjects showed rapid nonselective lexical activation, suggesting that intact lexical-semantic information could be accessed via automatic routines, similar to control subjects. Unlike control subjects, however, NS subjects were unable to sustain any form of significant activation, implying a selective impairment in the ability to manipulate lexical-semantic information through attentional/controlled processing. This breakdown was qualitatively different to the controlled processing disturbance evidenced by CL subjects, who maintained nonselective meaning facilitation over time, while PD subjects showed a pattern of selective priming consistent with a reduction in attentional processing. The emerging picture of a dissociation between intact automatic processing and compromised attentional/strategic lexical processing in the NS subjects was further elucidated in an experiment examining the processing of unequibiased lexical ambiguities in isolation. In this study, NS and PD subjects showed rapid nonselective meaning facilitation, again implying intact automatic lexical processing. While control and CL subjects evidenced multiple meaning activation followed by selective facilitation of the dominant meaning, NS and PD subjects were unable to achieve selective meaning facilitation, instead showing a protracted period of nonselective lexical activation. This finding suggested that when ambiguities were encountered in isolation, there was not an absolute breakdown in attentional processing per se, but rather a circumscribed deficit in the selective attentional engagement of the semantic network on the basis of meaning frequency, possibly implicating a disturbance of inhibitory mechanisms within the semantic network. A cross-modal priming experiment was used to investigate how lexical ambiguities were processed and resolved in a biased sentential context. Initially, lexical activation for the neurological patient groups appeared influenced by contextual information to a greater extent than in normal controls, which may indicate delayed lexical decision making or disturbed automatic lexical access. Only the PD and NS individuals failed to then maintain selective facilitation of the contextually appropriate meaning, suggesting a breakdown in the attention-based control and maintenance of semantic activation on the basis of integrated sentential constraints. This finding was extended in another cross-modal priming experiment, where NS and PD subjects appeared unable to use discourse-level information to select meanings and develop topical inferences via attentional/strategic mechanisms, while CL subjects showed a selective disturbance of inference development. The results of this thesis have served to delineate certain dynamic aspects of language processing in individuals with NS lesions in terms of automatic lexical processing components and processes involving the attentional/strategic selection of meaning on the basis of meaning frequency and various types of contextual information. In general, the NS group showed a demarcation between intact automatic processing and a breakdown in attentional/strategic processing which was manifest differently depending on the conditions under which processing was invoked. Furthermore, the performance of NS subjects on attentional operations was able to be dissociated under certain conditions from CL group performance and was similar to the PD group’s performance in certain instances. These preliminary findings are consistent with recent theories proposing a role for frontal-subcortical systems in the “top-down” modulation of semantic processing via executive attentional and strategic mechanisms. Although a disturbance in these systems provides a parsimonious explanation of the NS and PD group performance, such conclusions are drawn tentatively with the caveat that the precise neuropathological basis of cognitive-linguistic deficits in these individuals remains unclear at present.