A role of the basal ganglia in the occurrence of visual hallucinations (a hypothetical mechanism)

A hypothetical mechanism of the basal ganglia involvement in visual hallucinations is proposed. According to this mechanism, hallucination is the result of modulation of the efficacy of corticostriatal synaptic inputs and changes in spiny cell activity due to the rise of striatal dopamine concentration (or due to other reasons). These changes cause an inhibition of neurons in the substantia nigra pars reticulata and subsequent disinhibition of neurons in the superior colliculus and pedunculopontine nucleus (including its cholinergic cells). In the absence of afferentation from the retina this disinhibition leads to activation of neurons in the lateral geniculate nucleus, pulvinar and other thalamic nuclei projecting to the primary and highest visual cortical areas, prefrontal cortex, and also back to the striatum. Hallucinations as conscious visual patterns are the result of selection of signals circulating in several interconnected loops each of which includes one of above mentioned neocortical areas, one of thalamic nuclei, limbic and one of visual areas of the basal ganglia, superior colliculus and/or pedunculopontine nucleus. According to our model, cannabinoids, opioids and ketamine may lead to hallucinations due to their promotional role in the LTD of cortical inputs to GABAergic spiny cells of striatal striosomes projecting to dopaminergic neurons, disinhibition of the lasts, and increase in striatal dopamine concentration.     

Generation of Ponto-Geniculo-Occipital (PGO) waves as a possible reason of disturbances in visual perception in microsleep

A hypothesis is put forward that one of the reasons for disturbances in visual perception during microsleep could be a spontaneous generation of Ponto-Geniculo-Occipital (PGO) waves. If the PGO waves are generated in microsleep, they could propagate into different thalamic nuclei conveying visual infomation. Consequently, a propagation of visual infonnation from the retina (if the eyes are opened) to visual neocortical areas and to input basal ganglia nucleus, striatum could be impaired. According to previously proposed mechanism of visual processing, which includes visual attention, in absence of striatum activation by a visual stimulus, a disinhibition through the basal ganglia of superior colliculus that transfer visual information to dopaminergic structures becomes impossible. Due to absence of dopamine release in response to visual stimulus, the attention to this stimulus cannot start, and therefore its processing worsens in all visual cortical areas. The suggested hypothesis could be verified in experiments with artificially evoked microsleep using non-invasive methods for searching for the correlates of the PGO activity presence in the brain.     

A contribution of synaptic plasticity in the basal ganglia to processing of visual information

The mechanism of involvement of the basal ganglia in processing of visual information on the basis of dopamine-dependent modulation of efficacy of synaptic transmission in interconnected parallel associative and limbic loops (cortex--basal ganglia--thalamus--cortex) is proposed. Each loop consists of one of the visual or prefrontal cortical areas connected with the thalamic nucleus and corresponding loci in different nuclei of the basal ganglia. Circulation of activity in such a loop provides reentrance of information into the thalamus and neocortex. Dopamine releasing in response to a visual stimulus oppositely modulates the efficacy of "strong" and "weak" corticostriatal inputs. Subsequent reorganization of activity in the loop leads to a disinhibition (inhibition) of activity of those cortical neurons that were "strongly" ("weakly)" excited by the visual stimulus simultaneously with activation of dopaminergic cells. A selected neuronal pattern in each cortical area represents a property of the visual stimulus processed by this area. Excitation of dopaminergic cells by the visual stimulus via the superior colliculi requires parallel activation of a disinhibitory input to the superior colliculi via the thalamus and a "direct" pathway through the basal ganglia. The prefrontal cortex excited by the visual stimulus via the mediodorsal thalamic nucleus performs a top-down control over the dopaminergic cell activity, supervising simultaneous dopamine release in different striatal loci and thus promotes the interconnected selection of neuronal representations of individual properties of the visual stimulus and their binding in an integrated image.     

A role of dopamine-dependent activity reorganizations in the cortico-basal ganglia-thalamocortical loops in visual attention (hypothetical mechanism)

A mechanism of attention is proposed according to which its influence on visual processing is switched on by release of dopamine into the striatum. A dopamine release during involuntary attention is promoted by visual activation of striatonigral cells via the thalamus and subsequent disinhibition through the basal ganglia of the superior colliculus. A dopamine release during voluntary attention is promoted by activation of prefrontal cortex. The strengthening of responses of neocortical neurons to attended stimulus, and suppression of responses to other stimuli is the result of opposite modulatory action of dopamine on the efficacy of strong and weak corticostriatal inputs. This leads to changes in the output basal ganglia signals ("attentional filter") that exert disinhibitory and inhibitory influence (via the thalamus) on neocortical cells that initially were strongly and weakly activated by a stimulus, respectively. From proposed mechanism follows, that attention modulates only those components of responses of cortical neurons which latency exceeds the latency of reactions of dopaminergic cells (80-100 ms).     

Possible mechanisms of involvement of the subthalamic nucleus and structures interconnected with this nucleus in movement disorders evoked by dopamine depletion

A possible mechanism of involvement of the subthalamic nucleus (STN) in movement disorders evoked by dopamine deficit is suggested. Multifunctional role of the STN is based on following reasons. Various STN cells participate in the cortico-basal ganglia-thalamocortical loop and in the basal ganglia-pedunculopontine-basal ganglia loop. Complexity of neural circuits is determined by functional heterogeneity of neurons in the nuclei, reciprocally connected with the STN, as well as by opposite modulation of activity of these neurons by dopamine due to activation of different types of pre- and postsynaptic receptors. Dopamine influences activity of STN neurons directly, through pre- and postsynaptic receptors. It is assumed that high-frequency stimulation of the STN can reduce or eliminate Parkinsonian symptoms not only owing to inhibition of activity of GABAergic neurons in the output basal ganglia nuclei, projected into the thalamus or pedunculopontine nucleus, but also due to excitation of glutamatergic or cholinergic neurons in the output nuclei, and due to potentiation of excitatory inputs to preserved dopaminergic neurons and subsequent rise in dopamine concentration.     

Cellular principles underlying normal and pathological activity in the subthalamic nucleus

The motor symptoms of Parkinson's disease are associated with abnormal, correlated, low frequency, rhythmic burst activity in the subthalamic nucleus and connected nuclei. Research into the mechanisms controlling the pattern of subthalamic activity has intensified because therapies that manipulate the pattern of subthalamic activity, such as deep brain stimulation and levodopa administration, improve motor function in Parkinson's disease. Recent findings suggest that dopamine denervation of the striatum and extrastriatal basal ganglia profoundly alters the transmission and integration of glutamatergic cortical and GABAergic pallidal inputs to subthalamic neurons, leading to pathological activity that resonates throughout the basal ganglia and wider motor system.     

Common features of neural activity during singing and sleep periods in a basal ganglia nucleus critical for vocal learning in a juvenile songbird

Reactivations of waking experiences during sleep have been considered fundamental neural processes for memory consolidation. In songbirds, evidence suggests the importance of sleep-related neuronal activity in song system motor pathway nuclei for both juvenile vocal learning and maintenance of adult song. Like those in singing motor nuclei, neurons in the basal ganglia nucleus Area X, part of the basal ganglia-thalamocortical circuit essential for vocal plasticity, exhibit singing-related activity. It is unclear, however, whether Area X neurons show any distinctive spiking activity during sleep similar to that during singing. Here we demonstrate that, during sleep, Area X pallidal neurons exhibit phasic spiking activity, which shares some firing properties with activity during singing. Shorter interspike intervals that almost exclusively occurred during singing in awake periods were also observed during sleep. The level of firing variability was consistently higher during singing and sleep than during awake non-singing states. Moreover, deceleration of firing rate, which is considered to be an important firing property for transmitting signals from Area X to the thalamic nucleus DLM, was observed mainly during sleep as well as during singing. These results suggest that songbird basal ganglia circuitry may be involved in the off-line processing potentially critical for vocal learning during sensorimotor learning phase.     

The cortico-basal ganglia-thalamocortical circuit with synaptic plasticity. II. Mechanism of synergistic modulation of thalamic activity via the direct and indirect pathways through the basal ganglia

A possible mechanism underlying the modulatory role of dopamine, adenosine and acetylcholine in the modification of corticostriatal synapses, subsequent changes in signal transduction through the "direct" and "indirect" pathways in the basal ganglia and variations in thalamic and neocortical cell activity is proposed. According to this mechanism, simultaneous activation of dopamine D1/D2 receptors as well as inactivation of adenosine A1/A(2A) receptors or muscarinic M4/M1 receptors on striatonigral/striatopallidal inhibitory cells can promote the induction of long-term potentiation/depression in the efficacy of excitatory cortical inputs to these cells. Subsequently augmented inhibition of the activity of inhibitory neurons of the output nuclei of the basal ganglia through the "direct" pathway together with reduced disinhibition of these nuclei through the "indirect" pathway synergistically increase thalamic and neocortical cell firing. The proposed mechanism can underlie such well known effects as "excitatory" and "inhibitory" influence of dopamine on striatonigral and striatopallidal cells, respectively; the opposite action of dopamine and adenosine on these cells; antiparkinsonic effects of dopamine receptor agonists and adenosine or acetylcholine muscarinic receptor antagonists.     

Basal ganglia influences on the cerebellum of the cat

The changes in firing rate of intracerebellar nuclear neurons following electrical stimulation of the contralateral basal ganglia were investigated in adult cats, in which antidromic activation of cortico-pontine and/or cortico-olivar fibers arising in the area 6 had been excluded by chronic ablation of the motor cortex. Activation of putamen and caudate nucleus induced discharge changes in a low percentage (below 12.5%) of both medial and lateral cerebellar nuclei neurons, while stimulation of globus pallidus and especially of entopeduncular nucleus modified the spontaneous discharge of a greater percent of cells (up to 29%), mainly in the most lateral cerebellar portions. The basal ganglia-induced effects were abolished upon section of the brachium pontis but not of the restiform body. Latency values of the responses, which were predominantly excitatory in nature, suggest the involvement of structures interposed between basal ganglia and precerebellar systems. We postulated that impulses issued by the basal ganglia could reach the cerebellum through a pathway that involves the pedunculopontine nucleus and the nucleus reticularis tegmenti pontis.     

The distribution of cholinergic neurons in the human central nervous system

Choline acetyltransferase (ChAT), the enzyme responsible for the biosynthesis of acetylcholine, is presently the most specific marker for identifying cholinergic neurons in the central and peripheral nervous systems. The present article reviews immunohistochemical and in situ hybridization studies on the distribution of neurons expressing ChAT in the human central nervous system. Neurons with both immunoreactivity and in situ hybridization signals of ChAT are observed in the basal forebrain (diagonal band of Broca and nucleus basalis of Meynert), striatum (caudate nucleus, putamen and nucleus accumbens), cerebral cortex, mesopontine tegmental nuclei (pedunculopontine tegmental nucleus, laterodorsal tegmental nucleus and parabigeminal nucleus), cranial motor nuclei and spinal motor neurons. The cerebral cortex displays regional and laminal differences in the distribution of neurons with ChAT. The medial septal nucleus and medial habenular nucleus contain immunoreactive neurons for ChAT, which are devoid of ChAT mRNA signals. This is probably because there is a small number of cholinergic neurons with a low level of ChAT gene expression in these nuclei of human. Possible connections and speculated functions of these neurons are briefly summarized.     

Role of dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo---hippocampal loop in response decrement

The mechanism of response decrement in hippocampal and dopaminergic neurons on repeating stimuli based on the dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo--hippocampal loop is suggested. Activation of hippocampal neurons caused by new stimulus facilitates occurrence of reaction of dopaminergic cells due to their disinhibition through striatopallidal cells of nucleus accumbens and ventral pallidum. However, increase in dopamine level and activation accumbens and ventral pallidum. However, increase in dopamine level and activation of D2 receptors on the striatopallidal cell, while promoting depression of hippocampal inputs, prevents disinhibition of dopaminergic cells, and their reactions start their decrement. The subsequent decrease in D1 receptor activation leads to reduction of efficiency of neuron excitation in the hippocampal CA1 fields, as well as in striatonigral cells of nucleus accumbens. This leads to a decrease of disinhibition through a direct pathway via the basal ganglia of thalamic nucleus reunions which activates neurons of the CA1 field. This effect causes decrement of reactions of the hippocampal neurons, a subsequent reduction of dopaminergic cell disinhibition, and further decrement of their responses.     

A hypothetical role of cortico-basal ganglia-thalamocortical loops in visual processing

The goal of the present work was to define the mechanisms underlying the contribution of sensory and limbic cortico-basal ganglia-thalamocortical loops to visual processing and its attentional modulation. We proposed that visual processing is promoted by dopamine-dependent long-term modifications of synaptic transmission in the basal ganglia that favour a selection of neocortical patterns representing a visual stimulus. This selection is the result of the opposite sign of modulation of strong and weak cortico-basal ganglia inputs and subsequent activity reorganization in each loop. Reorganization leads to disinhibition/inhibition of cortical neurons strongly/weakly excited by stimulus during dopamine release. Recruitment of the thalamo-basal ganglia-collicular pathway is proposed to be necessary for stimulus-evoked dopamine release that underlies bottom-up attentional effects. Visual excitation of the prefrontal cortex and hippocampus (via the thalamus), their cooperation in control of the basal ganglia and dopaminergic cell firing, and simultaneous modulation of activity in diverse cortico-basal ganglia-thalamocortical loops is proposed to underlie top-down attentional effects. It follows from our model that only those components of cortical responses can be modulated by attention, whose onset exceeds the latency of visual responses of dopaminergic cells (50-110 ms). This and other consequences of the model are in accordance with known experimental data.     

Cholinergic and catecholaminergic neurons relay striatal information to the optic tectum in amphibians.

In the amphibians Rana perezi and Xenopus laevis, the involvement of cholinergic and catecholaminergic neurons in the relay of basal ganglia inputs to the tectum was investigated. Tract-tracing experiments, in which anterograde tracers were applied to the basal ganglia and retrograde tracers to the optic tectum, were combined with immunohistochemistry for choline acetyltransferase and tyrosine hydroxylase. The results of these experiments suggest that dopaminergic neurons of the suprachiasmatic nucleus and pretectal region, noradrenergic cells of the locus coeruleus and the cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei mediate at least part of the basal ganglia input to the tectum in anurans.     

Neural mechanisms in disorders of movement

1. Experimental models of ballism, chorea and Parkinson's disease have been developed in the primate, and the underlying neural mechanisms which mediate these disorders of movement have been investigated using the 2-deoxyglucose uptake technique. 2. In ballism, the subthalamic nucleus is either lesioned or underactive. Because of the excitatory nature of subthalamic efferent fibres, this leads to abnormal underactivity of neurons in the medical segment of the globus pallidus which project to the ventral anterior and ventral lateral nuclei of the thalamus, and to the pedunculopontine nucleus of the caudal midbrain. 3. In chorea, there is underactivity of GABAergic striatal (putaminal) neurons which project to the lateral segment of the globus pallidus. This leads to overacting of lateral pallidal neurons and, thus, physiological inhibition of the subthalamic nucleus. Common neural mechanisms, therefore, underlie the appearance of dyskinesia in ballism and chorea. 4. In parkinsonism, there is overactivity of putaminal neurons projecting to the lateral pallidal segment. This results in excessive inhibition of lateral pallidal neurons and, as a consequence, disinhibition of the subthalamic nucleus. Overactivity of the subthalamic nucleus provides excessive drive upon medial pallidal neurons projecting to thalamic and pedunculopontine nuclei.     

Neural Activity in the Macaque Putamen Associated with Saccades and Behavioral Outcome

It is now widely accepted that the basal ganglia nuclei form segregated, parallel loops with neocortical areas. The prevalent view is that the putamen is part of the motor loop, which receives inputs from sensorimotor areas, whereas the caudate, which receives inputs from frontal cortical eye fields and projects via the substantia nigra pars reticulata to the superior colliculus, belongs to the oculomotor loop. Tracer studies in monkeys and functional neuroimaging studies in human subjects, however, also suggest a potential role for the putamen in oculomotor control. To investigate the role of the putamen in saccadic eye movements, we recorded single neuron activity in the caudal putamen of two rhesus monkeys while they alternated between short blocks of pro- and anti-saccades. In each trial, the instruction cue was provided after the onset of the peripheral stimulus, thus the monkeys could either generate an immediate response to the stimulus based on the internal representation of the rule from the previous trial, or alternatively, could await the visual rule-instruction cue to guide their saccadic response. We found that a subset of putamen neurons showed saccade-related activity, that the preparatory mode (internally- versus externally-cued) influenced the expression of task-selectivity in roughly one third of the task-modulated neurons, and further that a large proportion of neurons encoded the outcome of the saccade. These results suggest that the caudal putamen may be part of the neural network for goal-directed saccades, wherein the monitoring of saccadic eye movements, context and performance feedback may be processed together to ensure optimal behavioural performance and outcomes are achieved during ongoing behaviour.     

Reduced noradrenaline,but not dopamine and serotonin in motor thalamus of the MPTP primate: relation to severity of Parkinsonism

We recently found severe noradrenaline deficits throughout the thalamus of patients with Parkinson's disease [C. Pifl, S. J. Kish and O. Hornykiewicz Mov Disord. 27, 2012, 1618.]. As this noradrenaline loss was especially severe in nuclei of the motor thalamus normally transmitting basal ganglia motor output to the cortex, we hypothesized that this noradrenaline loss aggravates the motor disorder of Parkinson's disease. Here, we analysed noradrenaline, dopamine and serotonin in motor (ventrolateral and ventroanterior) and non‐motor (mediodorsal, centromedian, ventroposterior lateral and reticular) thalamic nuclei in MPTP‐treated monkeys who were always asymptomatic; who recovered from mild parkinsonism; and monkeys with stable, either moderate or severe parkinsonism. We found that only the symptomatic parkinsonian animals had significant noradrenaline losses specifically in the motor thalamus, with the ventroanterior motor nucleus being affected only in the severe parkinsonian animals. In contrast, the striatal dopamine loss was identical in both the mild and severe symptom groups. MPTP‐treatment had no significant effect on noradrenaline in non‐motor thalamic nuclei or dopamine and serotonin in any thalamic subregion. We conclude that in the MPTP primate model, loss of noradrenaline in the motor thalamus may also contribute to the clinical expression of the parkinsonian motor disorder, corroborating experimentally our hypothesis on the role of thalamic noradrenaline deficit in Parkinson's disease.     

A neural model of basal ganglia-thalamocortical relations in normal and parkinsonian movement

 Anatomical, neurophysiological, and neurochemical evidence supports the notion of parallel basal ganglia–thalamocortical motor systems. We developed a neural network model for the functioning of these systems during normal and parkinsonian movement. Parkinson’s disease (PD), which results predominantly from nigrostriatal pathway damage, is used as a window to examine basal ganglia function. Simulations of dopamine depletion produce motor impairments consistent with motor deficits observed in PD that suggest the basal ganglia play a role in motor initiation and execution, and sequencing of motor programs. Stereotaxic lesions in the model’s globus pallidus and subthalamic nucleus suggest that these lesions, although reducing some PD symptoms, may constrain the repertoire of available movements. It is proposed that paradoxical observations of basal ganglia responses reported in the literature may result from regional functional neuronal specialization, and the non-uniform distributions of neurochemicals in the basal ganglia. It is hypothesized that dopamine depletion produces smaller-than-normal pallidothalamic gating signals that prevent rescalability of these signals to control variable movement speed, and that in PD can produce smaller-than-normal movement amplitudes. Received: 1 September 1994/Accepted in revised form: 16 May 1995     

Dichotomous organization of the external globus pallidus

Different striatal projection neurons are the origin of?a?dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in?vivo are?underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of?a dichotomous organization as fundamental as?that in striatum. Thus, two populations of GPe neuron?together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.     

Endogenous interaction of glutamate and dopamine in the basal ganglia of the awake rat during aging

The interaction of glutamate and dopamine in the basal ganglia of fully conscious rat during the normal process of aging is reviewed. Using a novel approach, that of blocking the reuptake of glutamate, the effects of increasing concentrations of endogenous glutamate on the extracellular concentrations of dopamine in striatum and nucleus accumbens in the young rat were investigated. It was found that increasing concentrations of glutamate correlated significantly with increasing concentrations of dopamine in striatum and nucleus accumbens. Moreover the increase of dopamine in both structures was significantly reduced after blockade of NMDA and AMPA/kainate glutamate receptors, suggesting that the increase of dopamine was mediated by glutamate. The interaction glutamate/dopamine expressed by its ratio showed a significant age-related decrease in nucleus accumbens but not in striatum, so that to a given amount of glutamate less increase of dopamine is produced. It is suggested that the interaction glutamate-dopamine represents a balanced input to the GABA neuron in the basal ganglia and that during aging this balance is disrupted. In addition, we also speculate on the significance of this glutamate-dopamine disruption in relation to the changes in motor behavior found with age.     

The Mechanism of Saccade Motor Pattern Generation Investigated by a Large-Scale Spiking Neuron Model of the Superior Colliculus

The subcortical saccade-generating system consists of the retina, superior colliculus, cerebellum and brainstem motoneuron areas. The superior colliculus is the site of sensory-motor convergence within this basic visuomotor loop preserved throughout the vertebrates. While the system has been extensively studied, there are still several outstanding questions regarding how and where the saccade eye movement profile is generated and the contribution of respective parts within this system. Here we construct a spiking neuron model of the whole intermediate layer of the superior colliculus based on the latest anatomy and physiology data. The model consists of conductance-based spiking neurons with quasi-visual, burst, buildup, local inhibitory, and deep layer inhibitory neurons. The visual input is given from the superficial superior colliculus and the burst neurons send the output to the brainstem oculomotor nuclei. Gating input from the basal ganglia and an integral feedback from the reticular formation are also included.We implement the model in the NEST simulator and show that the activity profile of bursting neurons can be reproduced by a combination of NMDA-type and cholinergic excitatory synaptic inputs and integrative inhibitory feedback. The model shows that the spreading neural activity observed in vivo can keep track of the collicular output over time and reset the system at the end of a saccade through activation of deep layer inhibitory neurons. We identify the model parameters according to neural recording data and show that the resulting model recreates the saccade size-velocity curves known as the saccadic main sequence in behavioral studies. The present model is consistent with theories that the superior colliculus takes a principal role in generating the temporal profiles of saccadic eye movements, rather than just specifying the end points of eye movements.