Non-motor basal ganglia functions: A review and proposal for a model of sensory predictability in auditory language perception

While the primary function of the basal ganglia (BG) is linked to motor behaviour, several investigations of non-motor behaviour allocate cognitive and language-specific functions to the BG. What may such seemingly discrepant functions have in common? Some neurophysiologic theories of motor behaviour assign temporal sequencing, others the sequencing of general cognitive patterns to the BG. Turning to auditory language perception and syntax in particular, one may consider syntactic processing as a hierarchical sequencing phenomenon. Furthermore, previous data have shown that if events are predictable, the processing of successively following events in a sequence is facilitated. We propose that sequencing is closely linked to the perception of predictable cues (regular beats, meter, temporal chunks etc.). If this is the case, syntactic processing should rely on the extraction of predictable cues in auditory language perception. Consequently, dysfunctional extraction of such cues in BG patients should then lead to secondary deficits in syntactic processing as evidenced in recent behavioural and electrophysiological evidence (ERP). The fact that such “secondary syntactic deficits” can be compensated by external and speech inherent predictable cues permits two conclusions: (i) syntactic deficits in BG patients are epiphenomenal, and (ii) sequencing dysfunctions of the pre-supplementary motor area (SMA)-BG circuit may be compensated by increased influence of the cerebellar-thalamic-pre-SMA pathway. In the current review we elaborate on this possibility drawing comparisons to similar proposals in motor and language production.     

Probing basal ganglia functions by saccade eye movements

The basal ganglia (BG) are a group of subcortical structures involved in diverse functions, such as motor, cognition and emotion. However, the BG do not control these functions directly, but rather modulate functional processes occurring in structures outside the BG. The BG form multiple functional loops, each of which controls different functions with similar architectures. Accordingly, to understand the modulatory role of the BG, it is strategic to uncover the mechanisms of signal processing within specific functional loops that control simple neural circuits outside the BG, and then extend the knowledge to other BG loops. The saccade control system is one of the best-understood neural circuits in the brain. Furthermore, sophisticated saccade paradigms have been used extensively in clinical research in patients with BG disorders as well as in basic research in behaving monkeys. In this review, we describe recent advances of BG research from the viewpoint of saccade control. Specifically, we account for experimental results from neuroimaging and clinical studies in humans based on the updated knowledge of BG functions derived from neurophysiological experiments in behaving monkeys by taking advantage of homologies in saccade behavior. It has become clear that the traditional BG network model for saccade control is too limited to account for recent evidence emerging from the roles of subcortical nuclei not incorporated in the model. Here, we extend the traditional model and propose a new hypothetical framework to facilitate clinical and basic BG research and dialogue in the future.     

A neurodynamical model for selective visual attention using oscillators.

We present a neurodynamical model to study and simulate visual search tasks experiments. The model consists of different pools of interconnected phase oscillators. Each oscillator is described by an integrate-and-fire type equation. Visual attention appears as an emergent property of the dynamic of the system, resulting from the temporal synchronization of the pools which bind the features of the searched target. The time courses observed in the psychophysical visual search experiments can be explained within a purely parallel dynamic and without assuming priority maps and serial spotlight mechanisms, as is usually done in the standard theories. The model fits also the measured activity reported for the neural responses in inferotemporal visual cortex of monkeys performing visual search tasks.     

Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated Parkinsonism

Dopamine (DA) depletion in the basal ganglia (BG) of Parkinson's patients gives rise to both frontal-like and implicit learning impairments. Dopaminergic medication alleviates some cognitive deficits but impairs those that depend on intact areas of the BG, apparently due to DA 'overdose.' These findings are difficult to accommodate with verbal theories of BG/DA function, owing to complexity of system dynamics: DA dynamically modulates function in the BG, which is itself a modulatory system. This article presents a neural network model that instantiates key biological properties and provides insight into the underlying role of DA in the BG during learning and execution of cognitive tasks. Specifically, the BG modulates the execution of 'actions' (e.g., motor different parts of the frontal cortex. Phasic changes in DA, which occur during error feedback, dynamically modulate the BG threshold for facilitating/suppressing a cortical command in response to particular stimuli. Reduced dynamic range of DA explains Parkinson and DA overdose deficits with a single underlying dysfunction, despite overall differences in raw DA levels. Simulated Parkinsonism and medication effects provide a theoretical basis for behavioral data in probabilistic classification and reversal tasks. The model also provides novel testable predictions for neuropsychological and pharmacological studies, and motivates further investigation of BG/DA interactions with the prefrontal cortex in working memory.     

Spinal genesis of Mayer waves

Variability in cardiovascular spectra was first described by Stephan Hales in 1733.Traube and Hering initially noted respirophasic variation of the arterial pressure waveform in 1865 and Sigmund Mayer noted a lower frequency oscillation of the same in anesthetized rabbits in 1876.Very low frequency oscillations were noted by Barcroft and Nisimaru in 1932,likely representing vasogenic autorhythmicity.While the origins of Traube Hering and very low frequency oscillatory variability in cardiovascular spectra are well described,genesis mechanisms and functional significance of Mayer waves remain in controversy.Various theories have posited baroreflex and central supraspinal mechanisms for genesis of Mayer waves.Several studies have demonstrated the persistence of Mayer waves following high cervical transection,indicating a spinal capacity for genesis of these oscillations.We suggest a general tendency for central sympathetic neurons to oscillate at the Mayer wave frequency,the presence of multiple Mayer wave oscillators throughout the brainstem and spinal cord,and possible contemporaneous genesis by baroreflex and vasomotor mechanisms.     

Do the basal ganglia inhibit seizure activity in temporal lobe epilepsy?

There is substantial evidence in the literature that the basal ganglia (BG), namely the striatum and pallidum, are involved in temporal lobe epilepsy (TLE). The BG are probably not involved in elaborating clinical seizures, as they do not produce specific epileptiform activity and there is no evident change in the electrical activity in the BG immediately after seizure onset. The data we obtained by direct ictal recording in the BG [1,2], as well as a large body of experimental and clinical evidence reported by other groups, suggest an inhibitory role of the BG during temporal lobe seizures. The BG may have a remote influence on cortical oscillatory processes related to control of epileptic seizures via their feedback pathways to the cortex.     

Food-anticipatory circadian rhythms: concepts and methods

Rats, mice and other species can behaviorally anticipate a predictable daily mealtime by entrainment of circadian oscillators (food-entrainable oscillators) distinct from those (light-entrainable oscillators) that regulate light-dark entrained rhythms of behavior and physiology. Neurobiological analysis of food-anticipatory rhythms has progressed slowly but is gaining pace. Food-anticipatory rhythms have proven to be surprisingly robust to many neural and circadian clock gene perturbations. A few neural ablation sites or gene mutations have been associated with loss or marked attenuation of anticipatory rhythms, but in each case there are apparently conflicting reports. Attenuation of food-anticipatory rhythms following neural or genetic perturbations could result from actions upstream or downstream from the clock mechanism, and could be limited to certain behavioral endpoints or recording conditions. Failure to observe attenuation could reflect compensation by alternate timing mechanisms that do not involve food-entrainable oscillators. To facilitate progress in neurobiological analysis of food-anticipatory rhythms, criteria for distinguishing among formally distinct mechanisms by which animals might anticipate a daily meal are reviewed, and procedural variables that can affect the expression of food-anticipatory rhythms in neurobiologically intact or compromised animals are identified.     

A consideration of sensory factors involved in motor functions of the basal ganglia

There is a sizeable literature concerning basal ganglia (BG) functioning that is based on data from experiments employing a method of analysis that is traditionally used with other motor areas. A brief review of this literature is presented and the following conclusion is reached: as compared to the success of traditional methodologies in elucidating the workings of other motor systems, their use in BG investigations has proven disappointing. A possible reason for the shortcomings of traditional analyses in BG research is discussed. The remainder of this review concerns an alternative approach to the study of the BG that follows from consideration of a variety of clinical and experimental findings. The literature suggests that sensory aspects of BG functioning must be taken into account to fully appreciate the role of this system in motor control. A review of the literature concerning the latter suggests two points: The BG function as sensory analyzer for motor systems. That is, the BG convert sensory data from a form that is receptor oriented to a form that is relevant for guiding movement. The BG ultimately affect movement by gating sensory inputs into other motor areas rather than by directly affecting these areas. This sensory-based model of BG functioning explains a number of apparent discrepancies in the literature. In addition, seemingly anomalous findings are reconciled with the overwhelming evidence that the BG are a motor system. In particular, the suggestions of a BG role in attention and cognition are viewed as being intrinsic rather than orthogonal to the role of the BG in movement.     

The brain network for deductive reasoning: a quantitative meta-analysis of 28 neuroimaging studies

Over the course of the past decade, contradictory claims have been made regarding the neural bases of deductive reasoning. Researchers have been puzzled by apparent inconsistencies in the literature. Some have even questioned the effectiveness of the methodology used to study the neural bases of deductive reasoning. However, the idea that neuroimaging findings are inconsistent is not based on any quantitative evidence. Here, we report the results of a quantitative meta-analysis of 28 neuroimaging studies of deductive reasoning published between 1997 and 2010, combining 382 participants. Consistent areas of activations across studies were identified using the multilevel kernel density analysis method. We found that results from neuroimaging studies are more consistent than what has been previously assumed. Overall, studies consistently report activations in specific regions of a left fronto-parietal system, as well as in the left BG. This brain system can be decomposed into three subsystems that are specific to particular types of deductive arguments: relational, categorical, and propositional. These dissociations explain inconstancies in the literature. However, they are incompatible with the notion that deductive reasoning is supported by a single cognitive system relying either on visuospatial or rule-based mechanisms. Our findings provide critical insight into the cognitive organization of deductive reasoning and need to be accounted for by cognitive theories.     

A consideration of sensory factors involved in motor functions of the basal ganglia

There is a sizeable literature concerning basal ganglia (BG) functioning that is based on data from experiments employing a method of analysis that is traditionally used with other motor areas. A brief review of this literature is presented and the following conclusion is reached: as compared to the success of traditional methodologies in elucidating the workings of other motor systems, their use in BG investigations has proven disappointing. A possible reason for the shortcomings of traditional analyses in BG research is discussed. The remainder of this review concerns an alternative approach to the study of the BG that follows from consideration of a variety of clinical and experimental findings. The literature suggests that sensory aspects of BG functioning must be taken into account to fully appreciate the role of this system in motor control. A review of the literature concerning the latter suggests two points:

1. 1. The BG function as sensory analyzer for motor systems. That is, the BG convert sensory data from a form that is receptor oriented to a form that is relevant for guiding movement.

2. 2. The BG ultimately affect movement by gating sensory inputs into other motor areas rather than by directly affecting these areas. This sensory-based model of BG functioning explains a number of apparent discrepancies in the literature. In addition, seemingly anomalous findings are reconciled with the overwhelming evidence that the BG are a motor system. In particular, the suggestions of a BG role in attention and cognition are viewed as being intrinsic rather than orthogonal to the role of the BG in movement.

Modifications of ongoing tremors and locomotion by sensory feedback.

In principle tremors can be produced by (1) mechanical oscillators (combination of masses and springs), (2) reflex oscillators arising from sensory feedback pathways, or (3) central oscillators generated by single "pacemaker" neurones or interconnected networks. Recent studies supporting each of these mechanisms under certain conditions are discussed. Differences between these mechanisms are clarified by recent studies in Edmonton on the premammillary cat. This preparation shows a prominent reflexly-induced tremor which can be modified by mechanical loading and electrical stimulation. It also shows spontaneous stepping on a treadmill which is known to be produced by a spinal "stepping generator", but can be modified in interesting ways by sensory perturbations. The applicability of these animal studies to human tremors is considered in relation to preliminary studies in Calgary on patients with Parkinson's disease or essential tremor. We have attempted to modify these tremors by application of torque pulses applied to the wrist. The results are described in terms of a normalized "resetting" index which has a high value (greater than 0.6) for all essential tremor patients studied, and a wide range of values for different parkinsonian patients. The resetting index may be useful in determining the relative importance of peripheral and central factors in producing tremor in a variety of patients.     

Comparing functional MRI protocols for small,iron‐rich basal ganglia nuclei such as the subthalamic nucleus at 7 T and 3 T

The basal ganglia (BG) form a network of subcortical nuclei. Functional magnetic resonance imaging (fMRI) in the BG could provide insight in its functioning and the underlying mechanisms of Deep Brain Stimulation (DBS). However, fMRI of the BG with high specificity is challenging, because the nuclei are small and variable in their anatomical location. High resolution fMRI at field strengths of 7 Tesla (T) could help resolve these challenges to some extent. A set of MR protocols was developed for functional imaging of the BG nuclei at 3 T and 7 T. The protocols were validated using a stop‐signal reaction task (Logan et al. [ 1984 ]: J Exp Psychol: Human Percept Perform 10:276–291). Compared with sub‐millimeter 7 T fMRI protocols aimed at cortex, a reduction of echo time and spatial resolution was strictly necessary to obtain robust Blood Oxygen Level Dependent (BOLD) sensitivity in the BG. An fMRI protocol at 3 T with identical resolution to the 7 T showed no robust BOLD sensitivity in any of the BG nuclei. The results suggest that the subthalamic nucleus, as well as the substantia nigra, red nucleus, and the internal and external parts of the globus pallidus show increased activation in failed stop trials compared with successful stop and go trials. Hum Brain Mapp 38:3226–3248, 2017. © 2017 Wiley Periodicals, Inc.     

Striatal dopamine modulates song spectral but not temporal features through D1 receptors

The activity of midbrain dopaminergic neurons and their projection to the basal ganglia (BG) are thought to play a critical role in the acquisition of motor skills through reinforcement learning, as well as in the expression of learned motor behaviors. The precise role of BG dopamine (DA) in mediating and modulating motor performance and learning, however, remains unclear. In songbirds, a specialized portion of the BG is responsible for song learning and plasticity. Previously we found that DA acts on D1 receptors in Area X to modulate the BG output signal and thereby trigger changes in song variability. Here, we investigate the effect of D1 receptor blockade in the BG on song behavior in the zebra finch. We report that this manipulation abolishes social context-dependent changes in variability not only in harmonic stacks, but also in other types of syllables. However, song timing seems not to be modulated by this BG DA signal. Indeed, injections of a D1 antagonist in the BG altered neither song duration nor the change of song duration with social context. Finally, D1 receptor activation in the BG was not necessary for the modulation of other features of song, such as the number of introductory notes or motif repetitions. Together, our results suggest that activation of D1 receptors in the BG is necessary for the modulation of fine acoustic features of song with social context, while it is not involved in the regulation of song timing and structure at a larger time scale.     

The impact of basal ganglia lesions on sensorimotor synchronization, spontaneous motor tempo, and the detection of tempo changes

The basal ganglia (BG) are part of extensive subcortico-cortical circuits that are involved in a variety of motor and non-motor cognitive functions. Accumulating evidence suggests that one specific function that engages the BG and associated cortico-striato-thalamo-cortical circuitry is temporal processing, i.e., the mechanisms that underlie the encoding, decoding and evaluation of temporal relations or temporal structure. In the current study we investigated the interplay of two processes that require precise representations of temporal structure, namely the perception of an auditory pacing signal and manual motor production by means of finger tapping in a sensorimotor synchronization task. Patients with focal lesions of the BG and healthy control participants were asked to align finger taps to tone sequences that either did or did not contain a tempo acceleration or tempo deceleration at a predefined position, and to continue tapping at the final tempo after the pacing sequence had ceased. Performance in this adaptive synchronization-continuation paradigm differed between the two groups. Selective damage to the BG affected the abilities to detect tempo changes and to perform attention-dependent error correction, particularly in response to tempo decelerations. An additional assessment of preferred spontaneous, i.e., unpaced but regular, production rates yielded more heterogeneous results in the patient group. Together these findings provide evidence for less efficient processing in the perception and the production of temporal structure in patients with focal BG lesions. The results also support the functional role of the BG system in attention-dependent temporal processing.     

Oscillatory activity in the basal ganglia

The exact mechanisms underlying the dysfunction of the basal ganglia (BG) that leads to movement disorders such as Parkinson's disease (PD) and dystonia still remain unclear. The classic model, based on two distinct pathways and described nearly 20 years ago by Albin and Delong, fails to explain why lesion or stimulation of the globus pallidus interna improves dyskinesias and why lesion or stimulation of the thalamus does not cause prominent bradykinesia. These paradoxes, initially highlighted out by Marsden and Obeso, led to the proposition that the pattern of neuronal discharge determines pathological function. Accordingly, over the past decade, attention has switched from considerations of discharge rate to the characterisation of synchronised activity within BG networks. Here we would like to briefly review current knowledge about synchronised oscillatory activity in the BG and focus on its relationship to abnormal motor function. In particular, we hypothesise that the frequency of synchronisation helps determine the nature of any motor deficit, perhaps as a consequence of the different tuning properties of basal ganglia-cortical sub-circuits.     

The golli-myelin basic protein negatively regulates signal transduction in T lymphocytes

Protein kinase C (PKC) plays a critical role in signal transduction controlling T lymphocyte activation. Both positive and negative regulation of signal transduction is needed for proper control of T lymphocyte activation. We have found that a golli product of the myelin basic protein (MBP) gene can serve as a negative regulator of signaling pathways in the T lymphocyte, particularly the PKC pathway. Increased expression of golli BG21 in Jurkat T cells strongly inhibits anti-CD3-induced IL-2-luciferase activity, an indicator of T lymphocyte activation. Golli BG21 can be phosphorylated by PKC in vitro and its phosphorylation increases in PMA-activated Jurkat cells. BG21 inhibits the PMA-induced increase in AP-1 or NF-kappaB activation, consistent with golli acting in a PKC-mediated cellular event. Golli BG21 inhibition of the PKC pathway is not due to a direct action on PKC activation but in the cascade following PKC activation, since BG21 neither reduces PKC enzyme activity nor blocks the membrane association of PKCtheta brought on by T lymphocyte activation. The inhibitory function of BG21 is independent of its phosphorylation by PKC because a mutant BG21, in which the PKC sites have been mutated, is as effective as the wild type BG21 in inhibiting the PMA-induced AP-1 activation. Structure-function assays indicate that BG21 inhibitory activity resides in the golli domain rather than in MBP domain of the molecule. These results reveal a novel role for MBP gene products in T lymphocytes within the immune system.     

Cost-efficient FPGA implementation of basal ganglia and their Parkinsonian analysis

The basal ganglia (BG) comprise multiple subcortical nuclei, which are responsible for cognition and other functions. Developing a brain–machine interface (BMI) demands a suitable solution for the real-time implementation of a portable BG. In this study, we used a digital hardware implementation of a BG network containing 256 modified Izhikevich neurons and 2048 synapses to reliably reproduce the biological characteristics of BG on a single field programmable gate array (FPGA) core. We also highlighted the role of Parkinsonian analysis by considering neural dynamics in the design of the hardware-based architecture. Thus, we developed a multi-precision architecture based on a precise analysis using the FPGA-based platform with fixed-point arithmetic. The proposed embedding BG network can be applied to intelligent agents and neurorobotics, as well as in BMI projects with clinical applications. Although we only characterized the BG network with Izhikevich models, the proposed approach can also be extended to more complex neuron models and other types of functional networks.     

The basal ganglia network mediates the planning of movement amplitude

This study addresses the hypothesis that the basal ganglia (BG) are involved specifically in the planning of movement amplitude (or covariates). Although often advanced, based on observations that Parkinson's disease (PD) patients exhibit hypokinesia in the absence of significant directional errors, this hypothesis has been challenged by a recent alternative, that parkinsonian hypometria could be caused by dysfunction of on-line feedback loops. To re-evaluate this issue, we conducted two successive experiments. In the first experiment we assumed that if BG are involved in extent planning then PD patients (who exhibit a major dysfunction within the BG network) should exhibit a preserved ability to use a direction precue with respect to normals, but an impaired ability to use an amplitude precue. Results were compatible with this prediction. Because this evidence did not prove conclusively that the BG is involved in amplitude planning (functional deficits are not restricted to the BG network in PD), a second experiment was conducted using positron emission tomography (PET). We hypothesized that if the BG is important for planning movement amplitude, a task requiring increased amplitude planning should produce increased activation in the BG network. In agreement with this prediction, we observed enhanced activation of BG structures under a precue condition that emphasized extent planning in comparison with conditions that emphasized direction planning or no planning. Considered together, our results are consistent with the idea that BG is directly involved in the planning of movement amplitude or of factors that covary with that parameter.     

Functional anatomy of the basal ganglia: Limbic aspects

IntroductionThe basal ganglia (BG) have been implicated in different processes that control action such as the control of movement parameters but also in processing cognitive and emotional information from the environment. Here, we review existing anatomical data on the interaction between the BG and the limbic system that support implication of the BG in limbic functions.State of the artThe BG form a system that is fairly different from the limbic system, but have strong ties, both anatomical and functional, to the latter. Different models have been proposed. In the parallel model, five segregated circuits from the frontal cortex are individualized and terminate in different regions of the BG and thalamus, before projecting back to their cortical area of origin. Based on the extrafrontal cortical projections, another model has been proposed. It subdivides the cortico-striatal projection into three functional territories: limbic, associative and sensorimotor. In a third spiral model, propagation is possible between limbic information processed by the most medial striatal neurons to motor information processed by the most lateral neurons.PerspectivesThree main levels of interaction between the BG system and the limbic system are considered. (1) The BG receive direct afferences from several structures associated with the limbic system. Limbic cortical areas project to the striatum, of which the internal architecture is particularly complex, with significant cross-species differences: a compartmental striosome/matrix subdivision described mainly in primates, and a core/shell topographic subdivision of the nucleus accumbens more sharply marked in rodents. (2) Projections from the amygdala form a patchy dorso-ventral progressive gradient in the nucleus accumbens and ventral caudate. (3) Both shell and striosomes receive limbic information from cortical and subcortical limbic structures and project to the dopaminergic neurons of the substantia nigra pars compacta, which in turn modulates their activity. (4) There is a significant overlap between the ventral portions of the BG, nucleus accumbens and ventral pallidum, and the ventral subcortical structures of the limbic system, extended amygdala and nucleus basalis.ConclusionImportant interactions exist between the limbic system and the BG system but questions remain about the role that this information plays in the functional organisation of this system. Is limbic information processed separately in the BG, or is it integrated to motor and cognitive information? Do pathological conditions such as obsessive-compulsive disorders or Tourette syndrome result from abnormal afferent limbic input to the BG or abnormal processing within the BG?     

Peripheral oscillators: the driving force for food-anticipatory activity

Food-anticipatory activity (FAA) and especially the food-entrained oscillator (FEO) have driven many scientists to seek their mechanisms and locations. Starting our research on FAA we, possibly like many other scientists, were convinced that clock genes held the key to the location and the underlying mechanisms for FAA. In this review, which is aimed especially at discussing the contribution of the peripheral oscillators, we have put together the accumulating evidence that the clock gene machinery as we know it today is not sufficient to explain food entrainment. We discuss the contribution of three types of oscillating processes: (i) within the suprachiasmatic nucleus (SCN), neurons capable of maintaining a 24-h oscillation in electrical activity driven by a set of clock genes; (ii) oscillations in metabolic genes and clock genes in other parts of the brain and in peripheral organs driven by the SCN or by food, which damp out after a few cycles; (iii) an FEO which, we propose, is a system built up of different oscillatory processes and consisting of an as-yet-unidentified network of central and peripheral structures. In view of the evidence that clock genes and metabolic oscillations are not essential for the persistence of FAA we propose that food entrainment is initiated by a repeated metabolic state of scarcity that drives an oscillating network of brain nuclei in interaction with peripheral oscillators. This complex may constitute the proposed FEO and is distributed in our peripheral organs as well as within the central nervous system.