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Basal Ganglia and Apraxia
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Introduction
Rehabilitation after a stroke is widely considered fundamental to improve secondary functional impairments. Accessible methods based on motor learning, motor transfer and virtual environments are necessary to help to improve stroke patients’ quality of life.
Objectives
Continuing the line of our previous studies, this work investigated the effect of our new and innovative game‐based virtual reality training using the control of virtual objects with gaze in three chronic stroke survivors.
Methods
All participants performed an eye‐controlled virtual training task for 4 weeks. Pre‐ and post‐training evaluation were carried out with the Fugl‐Meyer Assessment for upper extremity scale as well as performing a tracking task inside an MRI scanner with a MRI‐compatible eye‐tracker or a joystick.
Results
Neural results for each participant show the increase of activity in the motor cortex, basal ganglia and cerebellum for both effectors (hand or eye).
Conclusion
These promising results have a potential application as a new game‐based neurorehabilitation approach to enhance the motor activity of stroke patients.
Left hemispheric cerebral stroke can cause apraxia, a motor-cognitive disorder characterised by deficits of higher-order motor skills such as the failure to accurately produce meaningful gestures. This disorder provides unique insights into the anatomical and cognitive architecture of the human praxis system. The present study aimed to map the structural brain network that is damaged in apraxia. We assessed the ability to perform meaningful gestures with the hand in 101 patients with chronic left hemisphere stroke. Structural white matter fibre damage was directly assessed by diffusion tensor imaging and fractional anisotropy mapping. We used multivariate topographical inference on tract-based fractional anisotropy topographies to identify white matter disconnection associated with apraxia. We found relevant pathological white matter alterations in a densely connected fronto-temporo-parietal network of short and long association fibres. Hence, the findings suggest that heterogeneous topographical results in previous lesion mapping studies might not only result from differences in study design, but also from the general methodological limitations of univariate topographical mapping in uncovering the structural praxis network. A striking role of middle and superior temporal lobe disconnection, including temporo-temporal short association fibres, was found, suggesting strong involvement of the temporal lobe in the praxis network. Further, the results stressed the importance of subcortical disconnections for the emergence of apractic symptoms. Our study provides a fine-grain view into the structural connectivity of the human praxis network and suggests a potential value of disconnection measures in the clinical prediction of behavioural post-stroke outcome.
Link to the open access article:
https://academic.oup.com/braincomms/article/4/1/fcac004/6506574
Clinical tools involving immersive virtual reality (VR) may bring several advantages to cognitive neuroscience and neuropsychology. However, there are some technical and methodological pitfalls. The American Academy of Clinical Neuropsychology (AACN) and the National Academy of Neuropsychology (NAN) raised 8 key issues pertaining to Computerized Neuropsychological Assessment Devices. These issues pertain to: (1) the safety and effectivity; (2) the identity of the end-user; (3) the technical hardware and software features; (4) privacy and data security; (5) the psychometric properties; (6) examinee issues; (7) the use of reporting services; and (8) the reliability of the responses and results. The VR Everyday Assessment Lab (VR-EAL) is the first immersive VR neuropsychological battery with enhanced ecological validity for the assessment of everyday cognitive functions by offering a pleasant testing experience without inducing cybersickness. The VR-EAL meets the criteria of the NAN and AACN, addresses the methodological pitfalls, and brings advantages for neuropsychological testing. However, there are still shortcomings of the VR-EAL, which should be addressed. Future iterations should strive to improve the embodiment illusion in VR-EAL and the creation of an open access VR software library should be attempted. The discussed studies demonstrate the utility of VR methods in cognitive neuroscience and neuropsychology.
Given the rising incidence of stroke, several technology‐driven methods for rehabilitation have recently been developed. Virtual reality (VR) is a promising therapeutic technology among them. We recently developed a neuroscientifically grounded VR system to aid recovery of motor function poststroke. The developed system provides unilateral and bilateral upper extremity (UE) training in a fully immersive virtual environment that may stimulate and activate mirror neurons (MNs) in the brain necessary for UE rehabilitation. Twenty‐three participants were randomized to a VR group (n = 12) to receive VR intervention (8 h within 2 weeks) plus 8‐h occupational therapy (OT) or a control group (n = 11) to receive time‐matched OT alone. Treatment effects on motor recovery and cortical reorganization were investigated using the Barthel Index (BI), Fugl‐Meyer Upper Extremity (FM‐UE), and resting‐state fMRI. Both groups significantly improved BI (P < 0.05), reflecting the recovery of UE motor function. The VR group revealed significant improvements on FM‐UE scores (P < 0.05) than the control group. Neural activity increased after the intervention, particularly in the brain areas implicating MNs, such as in the primary motor cortex. Overall, results suggested that using a neuroscientifically grounded VR system might offer additional benefits for UE rehabilitation in patients receiving OT.
This work investigates the transfer of motor learning from the eye to the hand and its neural correlates by using functional magnetic resonance imaging (fMRI) and a sensorimotor task consisting of the continuous tracking of a virtual target. In pretraining evaluation, all the participants (experimental and control group) performed the tracking task inside an MRI scanner using their right hand and a joystick. After which, the experimental group practiced an eye‐controlled version of the task for 5 days using an eye tracking system outside the MRI environment. Post‐training evaluation was done 1 week after the first scanning session, where all the participants were scanned again while repeating the manual pretraining task. Behavioral results show that the training in the eye‐controlled task produced a better performance not only in the eye‐controlled modality (motor learning) but also in the hand‐controlled modality (motor transfer). Neural results indicate that eye to hand motor transfer is supported by the motor cortex, the basal ganglia and the cerebellum, which is consistent with previous research focused on other effectors. These results may be of interest in neurorehabilitation to activate the motor systems and help in the recovery of motor functions in stroke or movement disorder patients.
There are major concerns about the suitability of immersive virtual reality (VR) systems (i.e., head-mounted display; HMD) to be implemented in research and clinical settings, because of the presence of nausea, dizziness, disorientation, fatigue, and instability (i.e., VR induced symptoms and effects; VRISE). Research suggests that the duration of a VR session modulates the presence and intensity of VRISE, but there are no suggestions regarding the appropriate maximum duration of VR sessions. The implementation of high-end VR HMDs in conjunction with ergonomic VR software seems to mitigate the presence of VRISE substantially. However, a brief tool does not currently exist to appraise and report both the quality of software features and VRISE intensity quantitatively. The Virtual Reality Neuroscience Questionnaire (VRNQ) was developed to assess the quality of VR software in terms of user experience, game mechanics, in-game assistance, and VRISE. Forty participants aged between 28 and 43 years were recruited (18 gamers and 22 non-gamers) for the study. They participated in 3 different VR sessions until they felt weary or discomfort and subsequently filled in the VRNQ. Our results demonstrated that VRNQ is a valid tool for assessing VR software as it has good convergent, discriminant, and construct validity. The maximum duration of VR sessions should be between 55 and 70 min when the VR software meets or exceeds the parsimonious cut-offs of the VRNQ and the users are familiarized with the VR system. Also, the gaming experience does not seem to affect how long VR sessions should last. Also, while the quality of VR software substantially modulates the maximum duration of VR sessions, age and education do not. Finally, deeper immersion, better quality of graphics and sound, and more helpful in-game instructions and prompts were found to reduce VRISE intensity. The VRNQ facilitates the brief assessment and reporting of the quality of VR software features and/or the intensity of VRISE, while its minimum and parsimonious cut-offs may appraise the suitability of VR software for implementation in research and clinical settings. The findings of this study contribute to the establishment of rigorous VR methods that are crucial for the viability of immersive VR as a research and clinical tool in cognitive neuroscience and neuropsychology.
The basal ganglia have been implicated in motor planning and motor learning. In the study reported here, we directly tested for response plasticity in striatal neurons of macaque monkeys undergoing Pavlovian conditioning. To focus the study, we recorded from the tonically active neurons (TANs) of the striatum, which are known to respond to conditioned sensory stimuli that signal reward delivery and elicit behavioral reactions. The activities of 858 TANs were recorded extracellularly from the striatum in alert behaving macaque monkeys before, during, and after the acquisition of a classical conditioning task. Two monkeys were trained to lick reward juice delivered on a spoon simultaneously with the presentation of a click. Almost no licks were triggered by the cues at the start of training, but by the fifth day more than 90% of licks were triggered, and values were near 100% for the remainder of the 3 week training period. In the striatum, only a small number of TANs responded to the clicks at the start before conditioning (about 17%). During training, the numbers of responding TANs gradually increased, so that by the end of training more than 50– 70% of the TANs recorded (51.3–73.5%) became responsive to the clicks. The responses consisted of a pause in firing that occurred approximately 90 msec after the click and that was in some cells preceded by a brief activation and in most cells was followed by a rebound excitation. Prolonged recordings from single TANs (n = 6) showed that individual TANs can acquire a conditioned response within at least as short a time as 10 min. TANs retained such responsiveness after overtraining, and also after a 4 week intermission in training. When the monkey was trained to receive rewards in relation to a new conditioning stimulus, TANs were capable of switching their sensory response to the new stimulus. Histological reconstruction showed that the TANs that became responsive were broadly distributed in the region of striatum explored, which included the dorsal half to two-thirds of the caudate nucleus and putamen over a large anteroposterior span. We conclude that, during the acquisition of a sensorimotor association, TANs widely distributed through the striatum become responsive to sensory stimuli that induce conditioned behavior. This distributed change in activity could serve to modulate the activity of surrounding projection neurons in the striatum engaged in mediating learned behavior.
Sequence-specific postural motor learning in a target-directed weight-shifting task in 12 older and 12 young participants was assessed. In the implicit sequence learning condition participants performed a concurrent spatial cognitive task and in the two explicit conditions participants were required to discover the sequence order either with or without the concurrent cognitive task. Participants moved a cursor on the screen from the center location to one of the target locations projected in a semi-circle and back by shifting their center of pressure (CoP) on force plates. During the training the targets appeared in a simple fixed 5-target sequence. Plan-based control (i.e., direction of the CoP displacement in the first part of the target-directed movement) improved by anticipating the sequence order in the implicit condition but not in the explicit dual task condition. Only the young participants were able to use the explicit knowledge of the sequence structure to improve the directional error as indicated by a significant decrease in directional error over practice and an increase in directional error with sequence removal in the explicit single task condition. Time spent in the second part of the movement trajectory to stabilize the cursor on the target location improved over training in both the implicit and explicit sequence learning conditions, for both age groups. These results might indicate that an implicit motor learning method, which holds back explicit awareness of task relevant features, may be desirable for improving plan-based motor control in older adults.
In Parkinson’s disease (PD) the prevalence of apraxia increases with disease severity implying that patients in early stages may already have subclinical deficits. The aim of this exploratory fMRI study was to investigate if subclinical aberrations of the praxis network are already present in patients with early PD. In previous functional imaging literature only data on basal motor functions in PD exists. Thirteen patients with mild parkinsonian symptoms and without clinically diagnosed apraxia and 14 healthy controls entered this study. During fMRI participants performed a pantomime task in which they imitated the use of visually presented objects. Patients were measured ON and OFF dopaminergic therapy to evaluate a potential medication effect on praxis abilities and related brain functions. Although none of the patients was apraxic according to De Renzi ideomotor scores (range 62–72), patients OFF showed significantly lower praxis scores than controls. Patients exhibited significant hyperactivation in left fronto-parietal core areas of the praxis network. Frontal activations were clearly dominant in patients and were correlated with lower individual praxis scores. We conclude that early PD patients already show characteristic signs of praxis network dysfunctions and rely on specific hyperactivations to avoid clinically evident apraxic symptoms. Subclinical apraxic deficits were shown to correlate with an activation shift from left parietal to left frontal areas implying a prospective individual imaging marker for incipient apraxia.
In experiments on cats with injury of the cortico- and rubro-spinal pathways, we studied the dynamics of recovery of operant (instrumental) food-procuring reactions at different durations of presurgery learning of animals. Operant manipulatory food-procuring movements were realized under conditions of horizontal and vertical tests, which required training for and support of a strictly defined pose in the course of performance of such movements and determined a specific pattern and stability of the coordinated motor phenomenon. The severity of abnormalities of operant food-procuring activity after transection of the lateral funiculus of the spinal cord at the level of С5-С6 and the time interval necessary for compensation of disorders of the developed manipulatory reaction depended significantly on the duration of presurgery motor learning and decreased considerably with increase in this duration. Such increase determined transformation of the pattern of postural rearrangement, which demonstrated no dependence on the amplitude and trajectory of the forthcoming operant phasic movements and was observed under conditions of both horizontal and vertical motor tests. Our results indicate that the main factor providing successful compensation of disorders of the developed operant habit in cats after injury of the cortico- and rubro-spinal pathways is active involvement of the tecto-and reticulo-spinal systems in the process of formation of the reflex. This can be due to an increase in the duration and intensity of presurgery learning of animals.
Implicit sequence learning involves learning about dependencies in sequences of events without intent to learn or awareness of what has been learned. Sequence learning is related to striatal dopamine levels, striatal activation, and integrity of white matter connections. People with Parkinson’s disease (PD) have degeneration of dopamine-producing neurons, leading to dopamine deficiency and therefore striatal deficits, and they have difficulties with sequencing, including complex language comprehension and postural stability. Most research on implicit sequence learning in PD has used motor-based tasks. However, because PD presents with motor deficits, it is difficult to assess whether learning itself is impaired in these tasks. The present study used an implicit sequence learning task with a reduced motor component, the Triplets Learning Task (TLT). People with PD and age- and education-matched healthy older adults completed three sessions (each consisting of 10 blocks of 50 trials) of the TLT. Results revealed that the PD group was able to learn the sequence, however, when learning was examined using a Half Blocks analysis (Nemeth et al., 2013), which compared learning in the 1st 25/50 trials of all blocks to that in the 2nd 25/50 trials, the PD group showed significantly less learning than Controls in the 2nd Half Blocks, but not in the 1st. Nemeth et al. (2013) hypothesized that the 1st Half Blocks involve recall and reactivation of the sequence learned, thus reflecting hippocampal-dependent learning, while the 2nd Half Blocks involve proceduralized behavior of learned sequences, reflecting striatal-based learning. The present results suggest that the PD group had intact hippocampal-dependent implicit sequence learning, but impaired striatal-dependent learning. Thus, sequencing deficits in PD are likely due to striatal impairments, but other brain systems, such as the hippocampus, may be able to partially compensate for striatal decline to improve performance.
Assessing implicit learning in the continuous pursuit-tracking task usually concerns a repeated segment of target displacements masked by two random segments, as referred to as Pew's paradigm. Evidence for segment learning in this paradigm is scanty and contrasts with robust sequence learning in discrete tracking tasks. The present study investigates this issue with two experiments in which participants (N = 56) performed a continuous tracking task. Contrary to Pew's paradigm, participants were presented with a training sequence that was continuously cycled during 14 blocks of practice, but Block 12 in which a transfer sequence was introduced. Results demonstrate sequence learning in several conditions except in the condition that was obviously the most similar to previous studies failing to induce segment learning. Specifically, it is shown here that a target moving too slowly combined with variable time at which target reversal occurs prevents sequence learning. In addition, data from a post-experimental recognition test indicate that sequence learning was associated with explicit perceptual knowledge about the repetitive structure. We propose that learning repetition in a continuous tracking task is conditional on its capacity to (1) allow participants to detect the repeated regularities and (2) restrict feedback-based tracking strategies.
The ability to perform accurate sequential movements is essential to normal motor function. Learning a sequential motor behavior is comprised of two basic components: explicit identification of the order in which the sequence elements should be performed and implicit acquisition of spatial accuracy for each element. Here we investigated the time course of learning of these components for a first sequence (SEQA) and their susceptibility to interference from learning a second sequence (SEQB). We assessed explicit learning with a discrete index, the number of correct anticipatory movements, and implicit learning with a continuous variable, spatial error, which decreased during learning without subject awareness. Spatial accuracy to individual sequence elements reached asymptotic levels only when the whole sequence order was known. Interference with recall of the order of SEQA persisted even when SEQB was learned 24 h after SEQA. However, there was resistance to interference by SEQB with increased initial training with SEQA. For implicit learning of spatial accuracy, SEQB interfered at 5 min but not 24 h after SEQA. As in the case of sequence order, prolonged initial training with SEQA induced resistance to interference by SEQB. We conclude that explicit sequence learning is more susceptible to anterograde interference and implicit sequence learning is more susceptible to retrograde interference. However, both become resistant to interference with saturation training. We propose that an essential feature of motor skill learning is the process by which discrete explicit task elements are combined with continuous implicit features of movement to form flawless sequential actions.
The widely held belief in a central role of left parietal lesions for apraxia can be traced back to Liepmann's model of a posterior to anterior stream converting mental images of intended action into motor execution. Although this model has undergone significant changes, its modern descendants still attribute the parietal contribution to the existence of mental representations of intended movements which precede and direct their motor execution. They predict that pantomime of tool use should be particularly vulnerable to parietal lesions. A review of clinical studies contradicts these assumptions: The impact of parietal lobe damage on pantomime of tool use is inconstant if not absent altogether. The domains of action which are most affected by left parietal damage are the imitation of meaningless gestures and, although probably only in the context of additional more widespread brain damage, actual use of tools and objects. I hypothesize that imitation of meaningless gestures and use of tool and objects depend on left parietal lobe integrity because of their demands on categorical apprehension of spatial relationships between multiple objects or between multiple parts of objects. For use of tools and objects the spatial relationships are between the hand, the tool, its recipient, and the material it acts upon. Categorical apprehension concentrates on features of these relations which determine mechanical interactions. For imitation of meaningless gestures, categorical apprehension of demonstrated gesture results in "body part coding" which reduces the visual appearance of the demonstrated gestures to simple spatial relationships between a limited set of discrete body parts. The hypothesis that the role of the left parietal lobe in apraxia concerns categorical apprehension of spatial relationships fits well with more general theories of parietal lobe function and hemisphere asymmetries.
This article discusses the neurophysiological mechanisms underlying the spatiotemporal integration of different brain structures and the physiological systems of the body on performance of different types of motivated goal-oriented behavior.
The size of brain lesions is a variable that is frequently considered in cognitive neuropsychology. In particular, lesion-deficit inference studies often control for lesion size, and the association of lesion size with post-stroke cognitive deficits and its predictive value are studied. In the present article, the role of lesion size in cognitive deficits and its computational or design-wise consideration is discussed and questioned. First, I argue that the commonly discussed role or effect of lesion size in cognitive deficits eludes us. A generally valid understanding of the causal relation of lesion size, lesion location, and cognitive deficits is unachievable. Second, founded on the theory of causal inference, I argue that lesion size control is no generally appropriate covariate control. Instead, it is identified as a procedure with only situational benefits, which is supported by empirical data. This theoretical background is used to suggest possible research practices in lesion-deficit inference, post-stroke outcome prediction, and behavioural studies. Last, control for lesion size is put into a bigger historical context – it is identified to relate to a long-known association problem in neuropsychology, which was previously discussed from the perspectives of a mislocalisation in lesion-deficit mapping and the symptom complex approach.
Modelling behavioural deficits based on structural lesion imaging is a popular approach to map functions in the human brain, and efforts to translationally apply lesion-behaviour modelling to predict post-stroke outcomes are on the rise. The high-dimensional complexity of lesion data, however, evokes challenges in both lesion behaviour mapping and post stroke outcome prediction. This paper aims to deepen the understanding of this complexity by reframing it from the perspective of causal and non-causal dependencies in the data, and by discussing what this complexity implies for different data modelling approaches. By means of theoretical discussion and empirical examination, several common strategies and views are challenged, and future research perspectives are outlined. A main conclusion is that lesion-behaviour inference is subject to a lesion-anatomical bias that cannot be overcome by using multivariate models or any other algorithm that is blind to causality behind relations in the data. This affects the validity of lesion behaviour mapping and might even wrongfully identify paradoxical effects of lesion-induced functional facilitation - but, as this paper argues, only to a minor degree. Thus, multivariate lesion-brain inference appears to be a valuable tool to deepen our understanding of the human brain, but only because it takes into account the functional relation between brain areas. The perspective of causality and inter-variable dependence is further used to point out challenges in improving lesion behaviour models. Firstly, the dependencies in the data open up different possible strategies of data reduction, and considering those might improve post-stroke outcome prediction. Secondly, the role of non-topographical causal predictors of post stroke behaviour is discussed. The present article argues that, given these predictors, different strategies are required in the evaluation of model quality in lesion behaviour mapping and post stroke outcome prediction.
Experiments on rats were carried out to study the effects of fragmentation of visual navigation signals on search behavior in a radial maze with asymmetrical food reinforcement. The dopaminergic system of the brain was found to have an important role in impairments to the animals’ invariant perception of significant sensory objects on removal of one of two adjacent extramaze navigation cues and in determining the location of the largest reinforcement in the maze. The basis of these impairments was found to be deficit of associative memory between the remaining and the remote cues. Possible animal modeling of impairments to sensory perception in neurological diseases due to dysfunction of the dopaminergic system of the brain is assessed.
https://authors.elsevier.com/c/1Z8BE6govhQq3c
Limb apraxia is a heterogeneous disorder of skilled action and tool use that has long perplexed clinicians and researchers. It occurs after damage to various loci in a densely interconnected network of regions in the left temporal, parietal, and frontal lobes. Historically, a highly classificatory approach to the study of apraxia documented numerous patterns of performance related to two major apraxia subtypes: ideational and ideomotor apraxia. More recently, there have been advances in our understanding of the functional neuroanatomy and connectivity of the left-hemisphere "tool use network," and the patterns of performance that emerge from lesions to different loci within this network. This chapter focuses on the left inferior parietal lobe, and its role in tool and body representation, action prediction, and action selection, and how these functions relate to the deficits seen in patients with apraxia subsequent to parietal lesions. Finally, suggestions are offered for several future directions that will benefit the study of apraxia, including increased attention to research on rehabilitation of this disabling disorder.
Experiments on rats showed that sessions of retraining to find a new preferred reinforcement location in a radial maze, continuously repeated on the experimental day, led to impairment of the animals’ ability to use navigational orientation as the most adaptive tactic for maximizing reinforcement, with retention of less productive conditioned reflex responding to the presentation of signals within the maze. Some series of experiments showed that sleep had an adaptive role, including sleep induced by somnogenic neuropeptides, and was needed for the experimental animals to perform the behavioral task successfully in conditions of heightened emotional tension and to prevent any possible neurological disorders.
Experiments in rats addressing searching behavior in a maze with symmetrical reinforcement demonstrated an effect consisting of preference for food presented in a particular form. The dopaminergic system of the brain was shown to have an important role in forming reinforcement preference when the sensory properties of the food presented to the experiment animals changed. The possibility of using this type of discrete reinforcement as an experimental model for studies of the physiological mechanisms of addiction, which is directly related to food preference, as well as various forms of pathological dependence seen on consumption of pharmacological agents, was assessed.
Time is a subjective experience
Time, like space, is one of the fundamental dimensions of all our experiences. However, organisms do not work like clocks, and our judgment about the passage of time is variable, depending on circumstances. Soares et al. systematically investigated midbrain dopaminergic neurons during timing behavior in mice (see the Perspective by Simen and Matell). When measuring and manipulating mouse activity, the authors observed that dopaminergic neurons controlled temporal judgments on a time scale of seconds.
Science , this issue p. 1273 ; see also p. 1231
The paper describes a model of intentional form of tremor developed in experiments in animals. Experiments with lesion of nucleus caudatus revealed the important role of this structure to regulate normal relationships between activity of reciprocal muscles under producing the non stereotypic forms of motor behavior. The model may be used to study the etiology and pathogenesis of intentional tremor as well as for preclinical testing of pharmacological drugs potentially perspective for correction of given form of diskinesia in humans.
Seeking behavior of rats in a radial maze with asymmetric reward was studied by means of synchronous recording of cell activity in the hippocampus and ventral striatum. The synchrony of cell activity in the hippocampus and nucleus accumbens was modulated by spatial position and reward; the important role in this synchronization can be played by theta rhythm. This is in line with the anatomical and physiological data on the convergence of hippocampal spatially organized positional and reward value information inputs from the amygdala and ventral segmental area to n. accumbens.
In both perceptual and motor learning, numerous studies have shown specificity of learning to the trained eye or hand and to the physical features of the task. However, generalization of learning is possible in both perceptual and motor domains. Here, I review evidence for perceptual and motor learning generalization, suggesting that generalization patterns are affected by the way in which the original memory is encoded and consolidated. Generalization may be facilitated during fast learning, with possible engagement of higher-order brain areas recurrently interacting with the primary visual or motor cortices encoding the stimuli or movements memories. Such generalization may be supported by sleep, involving functional interactions between low and higher-order brain areas. Repeated exposure to the task may alter generalization patterns of learning and overall offline learning. Development of unifying frameworks across learning modalities and better understanding of the conditions under which learning can generalize may enable to gain insight regarding the neural mechanisms underlying procedural learning and have useful clinical implications.
Interneuronal communication in the central nervous system (CNS) have always been of basic importance for theories on the cerebral morphofunctional architecture. Our group has proposed that intercellular communication in the brain can be grouped into 2 broad classes based on some general features of the transmission: wiring (WT) and volume (VT) transmission. WT occurs via a relatively constrained cellular chain (wire), while VT consists of 3-dimensional diffusion of signals in the extracellular fluid (ECF) for distances larger than the synaptic cleft. Both morphological and functional evidence indicates that dopamine (DA) synapses in striatum are 'open' synapses, i.e., synapses which favor diffusion of the transmitter into the surrounding ECF and observations are compatible with the view that DA varicosities can synthesize, store and release DA for VT. The DAergic mesostriatal transmission has, therefore, been examined by several groups to give experimental support to VT. Moreover, due to its minor structural requirements, VT may become prevalent under some pathological conditions, e, g. Parkinson's disease. In animal models of DAergic pathway degeneration, it has been shown that a compensatory activation of surviving DA terminals may lead to a preferential potentiation of VT. WT and VT favor different and complementary types of computation. VT is markedly slower and less safe than WT, but has minor spatial constraints and allows the reach of a large number of targets. Models of neuronal systems integrating classical neuronal circuits and diffusible signals begin to show how WT and VT may interact in the neural tissue.
The basal ganglia are organized to facilitate voluntary movements and to inhibit competing movements that might interfere with the desired movement. Dysfunction of these circuits can lead to movement disorders that are characterized by impaired voluntary movement, the presence of involuntary movements, or both. Current models of basal ganglia function and dysfunction have played an important role in advancing knowledge about the pathophysiology of movement disorders, but they have not contained elements sufficiently specific to allow for understanding the fundamental differences among different involuntary movements, including chorea, dystonia, and tics. A new model is presented here, building on existing models and data to encompass hypotheses of the fundamental pathophysiologic mechanisms underlying chorea, dystonia, and tics.
The activity of single neurons in the superior colliculus was recorded while a rhesus monkey made arm movements to visual targets located on a screen in front of him. It was found that the activity of a subpopulation of cells was clearly related to these arm movements. The neurons began to discharge either with the onset of the movement, during the movement period, or well before the onset of electromyogram (EMG) activity and movement, and could be active for the entire duration of EMG activity. While the discharge pattern of some of these‘reach’neurons was not different for movements to different target positions, other cells showed graded changes in activity depending on the direction of movement. The peak discharge rate could rise to > 100 impulses/s. Some units received somatosensory input; other reach cells exhibited a visual response and/or presaccadic activity. It is likely that the primate superior colliculus is not only involved in the initiation and control of orientating movements of the eyes but also in reaching movements of the arms.
The encoding and storage of experience by the hippocampus is essential for the formation of episodic memories and the transformation of individual experiences into semantic structures such as maps and schemas. The rodent hippocampus compresses ongoing experience into repeating theta sequences, but the factors determining the content of theta sequences are not understood. Here we first show that the spatial paths represented by theta sequences in rats extend farther in front of the rat during acceleration and higher running speeds and begin farther behind the rat during deceleration. Second, the length of the path is directly related to the length of the theta cycle and the number of gamma cycles in it. Finally, theta sequences represent the environment in segments or 'chunks'. These results imply that information encoded in theta sequences is subject to powerful modulation by behavior and task variables. Furthermore, these findings suggest a potential mechanism for the cognitive 'chunking' of experience.
Recent studies indicate that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) convey distinct signals. To explore this difference, we comprehensively identified each area's monosynaptic inputs using the rabies virus. We show that dopamine neurons in both areas integrate inputs from a more diverse collection of areas than previously thought, including autonomic, motor, and somatosensory areas. SNc and VTA dopamine neurons receive contrasting excitatory inputs: the former from the somatosensory/motor cortex and subthalamic nucleus, which may explain their short-latency responses to salient events; and the latter from the lateral hypothalamus, which may explain their involvement in value coding. We demonstrate that neurons in the striatum that project directly to dopamine neurons form patches in both the dorsal and ventral striatum, whereas those projecting to GABAergic neurons are distributed in the matrix compartment. Neuron-type-specific connectivity lays a foundation for studying how dopamine neurons compute outputs.
The effects of bilateral injections of kainic acid into the anteromedial neostriatal region were examined behaviorally and anatomically in two groups of rats. Behaviorally, kainic acid injections resulted in a severe impairment of delayed alternation retention, while the ability for visual discrimination remained unaffected. Anatomically it was found that axons traversing the injected area remain able to transport horseradish peroxidase. Furthermore, histological examinations of the injected regions revealed a heavy loss of neurons and a decrease of histochemical staining for specific acetylcholinesterase. Silver impregnation showed slightly disorganized, but continuous, axons in bundles of the capsula interna. On the other hand, the axonal network throughout the neuropil of the injected area was markedly diminished. No conspicuous change was found in myelin staining or in the intensity or catecholamine fluorescence. The anatomical results suggest that kainic acid appears to affect only perikarya of the neostriatum and the axons originating from these perikarya, whereas passing axons seem to remain intact. Thus, the observed behavioral impairment must be attributed to changes in the neostriatum itself. It is concluded that the neostriatum has ‘complex’ or ‘cognitive’ functions and that some mental symptoms in Huntington's chorea may be attributed to a dysfunction of this part of the brain.
In order to better understand the impact of hippocampal processing on downstream neural structures and cognitive functions, neurons were simultaneously recorded in the hippocampus and in basal ganglia zones receiving inputs from hippocampus directly (the nucleus accumbens shell) or indirectly via the prefrontal cortex (nucleus accumbens core and ventromedial caudate nucleus) in rats performing spatial orientation tasks. In one series of experiments, the animals alternated between using intramaze and extramaze cues to find water rewards. In a second series, the rats were required to learn the distribution of different reward quantities provided at the respective goal boxes in a plus maze. Correct performance in the latter task has been shown to be impaired by lesions of the accumbens shell.Hippocampal place responses were anchored to the extramaze cues and were independent of reward values provided near or in the firing fields. While no hippocampal-like firing fields were found in accumbens neurons, neuronal activity during pre-reward, post-reward and reward approach behaviors was more intense at some locations than at others. This is consistent with anatomical and physiological observations corresponding to the convergence of hippocampal position information with reward related signals from the amygdala and ventral tegmental area (VTA).
Single unit activity of dopaminergic neurons in the substantia nigra was recorded in freely moving cats under a variety of conditions. These neurons displayed their highest discharge rate during active waking (3.68 ± 0.30 spikes/s), which was 20% greater than their discharge rate during quiet waking (3.07 ± 0.20). Although these cells fired somewhat faster during active waking, their activity displayed no correlation with phasic EMG changes, and, in general, their activity showed little relationship to overt behavioral changes. As the cat progressed from quiet waking through slow-wave sleep and REM sleep there was no significant change in either the rate or pattern of firing of dopaminergic neurons. In addition, no correlation was observed between the activity of these neurons and either sleep spindles or PGO waves. These neurons did respond, however, to the repeated presentation of a click or light flash with excitation followed by inhibition, with no evidence of habituation. One of the most impressive changes in dopaminergic unit acttivity was a large decrease in association with orienting responses. This was seen in over 50% of the cells in which this relationship was examined. As the behavioral orientation habituated with repeated stimulus presentation, so did the associated dopaminergic unit suppression. In conclusion, dopaminergic neurons maintain a remarkably constant rate and pattern of firing across a variety of behaviors and states. However, this stability can be dramatically altered under special circumtances, such as during and following orienting responses.
The three parts of the striatum — putamen, caudate nucleus and fundus striati — control intentional actions and not simple movements without conscious representation. According to its integrative function the striatum consists of at least four distinct types of nerve cells, the bulk of which (more than 90%) is formed by the small “spiny” neurons with intrinsic axons. In each part of the striatum nine discrete types of synapses are distinguished: one axo-spinous and one axo-dendritic (or axo-somatic) from the substantia nigra (type I and II); from the cortical fields (type III and VII); from the center median-parafascicular complex of the thalamus (type IV and VII) and type V as axon-collateral of the large efferent neurons; type VI with flattened vesicles of so far unknown origin; type VIII as dendritic terminal of Golgi type II cells; and type IX as intrinsic contacts between the small intrinsic and the large efferent neurons. The transmitter of the nigral afferents is dopamine (DA), that of the cortical afferents glutamic acid, that of the intrinsic synapses acetylcholine (ACh) and that of center median-parafascicular afferents also perhaps ACh. The results of the integrating activities of this synaptic organization are conducted by GABA-ergic, mostly inhibitory, fibers to the substantia nigra and to both segments of the pallidum.
Five cats were trained to perform a forelimb ballistic flexion on a reaction time paradigm including an upper limit of about 400 ms for reinforcement (food pellets). They were implanted with a cyrogenic probe thermically insulated, except at the tip, by a vacuum jacket (outer diameter, 1.1 mm).
Four cats had the probe inserted into the ventrolateral thalamic nucleus (VL), contralateral to the moving limb. During cooling they showed increased reaction times, which remained constant throughout daily sessions performed during many weeks, independent of the foreperiod but varying from 25 to 100 ms according to the subject. The temperatures used to upset the reaction times varied from +10 ° C to −8 ° C, depending on the localisation of the probe and on the insulation of the silver tip used to prevent nervous tissue reaction, but for each subject the reaction times always increased when the temperature was lowered. The fifth cat, with a probe inserted between VL and the Centre Median, showed a decrease of reaction times on cooling to 0 ° C and an increase of the reaction times for a cooling at −10 ° C.
For one of the four cats with a probe properly inserted into the VL, strain-gauges were stuck on the lever to measure the latency of the decrease of the pressure exerted by the subject when the subject initiated the forelimb flexion in response to the CS. Reaction times and latencies of pressure changes were closely correlated with the movement onset, and they were equally delayed during cooling. This result demonstrates that it is not by slowing down movement velocity that reaction times are upset during VL cooling but by delaying the movement onset.
Methods are described for performing one-stage ablation of the caudate nuclei through a midline approach in cats, for maintaining the animals indefinitely, and for their neurological and gross behavioral evaluation. Sixteen cats with extensive bilateral caudate lesions, 13 with extensive unilateral caudatectomy, 14 with bilateral removal of the frontal cortical areas, and eight sham-operated animals, were studied for months. The results of anatomical, neurological, and gross behavioral observations are described in this first paper. A behavioral change labeled “compulsory approaching syndrome” was observed following surgery in all cats with bilateral caudate ablation. This was a long-lasting effect persisting even under unusual conditions. The “syndrome” was characterized by stereotyped and prolonged approaching and/or following of persons, cats, or objects. Visual cues were most effective in eliciting the syndrome but acoustic and tactile stimuli were also adequate. Other components of the syndrome were marked passivity, exaggerated forelimb treading, marked purring, rooting, hyperactivity, hyperreactivity, and sexual changes. The magnitude and duration of the syndrome appeared to be related to the extent of the ablation with its essential features persisting for over 1 yr in cats with the largest ablations (70 to 100% of the nuclei). The syndrome was not observed in sham-operated cats. Bilaterally acaudate cats were remarkably free of permanent gross neurological deficits. Deficits such as motor weakness, faulty awareness, and defective eating and drinking were seen in the early postoperative period. Only moderate hyperactivity along with the compulsory approaching syndrome and some impoverishment and slowness of movements persisted in the chronic state. In all unilaterally acaudate cats, there was an absence of any permanent gross neurological or behavioral changes including the compulsory approaching. Our findings suggest that the caudate nuclei do not have any gross lateralized behavioral or neurological function and indicate a large functional reserve. The cats with bilateral frontal cortical areas removed exhibited early, short-lasting visual tracking, but none of the characteristics of the compulsory approaching syndrome was present (except in three animals, where the characteristics appeared transiently and combined with aggressiveness). Other neurological defects of frontally-operated cats were consequences of ablation of the sensory-motor areas. The syndrome is discussed in terms of the specificity of the caudate ablation in its production and it is tentatively explained as resulting from absence of an inhibitory caudate modulatory influence on polysensory inputs. It is concluded that total ablation of the caudate nuclei in cats is possible and produces a characteristic behavioral change of which the exact nature remains to be elucidated. The caudate does not appear to have an essential role in the control of basic metabolic functions, elementary sensory-motor functions, or elementary cognitive processes as previously postulated.
Basal ganglia contribute to a wide variety of behavioral functions, including skeletomotor, oculomotor, cognitive, and limbic processes. This chapter focuses on the basal ganglia-thalamocortical circuits. Basal ganglia-thalamocortical circuits are organized in a parallel manner and remain largely segregated from one another, both structurally and functionally. The central theme of the segregated circuits hypothesis is that structural convergence and functional integration occurs within each of the identified circuits. In primates, the basal ganglia motor pathways are focused principally on the putamen and its connections. This part of the neostriatum receives topographic projections from primary motor cortex (MC). The focus of the terminals originating in the putamen appears to lie somewhat dorsal to that of the terminals arising from the body of the caudate. The basal ganglia-thalamocortical circuits might be seen as having a unified role in modulating the operations of the entire frontal lobe, and thereby influencing—by common mechanisms, such as diverse frontal lobe processes—the maintenance and switching of behavioral sets and the planning and execution of limb and eye movements.
Information about the basal ganglia has accumulated at a prodigious pace over the past decade, necessitating major revisions in the authors' concepts of the structural and functional organization of these nuclei. Recent anatomical and physiological findings have further substantiated the concept of segregated basal ganglia-thalamocortical pathways, and reinforced the general principle that basal ganglia influences are transmitted only to restricted portions of the frontal lobe (even though the striatum receives projections from nearly the entire neocortex). Using the 'motor' circuit as a model, the authors have reexamined the available data on other portions of the basal ganglia-thalamocortical pathways and found that the evidence strongly suggests the existence of at least four additional circuits organized in parallel with the 'motor' circuit. In the discussion that follows, they review some of the anatomic and physiologic features of the 'motor circuit,' as well as the data that support the existence of the other proposed parallel circuits, which they have designated the 'oculomotor,' the 'dorsolateral prefrontal,' the 'lateral orbitofrontal,' and the 'anterior cingulate,' respectively. Each of these five basal ganglia-thalamocortical circuits appears to be centered upon a separate part of the frontal lobe. This list of basal ganglia-thalamocortical circuits is not intended to be exhaustive. In fact, if the conclusions suggested in this review are valid, future investigations might be expected to disclose not only further details (or the need for revisions) of these five circuits, but perhaps also the existence of additional parallel circuits whose identification is currently precluded by a paucity of data.
This study examines the differential contributions of motor cortex (MCx) and red nucleus (RN) neurons to the initiation of a targeted limb response and to the control of trajectory. These questions were assessed in two ways. First, by comparing the characteristics of task-related neuronal activity in MCx and RN. Second, by determining the changes in reaction time and trajectories produced by the reversible inactivation of corticospinal fibers in the crus cerebri (CSTc), the rubrospinal tract (RST) and the RN, using microinjections of lidocaine, gamma-aminobutyric acid, or muscimol. Neurons in forelimb areas of both MCx and RN were modulated in advance of forelimb force production. RN neurons more frequently had a phasic discharge pattern, while neurons in MCx more frequently had a tonic pattern. Whereas the modulation of most forelimb area neurons in MCx correlated with responses in a specific direction, the majority of RN neurons were non-directional. Reversible inactivation of CSTc, RN and RST prolonged reaction time. The normal stereotyped form of isometric force trajectories was unaffected by injections at any site. While CSTc inactivation resulted in hypometric responses, response amplitude was unchanged during RN and RST inactivation. We conclude that both MCx and RN contribute to response initiation, but that only MCx is involved in the proper scaling of targeted responses.
Reciprocal innervation of the soleus motoneurones upon initiation of voluntary ankle dorsiflexion was investigated in eight patients with Parkinson's disease. H-reflex and visually guided step tracking methods were used for testing motoneurone excitability and for controlling the timing of movement initiation, respectively. While reciprocal inhibition appeared almost simultaneously with the agonist electromyographic (EMG) onset in normal subjects (Kagamihara and Tanaka 1985), facilitation appeared in the majority of patients under the same onset condition. It increased slowly, reaching a maximum at about 100 ms after the EMG onset. It then subsided slowly at around 200-300 ms, and was replaced thereafter by an inhibitory effect. No coactivation of the soleus muscle was detected electromyographically. The facilitation between the EMG onset and the onset of mechanical contraction was attributed to the direct effect of the descending command from the brain, suggesting a certain disorder in controlling the system for reciprocal innervation.
The food-taking movement by which a cat uses its forepaw to take a piece of food and bring it to its mouth normally depends on the cortico- (CS) and rubrospinal (RS) tracts and disappears when they are transected in C5; a slow reappearance over months is due to bulbospinal (BS) take-over. After complete CS transection but minimal RS transection, food-taking remains. If, one month later, the RS tract is completely transected, food-taking is not abolished as it is when transection is made in one session. It is permanently abolished after a third transection of the ventral quadrant in C2. It is suggested that the food-taking remaining after the first lesion is due to combined RS and BS activity and that the RS tract induces the BS neurones to contribute to the extent that they can take over when the RS tract is completely transected.
The gait of normal subjects was examined electromyographically and the pattern was altered during preferential blockade of large nerve fibres to alternating activity in flexor and extensor muscles.The EMG activity was disrupted more in flexor than extensor muscles by preferential ischaemic blockade. Normal gait was associated with flexor contraction only when the foot was lifted and placed on the ground, whereas during ischaemic blockade flexor contraction continued during the interval between foot lifting and foot placement.The `freezing' or `blocking' gait in Parkinson's disease was found to be associated with coactivation of flexor and extensor muscles and this phenomenon occurred only in patients with features of flexion dystonia in the electromyographic recordings of their tonic stretch reflexes. Eight of nine patients with evidence of flexion dystonia showed a deterioration in their response to l-dopa therapy over a two year period, whereas four patients without flexion dystonia maintained their clinical improvement.
It is well known that a depletion of striatal DA is a pathological substrate of Parkinsonism. Furthermore, an experimental depletion of DA in the striatum of mammals is widely regarded as a valid model for Parkinsonism. The purpose of this study is to review the data on the effects of experimental depletions of striatal DA. Emphasis is placed on the discussion of mechanisms which are involved in the compensation for the arising deficits. Results from striatal DA depletions induced by lesions and by pharmacological agents are considered.