Cortico-striatal Loops Research Articles

Reduced levodopa-induced complications after 5 years of subthalamic stimulation in Parkinson’s disease: a second honeymoon

The purpose of this paper is to describe the effect of 5 years of subthalamic nucleus deep brain stimulation (STN DBS) on levodopa-induced complications, both in everyday life and during an acute challenge with levodopa. Thirty three patients were evaluated during an acute levodopa challenge before surgery and then 1 and 5 years afterwards (both off stim and on stim), using the UPDRS III scale and the CAPSIT-PD scales for dystonia and peak-dose dyskinesia. The UPDRS IV scale was used to assess motor complications in everyday life. The levodopa daily dose and DBS parameters were also recorded. Levodopa-induced complications in everyday life (UPDRS IV) and during an acute levodopa challenge had improved markedly after 1 year (both on and off stim) and still further at 5 years. Peak-dose dyskinesia decreased between the 1- and 5-year measurements. STN DBS decreases levodopa-induced motor complications over the long term. This phenomenon may be explained by (a) overall stabilization of the basal ganglia network and (b) striatal synaptic changes. Our results suggest that DBS leads to both qualitative and quantitative modulations in the corticostriatal loops.

Absence of cognitive deficits following deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease

Electrical stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of Parkinson's disease. While most patients who undergo this procedure do not appear to suffer behavioral side effects, a minority experience cognitive or emotional deficits, and longitudinal studies have reported declines; however, the measures of cognitive function used have been limited. One explanation for the possible disturbance of cognitive functions is that electrical stimulation of the subthalamic nucleus disrupts the normal flow of information within cortico-striatal loops involving prefrontal, associative, or limbic cortex. We wished to assess the effect of high frequency electrical stimulation of the subthalamic nucleus in Parkinson's disease patients while they performed a comprehensive neuropsychological test battery. We selected cognitive tasks known to test the function of different cortical areas, including tests of executive function, cognitive flexibility, attention, memory, language and visual perception. Patients were tested on two separate days, with the stimulators turned on or off. Test scores were also compared to preoperative performance. In our sample of 15 patients without dementia or major depression there was no deterioration on any cognitive test as a result of stimulation. We conclude that electrical stimulation of the motor subthalamic nucleus does not cause appreciable declines in cognitive function in well-selected patients.

Cocaine Seeking Habits Depend upon Dopamine-Dependent Serial Connectivity Linking the Ventral with the Dorsal Striatum

A neuroanatomical principle of striatal organization has been established through which ventral domains, including the nucleus accumbens, exert control over dorsal striatal processes mediated by so-called "spiraling," striato-nigro-striatal, circuitry. We have investigated the functional significance of this circuitry in the control over a cocaine-seeking habit by using an intrastriatal disconnection procedure that combined a selective, unilateral lesion of the nucleus accumbens core and infusion of a dopamine receptor antagonist into the contralateral dorsolateral striatum, thereby disrupting striato-midbrain-striatal serial connectivity bilaterally. We show that this disconnection selectively decreased drug-seeking behavior in rats extensively trained under a second-order schedule of cocaine reinforcement. These data thereby define the importance of interactions between ventral and dorsal domains of the striatum, mediated by dopaminergic transmission, in the neural mechanisms underlying the development and performance of cocaine-seeking habits that are a key characteristic of drug addiction.

Selective corticostriatal dysfunction in schizophrenia: Examination of motor and cognitive skill learning.

It has been suggested that patients with schizophrenia have corticostriatal circuit dysfunction (Carlsson & Carlsson, 1990). Skill learning is thought to rely on corticostriatal circuitry and different types of skill learning may be related to separable corticostriatal loops (Grafton, Hazeltine, & Ivry, 1995; Poldrack, Prabhakaran, Seger, & Gabrieli, 1999). The authors examined motor (Serial Reaction Time task, SRT) and cognitive (Probabilistic Classification task, PCT) skill learning in patients with schizophrenia and normal controls. Development of automaticity was examined, using a dual task paradigm, across three training sessions. Patients with schizophrenia were impaired at learning on the PCT compared to controls. Performance gains of controls occurred within the first session, whereas patients only improved gradually and never reached the performance level of controls. In contrast, patients were not impaired at learning on the SRT relative to controls, suggesting that patients with schizophrenia may have dysfunction in a specific corticostriatal subcircuit.

Functional imaging of the cerebral olfactory system in patients with Parkinson’s disease

Background:Olfactory dysfunction is a frequent non-motor symptom in Parkinson’s disease (PD) and is considered to be an early manifestation of the disease.Objective:To establish the cortical basis of olfactory function in...

Functional and Anatomical Magnetic Resonance Imaging in Parkinson’s Disease

For the past 15 years, measurements of cerebral blood flow as an indicator of neuronal activity have been used to gain a better understanding of the neural basis of motor and cognitive deficits in Parkinson's disease. The initial studies, using positron emission tomography, yielded results in keeping with the hypothesis that symptoms result from excessive cortical inhibition from cortico-striatal loops. However, subsequent studies with functional magnetic resonance imaging (fMRI) have shown that specific aspects of the paradigms used, such as the need to pay attention to one's movements, have a significant impact on activation patterns, which may complicate the interpretation of results. Functional neuroimaging has also been used to investigate the causes of cognitive impairment in Parkinson's disease. While some studies implicate dopamine loss in striatum, more recent investigations using anatomical MRI to measure cortical atrophy suggest that some cognitive deficits are attributable to direct cortical involvement by the disease.

Heterarchical reinforcement-learning model for integration of multiple cortico-striatal loops: fMRI examination in stimulus-action-reward association learning

The brain's most difficult computation in decision-making learning is searching for essential information related to rewards among vast multimodal inputs and then integrating it into beneficial behaviors. Contextual cues consisting of limbic, cognitive, visual, auditory, somatosensory, and motor signals need to be associated with both rewards and actions by utilizing an internal representation such as reward prediction and reward prediction error. Previous studies have suggested that a suitable brain structure for such integration is the neural circuitry associated with multiple cortico-striatal loops. However, computational exploration still remains into how the information in and around these multiple closed loops can be shared and transferred. Here, we propose a "heterarchical reinforcement learning" model, where reward prediction made by more limbic and cognitive loops is propagated to motor loops by spiral projections between the striatum and substantia nigra, assisted by cortical projections to the pedunculopontine tegmental nucleus, which sends excitatory input to the substantia nigra. The model makes several fMRI-testable predictions of brain activity during stimulus-action-reward association learning. The caudate nucleus and the cognitive cortical areas are correlated with reward prediction error, while the putamen and motor-related areas are correlated with stimulus-action-dependent reward prediction. Furthermore, a heterogeneous activity pattern within the striatum is predicted depending on learning difficulty, i.e., the anterior medial caudate nucleus will be correlated more with reward prediction error when learning becomes difficult, while the posterior putamen will be correlated more with stimulus-action-dependent reward prediction in easy learning. Our fMRI results revealed that different cortico-striatal loops are operating, as suggested by the proposed model.

Different Neural Correlates of Reward Expectation and Reward Expectation Error in the Putamen and Caudate Nucleus During Stimulus-Action-Reward Association Learning

To select appropriate behaviors leading to rewards, the brain needs to learn associations among sensory stimuli, selected behaviors, and rewards. Recent imaging and neural-recording studies have revealed that the dorsal striatum plays an important role in learning such stimulus-action-reward associations. However, the putamen and caudate nucleus are embedded in distinct cortico-striatal loop circuits, predominantly connected to motor-related cerebral cortical areas and frontal association areas, respectively. This difference in their cortical connections suggests that the putamen and caudate nucleus are engaged in different functional aspects of stimulus-action-reward association learning. To determine whether this is the case, we conducted an event-related and computational model-based functional MRI (fMRI) study with a stochastic decision-making task in which a stimulus-action-reward association must be learned. A simple reinforcement learning model not only reproduced the subject's action selections reasonably well but also allowed us to quantitatively estimate each subject's temporal profiles of stimulus-action-reward association and reward-prediction error during learning trials. These two internal representations were used in the fMRI correlation analysis. The results revealed that neural correlates of the stimulus-action-reward association reside in the putamen, whereas a correlation with reward-prediction error was found largely in the caudate nucleus and ventral striatum. These nonuniform spatiotemporal distributions of neural correlates within the dorsal striatum were maintained consistently at various levels of task difficulty, suggesting a functional difference in the dorsal striatum between the putamen and caudate nucleus during stimulus-action-reward association learning.

Reduced White Matter Volume of the Caudate Nucleus in Patients with Schizophrenia

To examine volumetric abnormality, the caudate nucleus was measured in patients with schizophrenia and healthy subjects using magnetic resonance imaging. The absolute and relative volumes of white matter in the caudate nucleus were found to be significantly smaller in patients with schizophrenia compared to those in healthy subjects. There were significant correlations between dosages of neuroleptics during the previous year and absolute gray matter volumes of the caudate nucleus as well as relative white matter volumes in patients with schizophrenia. These findings suggest that reduced white matter volume of the caudate nucleus may be a factor affecting the abnormal connectivity of the corticostriatal loop, and that neuroleptic medication would be related to white matter alteration in patients with schizophrenia. Our result replicates a previous study reporting that there is a lack of negative correlation between age and caudate nucleus volume. We also suggest that the disease process of schizophrenia might interfere with normal aging.

Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats.

An insidious feature of drug craving and drug seeking in humans is that it can be induced and maintained by conditioned stimuli after a prolonged drug-free period. Understanding the neural basis of this control over addictive behavior may aid in the development of treatments targeting drug seeking and thereby be beneficial in preventing drug use. In the present study, we used a well established animal model to investigate the functional importance of amygdala-nucleus accumbens interactions in cocaine seeking under the control of drug-associated conditioned reinforcers. To probe the direct neuroanatomical relationship between these structures within a functional corticostriatal loop, we used a neuropharmacological disconnection procedure. Thus, infusing a dopamine receptor antagonist unilaterally into the basolateral amygdala (which had no effect on its own) and an AMPA-kainate (KA) receptor antagonist into the contralateral nucleus accumbens core (which also had no effect on its own) greatly reduced cocaine seeking. We also show that bilateral infusions of the DA receptor antagonist into the amygdala, but not nucleus accumbens, or of the AMPA-KA receptor antagonist in the nucleus accumbens, but not the amygdala, also greatly reduced cocaine seeking. The results of this study demonstrate an amygdala-nucleus accumbens system that critically underlies stimulus-controlled cocaine seeking and indicate possible neurochemical targets for relapse-prevention medication.

Left hemisphere specialization for the control of voluntary movement rate

Although persuasive behavioral evidence demonstrates the superior dexterity of the right hand in most people under a variety of conditions, little is known about the neural mechanisms responsible for this phenomenon. As this lateralized superiority is most evident during the performance of repetitive, speeded movement, we used parametric rate variations to compare visually paced movement of the right and left hands. Twelve strongly right-handed subjects participated in a functional magnetic resonance imaging (fMRI) experiment involving variable rate thumb movements. For movements of the right hand, contralateral rate-related activity changes were identified in the precentral gyrus, thalamus, and posterior putamen. For left-hand movements, activity was seen only in the contralateral precentral gyrus, consistent with the existence of a rate-sensitive motor control subsystem involving the left, but not the right, medial premotor corticostriatal loop in right-handed individuals. We hypothesize that the right hemisphere system is less skilled at controlling variable-rate movements and becomes maximally engaged at a lower movement rate without further modulation. These findings demonstrate that right- and left-hand movements engage different neural systems to control movement, even during a relatively simple thumb flexion task. Specialization of the left hemisphere corticostriatal system for dexterity is reflected in asymmetric mechanisms for movement rate control.

Examination of the role of the pedunculopontine tegmental nucleus in radial maze tasks with or without a delay

Two radial maze tasks, random foraging and delayed spatial win-shift, have been used to investigate, in rats, the functions and inter-relationships of structures connected through the corticostriatal loops, such as the prelimbic cortex, nucleus accumbens, ventral pallidum and mediodorsal thalamus. The random foraging task is designed to investigate animals’ ability to use spatial information to guide foraging on-line. The delayed spatial win-shift task requires, in addition, that animals hold spatially relevant information in working memory across a delay period. The pedunculopontine tegmental nucleus receives direct output from ventral striatal systems and might therefore be expected to share functional properties with them. In the present experiments we have examined the performance of rats bearing bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus on both of these tasks. In acquisition tests rats were given bilateral lesions before any training took place, while in retention tests appropriate training to predetermined criterion levels of performance took place before lesions were made. In both tasks, and in both acquisition (no prelesion training) and retention (prelesion training) tests, rats with pedunculopontine lesions made significantly more errors in selecting arms to enter than did control rats. There was no motor impairment present in pedunculopontine tegmental nucleus-lesioned rats – on the contrary, on measures of speed (latency to make first arm choice and the mean time for subsequent choices) pedunculopontine-lesioned rats were slightly faster than control rats. We suggest that the pedunculopontine tegmental nucleus shares functional properties with frontostriatal systems and that it forms part of a brainstem-directed stream of striatal outflow different to the cortical re-entrant system via the thalamus.

Physiology and pathophysiology of basalganglia: Impact on motor system function

Non-pyramidal muscular initiation by/of basalganglia differs from pyramidal, central, and spinal motor system regulation, but their synergistic cooperation increases the efficiency of central muscular motor functions. Corticostriatal pathways of neurons from motor areas in cortex excite by glutamate striatal GABA(gamma-aminobutyric acid)ergic neurons via their receptors, causing the release of the inhibitory neurotransmitter GABA. Over direct and indirect projections GABAergic impulses reach several nuclei of basalganglia, while GABAergic impact is modulated by dopamine (DA) through inhibitory or excitatory DA receptor subtypes. Adequate DA release from nigrostriatal pathways of DAergic neurons of substantia nigra is essential for well adjusted propagation to motor exits of basalganglia. From basalganglia exit projections are forwarded to motor nuclei of thalamus whose basal activity can be attenuated by inhibition or increased by disinhibition. Impulses are projected from thalamus to motor areas in cortex, in which information on the conducted circuit through basalganglia is returned to basalganglia by corticostriatal loops, adapting the following projections from basalganglia according to the need. Simultaneously, thalamic output is projected via supplementary motor area to primary cortex and, thus, may also affect centrifugal pyramidal output. In addition to basalganglic motor pathways via thalamus to motor cortex, there also exist projections from substantia nigra reticularis to several areas of motor nuclei in the brain stem, which influence spinal motor system function, especially that of the γ-motoneuron regulating extention of muscle spindle. Understanding of the physiological function of basalganglia has been immensely enriched by clarification of the pathophysiology of Parkinson's disease (PD) and its therapy. PD is characterized by resting tremor, rigidity, bradykinesia or slowness, gait disturbance, and postural instability. Hypokinetic, rigid syndrome of PD is caused by striatal disinhibition after degeneration of DAergic neurons in the substantia nigra pars compacta, which are essential for the control of motor performance. The cardinal symptomatology of the above mentioned motor system impairments in PD is also affected by the changes in motor behavior, particularly in the case of implicit learning and memory dysfunctions in striatum. In addition to the implicit deficit, cerebral dementia increases with duration of PD. Thus, explicit learning and memory function declines. Especially in the case of increasing bradyphrenia, anticipation of prefrontal association cortex as well as its propagation via frontal-striatal pathways to associative sensomotor and motor areas with connection to motor cortex area 4, where centrifugal pyramidal projections originate, are disturbed. This process promotes the reduction of motor anticipative behavior in cortex and impairs the continuation of proper motor movements as well as their automatization. During execution of movements additional impairment of fluctuation in centripetal as well as centrifugal impulses cannot be corrected volitionally or by reflex in PD. They generally intensify the decline of non-pyramidal and pyramidal synergistic cooperation. With increasing cardinal symptoms in PD, consequent specific medicamentous or invasive treatments are required. The systematic addressing of motor behavior in special reeducation programs can positively influence motor system functions. Particularly tremor and rigor, which are pronounced in the case of implicit motor system dysfunction, can partly be improved by increased explicit learning and memory function, supported by explicit mental movement initiation. Special training of prefrontal associations and a consecutive increase of central-motor behavior associations can also reduce cerebral automatization deficits. By this, even in long existing PD, non-pyramidal motor impairments can be affected and striatal dysfunctions symptomatically improved. Each motor input and output level and their central representation has to be evaluated individually and be corrected in this learning state, so that the summation of mistakes in the final phase is kept as small as possible. Thus, special didactical learning strategies should be applied with frequent controls.

Impaired planning but intact decision making in early Huntington’s disease: implications for specific fronto-striatal pathology

Previous neuropsychological data have suggested that deficits in early Huntington’s disease (HD) include executive impairments, which often are linked with frontal-lobe dysfunction. This study sought to investigate the profile of cognitive deficits using two computerised tasks whose performance is known to rely on intact functions of separate areas of the prefrontal cortex. Twenty patients with early HD and 20 matched controls were given the one-touch Tower of London, a stringent measure of visuo-spatial planning, and a decision making task, which involved selecting and gambling on outcomes on the basis of their differing probabilities. Patients were significantly less accurate than controls on the planning test, which is sensitive to frontal lobe lesions and is strongly associated with the dorsolateral prefrontal cortex in functional imaging studies. On the decision making task, patients were unimpaired on the quality of their decision making, in contrast to previous reports of impairment on this task in patients with ventromedial prefrontal cortex lesions. This dissociation of performance is discussed in terms of the usual path of progression of HD through the striatum and the resultant pattern of disruption of the functioning of the different cortico-striatal functional loops.

Limbic cortical-ventral striatal systems underlying appetitive conditioning

Publisher Summary This chapter describes the results of the experiments involving excitotoxic lesions of different nodes of circuit, in an attempt to understand the functions of corticostriatal loops, involving the nucleus accumbens (NAcc) and associated limbic circuitry that are implicated in reward and motivational processes. In the studies, the chapter investigated the effects of manipulations to the NAcc core and shell and anterior cingulate cortex, as well as the central nucleus and basolateral area of the amygdala and the dorsal and ventral subiculum, on a number of theoretically well understood animal learning paradigms. It is found that NAcc as a critical site for the arousing, or modulatory, influence of Pavlovian appetitive conditioned stimuli on ongoing motor performance, including instrumental behavior and locomotor approach. This has been demonstrated clearly by Pavlovian-to-instrumental transfer (PIT) experiments. If an animal is trained to press a lever for food and subsequently tested in extinction, presentation of a Pavlovian conditioned stimulus (CS) that predicts the same food increases the rate of lever-pressing. Lesions of the NAcc core impair the basic PIT effect, as does systemic treatment with the dopamine receptor antagonist pimozide, leading one to speculate that the ability of an appetitive Pavlovian CS to potentiate instrumental behavior depends on the mesolimbic dopamine system.

Integration and segregation of limbic cortico-striatal loops at the thalamic level: an experimental tracing study in rats.

The frontal lobe and the basal ganglia are involved in a number of parallel, functionally segregated circuits. Information is thought to pass from distinct parts of the (pre)frontal cortex, via the striatum, the pallidum/substantia nigra and the thalamus, back to the premotor/prefrontal cortices. Currently, different views exist as to whether these circuits are to be considered as open or closed loops, as well as to the degree of interconnection between different circuits. The main goal of the present study is to answer some of these questions for the limbic corticostriatal circuits. The latter circuits involve the nucleus accumbens, the ventral pallidum/dorsomedial substantia nigra pars reticulata, the medial parts of the mediodorsal and ventromedial thalamic nuclei and the prefrontal cortex. Within the nucleus accumbens, a core and a shell region are recognized on the basis of anatomical and functional criteria. The shell of the nucleus accumbens projects predominantly to the mediodorsal, the midline and the reticular thalamic nuclei via the ventral pallidum, whereas the core reaches primarily the medial part of the ventromedial thalamic nucleus, the intralaminar and mediodorsal thalamic nuclei via a relay in the dorsomedial substantia nigra pars reticulata. By means of double labeling experiments with injections of anterograde tracers in both the ventral pallidum and the substantia nigra of rats, we were able to demonstrate that circuits involving the shell and the core of the nucleus accumbens remain largely segregated at the level of the thalamus. Only restricted areas of overlap of ventral pallidal and reticular nigral projections occur in the mediodorsal and ventromedial thalamic nuclei, which allows for a limited degree of integration, at the thalamic level, of information passing through the two circuits.

Robot-aided functional imaging: Application to a motor learning study

The purpose of this study was to examine the neural activity underlying an implicit motor learning task. In particular, our goals were to determine whether initial phases of procedural learning of a motor task involve areas of the brain distinct from those involved in later phases of learning the task, and what changes in neural activity coincide with performance improvement. We describe a novel integration of robotic technology with functional brain imaging and its use in this study of implicit motor learning. A portable robotic device was used to generate forces that disturbed the subjects' arm movements, thereby generating a "virtual mechanical environment" that the subjects learned to manipulate. Positron emission tomography (PET) was used to measure indices of neural activity underlying learning of the motor task. Eight health, right-handed male subjects participated in the study. Results support the hypothesis that different stages of implicit learning (early and late implicit learning) occur in an orderly fashion, and that distinct neural structures may be involved in these different stages. In particular, neuroimaging results indicate that the cortico-striatal loop may play a significant role during early learning, and that the cortico-cerebellar loop may play a significant role during late learning.

SYDENHAM'S CHOREA

Sydenham's chorea (SC) is a disorder of the central nervous system (CNS) characterized by sudden, involuntary, arrhythmic, clonic, and purposeless movements. SC appears to provide a model for understanding various neuropsychiatric dysfunctions. Its relationship with attentional deficits, obsessive-compulsive symptoms (OCS) as well as movement disorders provides support for the hypothesis of the involvement of the corticostriatal loops in the pathophysiology of the disorder.

Dopamine efflux in the rat nucleus accumbens evoked by dopamine receptor stimulation in the entorhinal cortex is modulated by oestradiol and progesterone

This study compared the effects of dopamine receptor stimulation in the entorhinal cortex on dopamine release in the nucleus accumbens, measured by in vivo microdialysis in conscious Sprague-Dawley rats, with and without oestradiol and progesterone priming. Nonselective dopamine receptor stimulation with apomorphine reduced dopamine release in the nucleus accumbens, an effect which was prevented by injection of cis-flupenthixol into the entorhinal cortex. Selective D1 receptor stimulation with SKF38393 increased dopamine release, whereas selective D2 receptor stimulation with quinpirole did not affect dopamine release. Combined administration of oestradiol and progesterone potentiated the response to apomorphine and prevented the response to SKF38393. The effects of single hormone administration on the response to apomorphine suggested that the modulation was primarily due to oestradiol enhancing effects of progesterone. Experiments with high [K+] suggested these hormonal effects were exerted predominantly in the entorhinal cortex. The present experiments have demonstrated that dopaminergic modulation of transmission in a cortico-striatal loop linking temporal and prefrontal cortex is regulated by oestradiol and progesterone. Dysfunction in this system in humans may give rise to affective and cognitive symptoms which may, if initiated by a postpartum fall in oestrogen and progesterone concentrations, constitute the core pathophysiology of puerperal psychosis.

SIMPLE AND CHOICE REACTION TIME PERFORMANCE FOLLOWING UNILATERAL STRIATAL DOPAMINE DEPLETION IN THE RAT

Rats were trained to perform a visual spatial discrimination, where stimulus luminance provided information regarding the required direction of response. The visual stimuli were presented either in advance of a temporally unpredictable auditory imperative stimulus (simple reaction time condition) or simultaneously with the imperative stimulus (choice reaction time condition). Following unilateral striatal dopamine depletion, produced by intracerebral infusion of 6-hydroxydopamine, there was not only a marked spatial response bias towards the side of the dopamine depletion but also an abolition of the delay-dependent speeding of reaction time that reflects motor readiness, on the side contralateral to the lesion. Nevertheless, the rats continued to show a benefit in performance of the simple reaction time condition compared with the choice reaction time condition, indicating that they were able to use advance information to select and prepare responses. The results are discussed in the context of differential deficits shown by patients with Parkinson's disease in simple versus choice reaction time performance, and of the functions of parallel corticostriatal loops subserving the normal control of action.