The functional connectivity of intralaminar thalamic nuclei in the human basal ganglia

Projections of the centromedian‐parafasicularis neurons of the intralaminar thalamus are major inputs of the striatum. Their functional role in the activity of human basal ganglia (BG) is not well known. The aim of this work was to study the functional connectivity of intralaminar thalamic nuclei with other BG by using the correlations of the BOLD signal recorded during “resting” and a motor task. Intralaminar nuclei showed a marked functional connectivity with all the tested BG, which was observed during “resting” and did not change with the motor task. As regards the intralaminar nuclei, BG connectivity was much lower for the medial dorsal nucleus (a thalamic nucleus bordering the intralaminar nuclei) and for the default mode network (although intralaminar nuclei showed a negative correlation with the default mode network). After the “regression” of intralaminar nuclei activity (partial correlation), the functional connectivity of the caudate and putamen nuclei with other BG decreased (but not with the primary sensorimotor cortex). Present data provide evidence that intralaminar nuclei are not only critical for striatal activity but also for the global performance of human BG, an action involving subcortical BG loops more than cortico‐subcortical loops. The high correlation found between BG suggest that, similarly to that reported in other brain centers, the very‐slow frequency fluctuations are relevant for the functional activity of these centers. Hum Brain Mapp 36:1335–1347, 2015. © 2014 Wiley Periodicals, Inc .     

The motor circuit of the human basal ganglia reconsidered

The standard model of human basal ganglia organization was introduced in the 1980s on the basis of animal experiments and clinical experience of various human motor disorders. This paper reviews evidence from various sources which suggests that this standard model only incompletely accounts for aspects of basal ganglia function, and thus requires modification.     

Altered functional connectivity of basal ganglia circuitry in dental phobia

Recent symptom provocation studies that compared patients suffering from dental phobia with healthy controls identified hyperactivation of basal ganglia structures, but none have assessed striatal functional connectivity. We reanalyzed data from a previous functional magnetic resonance imaging study on dental phobia. Patients (20 men, 25 women) and healthy controls (18 men, 23 women) had been exposed to pictures showing dental treatment, and neutral contents. We conducted connectivity analyses via psychophysiological interactions (PPIs). Relative to non-phobic controls, the patients showed decreased connectivity between prefrontal and basal ganglia regions. Moreover, the clinical group was characterized by increased internal basal ganglia connectivity, which was more pronounced in female compared with male patients. This study provides first evidence for an altered information flow within a fronto-striatal network in dentophobic individuals during visual symptom provocation, which can be considered a neuromarker of this disorder.     

Increased functional connectivity in the resting-state basal ganglia network after acute heroin substitution

Reinforcement signals in the striatum are known to be crucial for mediating the subjective rewarding effects of acute drug intake. It is proposed that these effects may be more involved in early phases of drug addiction, whereas negative reinforcement effects may occur more in later stages of the illness. This study used resting-state functional magnetic resonance imaging to explore whether acute heroin substitution also induced positive reinforcement effects in striatal brain regions of protracted heroin-maintained patients. Using independent component analysis and a dual regression approach, we compared resting-state functional connectivity (rsFC) strengths within the basal ganglia/limbic network across a group of heroin-dependent patients receiving both an acute infusion of heroin and placebo and 20 healthy subjects who received placebo only. Subsequent correlation analyses were performed to test whether the rsFC strength under heroin exposure correlated with the subjective rewarding effect and with plasma concentrations of heroin and its main metabolites morphine. Relative to the placebo treatment in patients, heroin significantly increased rsFC of the left putamen within the basal ganglia/limbic network, the extent of which correlated positively with patients'' feelings of rush and with the plasma level of morphine. Furthermore, healthy controls revealed increased rsFC of the posterior cingulate cortex/precuneus in this network relative to the placebo treatment in patients. Our results indicate that acute heroin substitution induces a subjective rewarding effect via increased striatal connectivity in heroin-dependent patients, suggesting that positive reinforcement effects in the striatum still occur after protracted maintenance therapy.     

精神分裂症患者基底节功能连接的静息态fMRI研究

目的通过功能磁共振(fMRI)技术,探讨精神分裂症患者静息状态下与基底节异常连接的脑区。方法采用3.0T功能磁共振成像技术检测15例精神分裂症患者与12例正常对照组在静息状态下的全脑功能活动。采用功能连接分析对比两组被试的基底节(双侧尾状核、壳核和苍白球共6个区域)与全脑功能连接的差异。结果与对照组相比,精神分裂症患者的内侧额上回、后扣带与尾状核的功能连接上升;左侧额上回、右侧前扣带与左侧苍白球功能连接上升;左内侧额上回与右侧苍白球功能连接上升;左侧额上回与左侧壳核功能连接上升。差异均有统计学意义。结论精神分裂症患者的基底节区域与默认网络的重要节点功能连接上升,提示基底节-默认网络环路出现异常,这可能与精神分裂症的病理机制有关。     

The functional anatomy of basal ganglia disorders

Basal ganglia disorders are a heterogeneous group of clinical syndromes with a common anatomic locus within the basal ganglia. To account for the variety of clinical manifestations associated with insults to various parts of the basal ganglia we propose a model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons. This model is based on a synthesis of experimental animal and post-mortem human anatomic and neurochemical data. Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus. Hypokinetic disorders, such as Parkinson's disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output. This model suggests that the activity of subpopulations of striatal projection neurons is differentially regulated by striatal afferents and that different striatal projection neuron subpopulations may mediate different aspects of motor control.     

Alpha frequency modulation in the human basal ganglia is dependent on motor task

Depth recordings from the basal ganglia of patients suffering from Parkinson's disease (PD) or dystonia have revealed local field potential (LFP) activity in specific frequency bands. Depth recordings also allow us to study LFP power spectra during different types of limb movements, thus helping to elucidate the role of the basal ganglia in specific motor tasks. Accordingly, we recorded bilateral LFP activity from the subthalamic nucleus (STN) of patients with PD (n=9) and from the globus pallidus internum (GPi) of patients with dystonia (n=8). Recordings were taken during the performance of repetitive passive, active and ballistic fast extensions and flexions of the elbow joint and during rest. The first result was that the frequency spectra varied task-specifically in a similar fashion in GPi and STN. The amplitude of the alpha frequency on the contralateral side was significantly higher in ballistic fast movements compared with rest, passive and active performance in both STN and GPi. In conclusion, ballistic fast movements cause synchronized basal ganglia activity in the alpha range. Because this was seen in both patient groups (PD and dystonia) we consider this activity as task-specific rather than disease-related.     

The basal ganglia in human learning.

For many years, the basal ganglia were described in anatomy courses as strictly motor structures. Certainly, some of the most obvious and debilitating symptoms shown by persons with basal ganglia disorders are problems in motor control. However, the basal ganglia are not limited to motoric aspects of behavior: recent research shows that they are involved in most areas of cognitive and emotional functioning, consistent with their anatomical connections with all areas of the cortex. This review will focus on the roles of the basal ganglia in human learning, particularly sequence learning and category learning. Current areas of research that are discussed include the differing roles of different basal ganglia regions, patterns of interaction between the cortex and basal ganglia, differences in positive and negative association learning, effects of dopaminergic medication on learning, whether basal ganglia-mediated learning is implicit or explicit, and how the basal ganglia learning systems interact with other learning systems, particularly within the medial temporal lobe.     

Reappraisal of the motor role of basal ganglia: a functional magnetic resonance image study

The importance of the basal ganglia in controlling motor function is well known. However, neuroimaging studies have failed to show either movement-rate dependence or different activation patterns caused by self-initiated (SI) and externally triggered (ET) movements in the basal ganglia-thalamo-motor loop. We herein report the functional magnetic resonance image (fMRI) mapping of sequential left-hand finger movements at five different rates under SI and ET conditions. Significant movement-rate dependence was found in the whole right basal ganglia-thalamo-motor loop only during the SI task. Network analysis also showed strong interactions within this loop during SI movement, whereas interactions were present only from the premotor cortex to the putamen via the sensorimotor cortex during the ET task. Furthermore, psychophysiological interaction analysis confirmed the different modulation between the two tasks in the putamen. fMRI provides evidence that the basal ganglia-thalamo-motor loop plays a key role in controlling the rate of sequential finger movements in SI movement but not in ET movement.     

Longitudinal changes in functional connectivity of cortico‐basal ganglia networks in manifests and premanifest huntington's disease

Huntington's disease (HD) is a genetic neurological disorder resulting in cognitive and motor impairments. We evaluated the longitudinal changes of functional connectivity in sensorimotor, associative and limbic cortico‐basal ganglia networks. We acquired structural MRI and resting‐state fMRI in three visits one year apart, in 18 adult HD patients, 24 asymptomatic mutation carriers (preHD) and 18 gender‐ and age‐matched healthy volunteers from the TRACK‐HD study. We inferred topological changes in functional connectivity between 182 regions within cortico‐basal ganglia networks using graph theory measures. We found significant differences for global graph theory measures in HD but not in preHD. The average shortest path length (L) decreased, which indicated a change toward the random network topology. HD patients also demonstrated increases in degree k, reduced betweeness centrality bc and reduced clustering C. Changes predominated in the sensorimotor network for bc and C and were observed in all circuits for k. Hubs were reduced in preHD and no longer detectable in HD in the sensorimotor and associative networks. Changes in graph theory metrics (L, k, C and bc) correlated with four clinical and cognitive measures (symbol digit modalities test, Stroop, Burden and UHDRS). There were no changes in graph theory metrics across sessions, which suggests that these measures are not reliable biomarkers of longitudinal changes in HD. preHD is characterized by progressive decreasing hub organization, and these changes aggravate in HD patients with changes in local metrics. HD is characterized by progressive changes in global network interconnectivity, whose network topology becomes more random over time. Hum Brain Mapp 37:4112–4128, 2016. © 2016 Wiley Periodicals, Inc.     

The corticotopic organization of the human basal forebrain as revealed by regionally selective functional connectivity profiles

The cholinergic basal forebrain (CBF), comprising different groups of cortically projecting cholinergic neurons, plays a crucial role in higher cognitive processes and has been implicated in diverse neuropsychiatric disorders. A distinct corticotopic organization of CBF projections has been revealed in animal studies, but little is known about their organization in the human brain. We explored regional differences in functional connectivity (FC) profiles within the human CBF by applying a clustering approach to resting‐state functional magnetic resonance imaging (rs‐fMRI) data of healthy adult individuals (N = 85; 19–85 years). We further examined effects of age on FC of the identified CBF clusters and assessed the reproducibility of cluster‐specific FC profiles in independent data from healthy older individuals (N = 25; 65–89 years). Results showed that the human CBF is functionally organized into distinct anterior‐medial and posterior‐lateral subdivisions that largely follow anatomically defined boundaries of the medial septum/diagonal band and nucleus basalis Meynert. The anterior‐medial CBF subdivision was characterized by connectivity with the hippocampus and interconnected nodes of an extended medial cortical memory network, whereas the posterior‐lateral subdivision was specifically connected to anterior insula and dorsal anterior cingulate components of a salience/attention network. FC of both CBF subdivisions declined with increasing age, but the overall topography of subregion‐specific FC profiles was reproduced in independent rs‐fMRI data of healthy older individuals acquired in a typical clinical setting. Rs‐fMRI‐based assessments of subregion‐specific CBF function may complement established volumetric approaches for the in vivo study of CBF involvement in neuropsychiatric disorders.     

Structural and functional evolution of the basal ganglia in vertebrates

While a basal ganglia with striatal and pallidal subdivisions is¹ clearly present in many extant anamniote species, this basal ganglia is cell sparse and receives only a relatively modest tegmental dopaminergic input and little if any cortical input. The major basal ganglia influence on motor functions in anamniotes appears to be exerted via output circuits to the tectum. In contrast, in modern mammals, birds, and reptiles (i.e., modern amniotes), the striatal and pallidal parts of the basal ganglia are very neuron-rich, both consist of the same basic populations of neurons in all amniotes, and the striatum receives abundant tegmental dopaminergic and cortical input. The functional circuitry of the basal ganglia also seems very similar in all amniotes, since the major basal ganglia influences on motor functions appear to be exerted via output circuits to both cerebral cortex and tectum in sauropsids (i.e., birds and reptiles) and mammals. The basal ganglia, output circuits to the cortex, however, appear to be considerably more developed in mammals than in birds and reptiles. The basal ganglia, thus, appears to have undergone a major elaboration during the evolutionary transition from amphibians to reptiles. This elaboration may have enabled amniotes to learn and/or execute a more sophisticated repertoire of behaviors and movements, and this ability may have been an important element of the successful adaptation of amniotes to a fully terrestrial habitat. The mammalian lineage appears, however, to have diverged somewhat from the sauropsid lineage with respect to the emergence of the cerebral cortex as the major target of the basal ganglia circuitry devoted to executing the basal ganglia-mediated control of movement.     

Normal sexual dimorphism in the human basal ganglia

Male and female brains differ in both structure and function. Investigating this sexual dimorphism in healthy subjects is an important first step to ultimately gain insight into sex-specific differences in behavior and risk for neuropsychiatric disorders. The basal ganglia are among the main regions containing sex steroid receptors in the brain and play a central role in cognitive (dys)functioning. However, little is known about sexual dimorphism of different basal ganglia nuclei. The aim of the present study was to investigate sex-specific differences in basal ganglia morphology using MRI. We applied automatic volumetry on anatomical MRI data of two large cohorts of healthy young adults (n = 463 and n = 541) and assessed the volume of four major nuclei of the basal ganglia: caudate nucleus, globus pallidus, nucleus accumbens, and putamen, while controlling for total gray matter volume, total white matter volume, and age of the participant. No significant sex differences were found for caudate nucleus and nucleus accumbens, but males showed significantly larger volumes for globus pallidus and putamen, as confirmed in both cohorts. These results show that sexual dimorphism is neither a general effect in the basal ganglia nor confined to just one specific nucleus, and will aid the interpretation of differences in basal ganglia (dys)function between males and females.     

Discharge pattern of single motor units in basal ganglia disorders

We studied the discharge pattern of motor units (MUs) from the first dorsal interosseous muscle during slight stationary isometric contraction. In six controls, seven patients with parkinsonism, and five patients with choreic disorders, we analyzed 78 MUs. About one-half of the MUs in both patient groups fired irregularly as shown by interval histograms, joint interval histograms, and corresponding statistical calculations. Cross-correlation techniques revealed a characteristic type of MU synchronization in parkinsonism. Analysis of the MU discharge pattern can be useful in clinical assessment of these disorders.     

Function of the 'direct' and 'indirect' pathways of the basal ganglia motor loop: evidence from reciprocal aiming movements in Parkinson's disease

The purpose of this study was to test the validity of a neural-network model of the basal ganglia developed by Bischoff and colleagues (A. Bischoff, Modeling the basal ganglia in the control of arm movements (Doctoral dissertation, University of Southern California, 1998). Dissertation Abstr. Int. 59-08B (1998) 3924, 0208; A. Bischoff, M.A. Arbib, Modeling the role of basal ganglia and supplementary motor areas in sequential arm movements, Abstr. Soc. Neurosci. 23 (1997) 466; A. Bischoff, M.A. Arbib, C.J. Winstein, Modeling the role of the basal ganglia in reciprocal aiming task, Proceedings of the Fourth Annual Joint Symposium on Neural Computation, University of Southern California, Los Angeles, 7, 1997, pp. 20-27), and to examine the effects of levodopa on aiming movement performance. Findings confirm the model predictions for repetitive aiming movements. Individuals with late stage Parkinson's disease demonstrated longer movement times and longer pauses between aiming sequences compared to controls. Levodopa only slightly improved bradykinesia but not akinesia in these patients.     

Functional architecture of the cortico‐basal ganglia circuitry during motor task execution: Correlations of strength of functional connectivity with neuropsychological task performance among female subjects

The primary aim of this study was to enhance our understanding of the functional architecture of the cortico‐basal ganglia circuitry during motor task execution. Twenty right‐handed female subjects without any history of neuropsychiatric illness underwent fMRI at 3 T. The activation paradigm was a complex motor task completed with the nondominant hand. Analyses of functional connectivity strength were conducted for pairs of structures in input, intrinsic, and output segments of the circuitry. Next, connectivity strengths were correlated with results of neurocognitive testing conducted outside of the scanner, which provided information about both motor and cognitive processes. For input pathways, results indicate that SMA–striatum interactions are particularly relevant for motor behavior and disruptions may impact both motor and cognitive functions. For intrinsic pathways, results indicate that thalamus (VA nucleus) to striatum feedback pathway appears to have an important role during task execution and carries information relevant for motor planning. Together, these findings add to accumulating evidence that the GPe may play a role in higher order basal ganglia processing. A potentially controversial finding was that strong functional connectivity appears to occur across intrinsic inhibitory pathways. Finally, output (thalamus to cortex) feedback was only correlated with motor planning. This result suggests circuit processes may be more relevant for future behaviors than the execution of the current task. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Cortex, basal ganglia and cerebellum in motor control.

For voluntary movement, function generators are necessary that are located in the brain-stem, cerebellum and basal ganglia. Following lesions of these generators, voluntary movements are impaired while stimulus-dependent movements are still possible. This discussion also applies to speech production. The motor function generators cooperate with the whole cerebral cortex since both tactical adaptation to the environment and strategic guidance by the motivation system contribute to voluntary action. The motor cortex plays an epicritical role, adding advanced tactile and proprioceptive guidance for those movements that need this kind of regulation, especially the fine finger movements which depend entirely on the motor cortex. The complexity of the cerebral potentials preceding voluntary movement corresponds to the activity of several motor subsystems acting in concert.