Search

On the basis of the functional model of the basal ganglia developed in the 1980s and the neuropathological findings in Huntington's disease (HD), changes in the neuronal activity of the basal ganglia have previously been proposed to explain the abnormal movements observed in this pathology. In particular, it has been stated that the neurodegenerative process affecting the basal ganglia in the disease should provoke a hypoactivity in the internal segment of the pallidum (GPi) that could explain choreic movements observed in the disease. To test this functional hypothesis, we performed an in situ hybridization study on control and HD brains postmortem, taking cytochrome oxidase subunit I (COI) mRNAs expression as index of neuronal activity. As most of the HD patients studied were under chronic neuroleptic (NL) treatment, we also studied the brains of non-HD patients under chronic NL treatment. Our results show that in HD brain the number of neurons expressing COI mRNA tends to be lower in the striatum, GPe and GPi, suggesting a severe involvement of these structures during the neurodegenerative process. Moreover, COI mRNA level of expression was markedly reduced within neurons of the putamen and GPe. Surprisingly, COI mRNA expression was not modified in the GPi in HD brains compared with controls. This paradoxical result in the GPi may be explained by the antagonistic effect of GPe hypoactivity and the degenerative process involving neurons of GPi. Our results indicate that the functional modifications, and consequently the pathophysiology of␣abnormal movements, observed in HD basal ganglia are more complex than expected from the currently accepted model of the basal ganglia organization. [ABSTRACT FROM AUTHOR]

Abstract Cellular expression of cytochrome oxidase subunit I (COI) mRNA has recently been used as a metabolic marker for neuronal activity to study the functional changes in the subthalamic nucleus (STN) in parkinsonism. The previous experimental studies have been performed when the pathological state was stabilized at a maximal level. In order to determine the evolution of changes in neuronal activity in the STN after nigrostriatal denervation, we analysed by in situ hybridization the cellular expression of COI mRNA in the subthalamic neurons at different times, from 6 h to 14 days, after unilateral intranigral microinjection of 6-hydroxydopamine (6-OHDA) in rats. In parallel, the time-dependent changes of the unit neuronal activity of subthalamic neurons have been recorded. Levels of COI mRNA increased by 41% in subthalamic neurons from 24 h after 6-OHDA intoxication, to 14 days (+26%). Similarly, electrical activity started to increase slightly 24 h after lesion (+20%) and remained significantly higher at 14 days after the lesion (+189%). Changes in neuronal mean discharge rate were associated with changes in the pattern of spiking activity, from a regular firing pattern to an irregular one with a high bursting activity. These results show that: (i) the hyperactivity of the STN represents a very early phenomenon in the physiopathology of parkinsonian syndromes; and (ii) that changes in COI mRNA expression slightly precede changes in electrical neuronal activity. [ABSTRACT FROM AUTHOR]

Alcohol consumption affects motor behavior and motor control. Both acute and chronic alcohol abuse have been extensively investigated; however, the therapeutic efficacy of alcohol on some movement disorders, such as myoclonus‐dystonia or essential tremor, still does not have a plausible mechanistic explanation. Yet, there are surprisingly few systematic trials with known GABAergic drugs mimicking the effect of alcohol on neurotransmission. In this brief survey, we aim to summarize the effects of EtOH on striatal function, providing an overview of its cellular and synaptic actions in a 'circuit‐centered' view. In addition, we will review both experimental and clinical evidence, in the attempt to provide a plausible mechanistic explanation for alcohol‐responsive movement disorders, with particular emphasis on dystonia. Different hypotheses emerge, which may provide a rationale for the utilization of drugs that mimic alcohol effects, predicting potential drug repositioning. [ABSTRACT FROM AUTHOR]

A distinct population of dopamine neurons in the substantia nigra pars lateralis (SNL) has a unique projection to the most caudolateral (tail) region of the striatum. Here, using two electrochemical techniques to measure basal dopamine and electrically evoked dopamine release in anesthetized rats, we characterized this pathway, and compared it with the 'classic' nigrostriatal pathway from neighboring substantia nigra pars compacta (SNc) dopamine neurons to the dorsolateral striatum. We found that the tail striatum constitutes a distinct dopamine domain compared with the dorsolateral striatum, with consistently lower basal and evoked dopamine, and diverse dopamine release kinetics. Importantly, electrical stimulation of the SNL and SNc evoked dopamine release in entirely separate striatal regions; the tail and dorsolateral striatum, respectively. Furthermore, we showed that stimulation of the subthalamic nucleus (STN) evoked dopamine release exclusively in the tail striatum, likely via the SNL, consistent with previous anatomical evidence of STN afferents to SNL dopamine neurons. Our work identifies the STN as an important modulator of dopamine release in a novel dopamine pathway to the tail striatum, largely independent of the classic nigrostriatal pathway, which necessitates a revision of the basal ganglia circuitry with the STN positioned as a central integrator of striatal information. [ABSTRACT FROM AUTHOR]

Brain iron load is one of the most important neuropathological hallmarks in movement disorders. Specifically, the iron provides most of the paramagnetic metal signals in the brain and its accumulation seems to play a key role, although not completely explained, in the degeneration of the basal ganglia, as well as other brain structures. Moreover, iron distribution patterns have been implicated in depicting different movement disorders. This work reviewed current literature on Magnetic Resonance Imaging for Brain Iron Detection and Quantification (MRI-BIDQ) in neurodegenerative processes underlying movement disorders. [ABSTRACT FROM AUTHOR]

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in primates results in a heterogeneous loss of dopamine in the striatum, predominating in the dorsal and caudal parts of the structure, causing functional impairment that appears to be essentially motor and cognitive. The aim of the present study was to quantify the loss of dopamine in relation to the anatomo-functional subdivisions of the striatum, and also of the pallidum and cortex of MPTP-treated monkeys. A severe loss of dopaminergic innervation was observed in both the sensorimotor and associative territories of all these structures in MPTP-treated monkeys. Comparatively, the limbic territories of all these structures were little affected. The preservation of dopaminergic innervation of the limbic part of cerebral structures may explain the preservation of motivational processes mediated by these limbic regions in MPTP-treated monkeys. [ABSTRACT FROM AUTHOR]

In Parkinson’s disease, nigrostriatal denervation leads to an overactivity of the subthalamic nucleus and its target areas, which is responsible of the clinical manifestations of the disease. Because the subthalamic nucleus uses glutamate as neurotransmitter and is innervated by glutamatergic fibers, pharmacological blockade of glutamate transmission might be expected to restore the cascade of neurochemical changes induced by a dopaminergic denervation within the basal ganglia. To test this hypothesis, two types of glutamate antagonists, the NMDA receptor antagonist MK-801 and the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist LY293558, were administered systemically, either alone or in combination with L-DOPA, in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. The effect of treatment was assessed neurochemically by analyzing at the cellular level the functional activity of basal ganglia output structures and the subthalamic nucleus using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase, respectively, as molecular markers of neuronal activity. The present study shows that treatment with glutamate antagonists, and particularly with AMPA antagonists, alone or in combination with L-DOPA, reverses the overactivity of the subthalamic nucleus and its target areas induced by nigrostriatal denervation. These results furnish the neurochemical basis for the potential use of glutamate antagonists as therapeutic agents in Parkinson’s disease. [ABSTRACT FROM AUTHOR]

The central cholinergic system includes the basal forebrain nuclei, mainly projecting to the cortex, the mesopontine tegmental nuclei, mainly projecting to the thalamus and subcortical structures, and other groups of projecting neurons and interneurons. This system regulates many functions of human behavior such as cognition, locomotion, and sleep. In Parkinson's disease (PD), disruption of central cholinergic transmission has been associated with cognitive decline, gait problems, freezing of gait (FOG), falls, REM sleep behavior disorder (RBD), neuropsychiatric manifestations, and olfactory dysfunction. Neuropathological and neuroimaging evidence suggests that basal forebrain pathology occurs simultaneously with nigrostriatal denervation, whereas pathology in the pontine nuclei may occur before the onset of motor symptoms. These studies have also detailed the clinical implications of cholinergic dysfunction in PD. Degeneration of basal forebrain nuclei and consequential cortical cholinergic denervation are associated with and may predict the subsequent development of cognitive decline and neuropsychiatric symptoms. Gait problems, FOG, and falls are associated with a complex dysfunction of both pontine and basal forebrain nuclei. Olfactory impairment is associated with cholinergic denervation of the limbic archicortex, specifically hippocampus and amygdala. Available evidence suggests that cholinergic dysfunction, alongside failure of the dopaminergic and other neurotransmitters systems, contributes to the generation of a specific set of clinical manifestations. Therefore, a "cholinergic phenotype" can be identified in people presenting with cognitive decline, falls, and RBD. In this review, we will summarize the organization of the central cholinergic system and the clinical correlates of cholinergic dysfunction in PD. [ABSTRACT FROM AUTHOR]

Patients with Parkinson's disease (PD patients) have been shown to exhibit abnormally low levels of synergy in their posture control. The goal of this study was to determine how synergic interactions between vision and posture are affected in PD patients. These synergic interactions were expected to be impaired because PD affects the basal ganglia, which are involved in the modulation of both types of movement. Twenty patients (mean age: 60) on levodopa and 20 age‐matched‐controls (mean age: 61) performed a precise visual task (searching for targets in an image) and an unprecise control task (randomly looking at an image) in which images were projected onto a large panoramic display. Lower back, upper back, head and eye movements were recorded simultaneously. To test behavioural synergies, Pearson correlations between eye and postural movements were analysed. The relationships between eye movements and upper and lower back movements were impaired in the patients. The age‐matched controls did not show any significant correlations between eye and postural movements. Overall, our results showed that the PD patients failed to adjust and control their postural stability for success in the visual task. The impaired synergy between eye and postural movements was not related to clinical variables—probably because our patients had early‐stage PD. Our results showed that impairments in synergy can occur very early in PD. Hence, the analysis of this synergy might provide a better understanding of postural instability, visual task performance in the upright stance, and perhaps the risk of falls in PD patients. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) surgery has been shown to dramatically improve the quality of life for patients with various motor dysfunctions, such as those afflicted with Parkinson's disease (PD), dystonia, and essential tremor (ET), by relieving motor symptoms associated with such pathologies. The success of DBS procedures is directly related to the proper placement of the electrodes, which requires the ability to accurately detect and identify relevant target structures within the subcortical basal ganglia region. In particular, accurate and reliable segmentation of the globus pallidus (GP) interna is of great interest for DBS surgery for PD and dystonia. In this study, we present a deep‐learning based neural network, which we term GP‐net, for the automatic segmentation of both the external and internal segments of the globus pallidus. High resolution 7 Tesla images from 101 subjects were used in this study; GP‐net is trained on a cohort of 58 subjects, containing patients with movement disorders as well as healthy control subjects. GP‐net performs 3D inference in a patient‐specific manner, alleviating the need for atlas‐based segmentation. GP‐net was extensively validated, both quantitatively and qualitatively over 43 test subjects including patients with movement disorders and healthy control and is shown to consistently produce improved segmentation results compared with state‐of‐the‐art atlas‐based segmentations. We also demonstrate a postoperative lead location assessment with respect to a segmented globus pallidus obtained by GP‐net. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) has been most widely used in the management of movement disorders, but more recently to treat a growing number of neurological and psychiatric conditions. It is know to have a variety of effects upon oculomotor function, depending not only on the location of the stimulation, but also the underlying pathology being treated. Understanding how DBS affects eye movements is important, given the widespread nature of eye movement control and its inevitable overlap with many of the networks targeted by the stimulation. Moreover, it can also offer additional mechanistic insights into neural circuits involved in complex eye movement control. Here, we discuss the application of DBS treatment across different diseases and explore how distinct stimulation locations interfere with known eye movement circuits and the ensuing oculomotor and visual effects it can produce. We also discuss more experimental DBS targets and its effects on ocular motility, as well as discussing unilateral versus bilateral deep brain stimulation and possible hemispheric asymmetry in relation to eye movement control. Contradictory findings across studies reporting DBS effects on eye movements likely relate to differences in the methodological approaches used, levodopa medication status, as well as possible variability in DBS electrode placement. We highlight the need for further research with less common DBS targets on the possible effects upon eye movements. [ABSTRACT FROM AUTHOR]

Aims: Neuroferritinopathy (NF) or hereditary ferritinopathy (HF) is an autosomal dominant movement disorder due to mutation in the light chain of the iron storage protein ferritin (FTL). HF is the only late‐onset neurodegeneration with brain iron accumulation disorder and study of HF offers a unique opportunity to understand the role of iron in more common neurodegenerative syndromes. Methods: We carried out pathological and biochemical studies of six individuals with the same pathogenic FTL mutation. Results: CNS pathological changes were most prominent in the basal ganglia and cerebellar dentate, echoing the normal pattern of brain iron accumulation. Accumulation of ferritin and iron was conspicuous in cells with a phenotype suggesting oligodendrocytes, with accompanying neuronal pathology and neuronal loss. Neurons still survived, however, despite extensive adjacent glial iron deposition, suggesting neuronal loss is a downstream event. Typical age‐related neurodegenerative pathology was not normally present. Uniquely, the extensive aggregates of ubiquitinated ferritin identified indicate that abnormal FTL can aggregate, reflecting the intrinsic ability of FTL to self‐assemble. Ferritin aggregates were seen in neuronal and glial nuclei showing parallels with Huntington's disease. There was neither evidence of oxidative stress activation nor any significant mitochondrial pathology in the affected basal ganglia. Conclusions: HF shows hallmarks of a protein aggregation disorder, in addition to iron accumulation. Degeneration in HF is not accompanied by age‐related neurodegenerative pathology and the lack of evidence of oxidative stress and mitochondrial damage suggests that these are not key mediators of neurodegeneration in HF, casting light on other neurodegenerative diseases characterized by iron deposition. [ABSTRACT FROM AUTHOR]

Internal and external segments of globus pallidus (GP) exert different functions in basal ganglia circuitry, despite their main connectional systems share the same topographical organization, delineating limbic, associative, and sensorimotor territories. The identification of internal GP sensorimotor territory has therapeutic implications in functional neurosurgery settings. This study is aimed at assessing the spatial coherence of striatopallidal, subthalamopallidal, and pallidothalamic pathways by using tractography‐derived connectivity‐based parcellation (CBP) on high quality diffusion MRI data of 100 unrelated healthy subjects from the Human Connectome Project. A two‐stage hypothesis‐driven CBP approach has been carried out on the internal and external GP. Dice coefficient between functionally homologous pairs of pallidal maps has been computed. In addition, reproducibility of parcellation according to different pathways of interest has been investigated, as well as spatial relations between connectivity maps and existing optimal stimulation points for dystonic patients. The spatial organization of connectivity clusters revealed anterior limbic, intermediate associative and posterior sensorimotor maps within both internal and external GP. Dice coefficients showed high degree of coherence between functionally similar maps derived from the different bundles of interest. Sensorimotor maps derived from the subthalamopallidal pathway resulted to be the nearest to known optimal pallidal stimulation sites for dystonic patients. Our findings suggest that functionally homologous afferent and efferent connections may share similar spatial territory within the GP and that subcortical pallidal connectional systems may have distinct implications in the treatment of movement disorders. [ABSTRACT FROM AUTHOR]

Key points: Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key network within the basal ganglia.In Parkinson's disease and its models, abnormal rates and patterns of GPe‐STN network activity are linked to motor dysfunction.Using cell class‐specific optogenetic identification and inhibition during cortical slow‐wave activity and activation, we report that, in dopamine‐depleted mice, (1) D2 dopamine receptor expressing striatal projection neurons (D2‐SPNs) discharge at higher rates, especially during cortical activation, (2) prototypic parvalbumin‐expressing GPe neurons are excessively patterned by D2‐SPNs even though their autonomous activity is upregulated, (3) despite being disinhibited, STN neurons are not hyperactive, and (4) STN activity opposes striatopallidal patterning.These data argue that in parkinsonian mice abnormal, temporally offset prototypic GPe and STN neuron firing results in part from increased striatopallidal transmission and that compensatory plasticity limits STN hyperactivity and cortical entrainment. Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key, centrally positioned network within the basal ganglia. In Parkinson's disease and its models, abnormal rates and patterns of GPe‐STN network activity are linked to motor dysfunction. Following the loss of dopamine, the activities of GPe and STN neurons become more temporally offset and strongly correlated with cortical oscillations below 40 Hz. Previous studies utilized cortical slow‐wave activity and/or cortical activation (ACT) under anaesthesia to probe the mechanisms underlying the normal and pathological patterning of basal ganglia activity. Here, we combined this approach with in vivo optogenetic inhibition to identify and interrupt the activity of D2 dopamine receptor‐expressing striatal projection neurons (D2‐SPNs), parvalbumin‐expressing prototypic GPe (PV GPe) neurons, and STN neurons. We found that, in dopamine‐depleted mice, (1) the firing rate of D2‐SPNs was elevated, especially during cortical ACT, (2) abnormal phasic suppression of PV GPe neuron activity was ameliorated by optogenetic inhibition of coincident D2‐SPN activity, (3) autonomous PV GPe neuron firing ex vivo was upregulated, presumably through homeostatic mechanisms, (4) STN neurons were not hyperactive, despite being disinhibited, (5) optogenetic inhibition of the STN exacerbated abnormal GPe activity, and (6) exaggerated beta band activity was not present in the cortex or GPe‐STN network. Together with recent studies, these data suggest that in dopamine‐depleted mice abnormally correlated and temporally offset PV GPe and STN neuron activity is generated in part by elevated striatopallidal transmission, while compensatory plasticity prevents STN hyperactivity and limits cortical entrainment. Key points: Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key network within the basal ganglia.In Parkinson's disease and its models, abnormal rates and patterns of GPe‐STN network activity are linked to motor dysfunction.Using cell class‐specific optogenetic identification and inhibition during cortical slow‐wave activity and activation, we report that, in dopamine‐depleted mice, (1) D2 dopamine receptor expressing striatal projection neurons (D2‐SPNs) discharge at higher rates, especially during cortical activation, (2) prototypic parvalbumin‐expressing GPe neurons are excessively patterned by D2‐SPNs even though their autonomous activity is upregulated, (3) despite being disinhibited, STN neurons are not hyperactive, and (4) STN activity opposes striatopallidal patterning.These data argue that in parkinsonian mice abnormal, temporally offset prototypic GPe and STN neuron firing results in part from increased striatopallidal transmission and that compensatory plasticity limits STN hyperactivity and cortical entrainment. [ABSTRACT FROM AUTHOR]

Neurological diseases particularly Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and epilepsy are on the rise all around the world causing morbidity and mortality globally with a common symptom of gradual loss or impairment of motor behaviour. Striatum, which is a component of the basal ganglia, is involved in facilitating voluntary movement while the cerebellum is involved in the maintenance of balance and coordination of voluntary movements. Dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate, to name a few, interact in regulating the excitation and inhibition of motor neurons. In another hand, interestingly, the motor loss associated with neurological diseases is possibly resulted from neuroinflammation induced by the neuroimmune system. Toll-like receptors (TLRs) are present in the central nervous system (CNS), specifically and primarily expressed in microglia and are also found on neurons and astrocytes, functioning mainly in the regulation of proinflammatory cytokine production. TLRs are always found to be associated or involved in the induction of neuroinflammation in neurodegenerative diseases. Activation of toll-like receptor 4 (TLR4) through TLR4 agonist, lipopolysaccharide (LPS), stimulation initiate a signaling cascade whereby the TLR4-LPS interaction has been found to result in physiological and behavioural changes including retardation of motor activity in the mouse model. TLR4 inhibitor TAK-242 was reflected in the reduction of the spinal cord pathology along with the motor improvement in ALS mouse. There is cross talk with neuroinflammation and neurochemicals. For example, TLR4 activation by LPS is noted to release proinflammatory cytokines, IL-1β, from microglia that subsequently suppresses GABA receptor activities at the postsynaptic site and reduces GABA synthesis at the presynaptic site. Glial glutamate transporter activities are also found to be suppressed, showing the association between TLR4 activation and the related neurotransmitters and corresponding receptors and transporters in the event of neuroinflammation. This review is helpful to understand the connection between neurotransmitter and neuroinflammation in striatum- and cerebellum-mediated motor behaviour. [ABSTRACT FROM AUTHOR]

It is well established clinically that rhythmic auditory cues can improve gait and other motor behaviors in Parkinson's disease (PD) and other disorders. However, the neural systems underlying this therapeutic effect are largely unknown. To investigate this question we scanned people with PD and age‐matched healthy controls using functional magnetic resonance imaging (fMRI). All subjects performed a rhythmic motor behavior (right hand finger tapping) with and without simultaneous auditory rhythmic cues at two different speeds (1 and 4 Hz). We used spatial independent component analysis (ICA) and regression to identify task‐related functional connectivity networks and assessed differences between groups in intra‐ and inter‐network connectivity. Overall, the control group showed greater intra‐network connectivity in perceptual and motor related networks during motor tapping both with and without rhythmic cues. The PD group showed greater inter‐network connectivity between the auditory network and the executive control network, and between the executive control network and the motor/cerebellar network associated with the motor task performance. We interpret our results as indicating that the temporal rhythmic auditory information may assist compensatory mechanisms through network‐level effects, reflected in increased interaction between auditory and executive networks that in turn modulate activity in cortico‐cerebellar networks. Greater inter‐network correlations during motor tapping in a Rhythmic Auditory Stimulation paradigm in subjects with Parkinson's disease compared with controls. [ABSTRACT FROM AUTHOR]

The basal ganglia (BG) are involved in motivation and goal‐directed behavior. Recent studies suggest that limbic territories of BG not only support reward seeking (appetitive approach) but also the encoding of aversive conditioned stimuli (CS) and the production of aversive‐related behaviors (avoidance or escape). This study aimed to identify inside two BG nuclei, the striatum and pallidum, the territories involved in aversive behaviors and to compare the effects of stimulating these territories to those resulting from stimulation of the anterior Insula (aIns), a region that is well‐known to be involved in aversive encoding and associated behaviors. Two monkeys performed an approach/avoidance task in which they had to choose a behavior (approach or avoidance) in an appetitive (reward) or aversive (air‐puff) context. During this task, either one (single‐cue) or two (dual‐cue) CS provided essential information about which context‐adapted behavior should be selected. Microstimulation was applied during the CS presentation. Stimulation generally reduced approaches in the appetitive contexts and increased escape behaviors (premature responses) and/or passive avoidance (noninitiated action) in aversive context. These effects were more pronounced in ventral parts of all examined structures, with significant differences observed between stimulated structures. Thresholds to induce effects were lowest in the pallidum. Striatal stimulation led to the largest diversity of effects, with a subregion even leading to enhanced active avoidance. Finally, aIns stimulations produced stronger effects in the dual‐cue context. These results provide causal evidence that limbic territories of BG, like aIns, play crucial roles in the selection of context‐motivated behaviors. Microstimulation was applied in basal ganglia and anterior Insula of monkeys performing an approach‐avoidance task. Stimulation of ventral parts of all structures reduced approach behavior and increased aversive behavior. The pallidum was the most effective site for inducing aversive behavior and the ventral striatum the only site improving avoidance. This provides causal evidence that BG limbic territories and aIns play crucial roles in both aversive and appetitive behavior. [ABSTRACT FROM AUTHOR]

Although the nucleus of the vertical limb of the diagonal band of Broca (nvlDBB) is the second largest cholinergic nucleus in the basal forebrain, after the nucleus basalis of Meynert, it has not generally been a focus for studies of neurodegenerative disorders. However, the nvlDBB has an important projection to the hippocampus and discrete lesions of the rostral basal forebrain have been shown to disrupt retrieval memory function, a major deficit seen in patients with Lewy body disorders. One reason for its neglect is that the anatomical boundaries of the nvlDBB are ill defined and this area of the brain is not part of routine diagnostic sampling protocols. We have reviewed the history and anatomy of the nvlDBB and now propose guidelines for distinguishing nvlDBB from other neighbouring cholinergic cell groups for standardizing future clinicopathological work. Thorough review of the literature regarding neurodegenerative conditions reveals inconsistent results in terms of cholinergic neuronal loss within the nvlDBB. This is likely to be due to the use of variable neuronal inclusion criteria and omission of cholinergic immunohistochemical markers. Extrapolating from those studies showing a significant nvlDBB neuronal loss in Lewy body dementia, we propose an anatomical and functional connection between the cholinergic component of the nvlDBB (Ch2) and the CA2 subfield in the hippocampus which may be especially vulnerable in Lewy body disorders. [ABSTRACT FROM AUTHOR]

Objective: The basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome-wide association study (GWAS) to identify genetic determinants of PSP phenotype.Methods: Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non-RS groups. We carried out separate logistic regression GWASs to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS = 367, non-RS = 130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/coexpression patterns of our identified genes and used our data to carry out gene-based association testing.Results: Our lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome-wide significance in our whole cohort analysis (odds ratio = 5.5, 95% confidence interval = 3.2-10.0, p = 1.7 × 10-9 ). rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene-based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia.Interpretation: Our study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease-modifying therapies. Ann Neurol 2018;84:485-496. [ABSTRACT FROM AUTHOR]

Subthalamic nucleus ( STN) deep brain stimulation ( DBS) has recently advanced our understanding of the major role played by this basal ganglion in human emotion. Research indicates that STN DBS can induce modifications in all components of emotion, and neuroimaging studies have shown that the metabolic modifications correlated with these emotional disturbances following surgery are both task- and sensory input-dependent. Nevertheless, to date, these modifications have not been confirmed for all emotional components, notably subjective emotional experience, or feelings. To identify the neural network underlying the modification of feelings following STN DBS, we assessed 16 patients with Parkinson's disease before and after surgery, using both subjective assessments of emotional experience and 18[ F]fluorodeoxyglucose positron emission tomography (18 FDG- PET). The patients viewed six film excerpts intended to elicit happy, angry, fearful, sad, disgusted, and neutral feelings, and they self-rated the intensity of these feelings. After DBS, there was a significant reduction in the intensity of the disgust feeling. Correlations were observed between decreased disgust experience and cerebral glucose metabolism ( FDG uptake) in the bilateral pre-frontal cortices (orbitofrontal, dorsolateral, and inferior frontal gyri), bilateral insula, and right cerebellum. We suggest that the STN contributes to the synchronization process underlying the emergence of feelings. [ABSTRACT FROM AUTHOR]

Background and Objectives: To study selective regional binding for tau pathology in vivo, using PET with [11 C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy.Methods: Dynamic PET scans were obtained for 70 minutes after the bolus injection of [11 C]PBB3 in 5 PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype, 3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 6 healthy controls of similar age. Tissue reference Logan analysis was applied to each region of interest using a cerebellar white matter reference region.Results: In comparison to the control group, PSP subjects showed specific uptake of [11 C]PBB3 in putamen, midbrain, GP, and SN. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. A DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and GP. In SNCA duplication carriers, there was a significant increase of [11 C] PBB3 binding in GP, putamen, thalamus, ventral striatum, SN, and pedunculopontine nucleus. The MSA case showed increased binding in frontal lobe, GP, midbrain, parietal lobe, putamen, temporal lobe, SN, thalamus, and ventral striatum.Conclusions: All PSP patients showed increased retention of the tracer in the basal ganglia, as expected. Binding was also present in asymptomatic SNCA duplication carriers and in an MSA case, which are not typically associated with pathological tau deposition. This suggests the possibility that [11 C]PBB3 binds to alpha-synuclein. © 2017 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

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

The subthalamic nucleus (STN) and globus pallidus internus (GPi) have recently been shown to encode reward, but few studies have been performed in humans. We investigated STN and GPi encoding of reward and loss (i.e., valence) in humans with Parkinson's disease. To test the hypothesis that STN and GPi neurons would change their firing rate in response to reward- and loss-related stimuli, we recorded the activity of individual neurons while participants performed a behavioral task. In the task, action choices were associated with potential rewarding, punitive, or neutral outcomes. We found that STN and GPi neurons encode valence-related information during action control, but the proportion of valence-responsive neurons was greater in the STN compared to the GPi. In the STN, reward-related stimuli mobilized a greater proportion of neurons than loss-related stimuli. We also found surprising limbic overlap with the sensorimotor regions in both the STN and GPi, and this overlap was greater than has been previously reported. These findings may help to explain alterations in limbic function that have been observed following deep brain stimulation therapy of the STN and GPi. Hum Brain Mapp 38:1952-1964, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The basal ganglia are key structures for motor, cognitive and behavioral functions. They undergo several changes with aging and disease, such as Parkinson's or Huntington's disease, for example. Iron accumulation in basal ganglia is often related to these diseases, which is conventionally monitored by the transverse relaxation rate ( R2*). Quantitative susceptibility mapping (QSM) is a novel contrast mechanism in MRI produced by adding information taken from the phase of the MR signal to its magnitude. It has been shown to be more sensitive to subtle changes in Parkinson's disease. In order to be applied widely to various pathologies, its reproducibility must be evaluated in order to assess intra-subject variability and to disseminate into clinical and pharmaceutical studies. In this work, we studied the reproducibility and sensitivity of several QSM techniques. Fourteen subjects were scanned four times, and QSM and R2* images were reconstructed and registered. An atlas of the basal ganglia was used to automatically define regions of interest. We found that QSM measurements are indeed reproducible in the basal ganglia of healthy subjects and can be widely used as a replacement for R2* mapping in iron-rich regions. This reproducibility study could lead to several lines of research in relaxometry and susceptibility measurements, in vivo iron load evaluation as well as pharmacological assessment and biomarker development. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work-up of PSP.Methods: Regional tau accumulation was studied using 18 F-AV-1451 PET in 11 patients with PSP and 11 age-matched healthy controls in the Swedish BioFinder study.Results: 18 F-AV-1451 standard uptake volume ratios were significantly higher in the basal ganglia in PSP patients when compared with controls (globus pallidus 1.75 vs 1.50; putamen 1.51 vs 1.35). Retention in the basal ganglia was correlated with age in both groups (r = .43-.78, P < .05). In PSP, we observed a significant correlation between clinical deterioration measured with the PSP rating scale and standard uptake volume ratios in the globus pallidus (r = .74, P < .05). However, no 18 F-AV-1451 retention was observed in the cerebral cortex or white matter of either PSP patients or controls, and autoradiography did not reveal any specific binding of AV-1451 to PSP tau aggregates.Conclusion: We found higher 18 F-AV-1451 retention in the basal ganglia of PSP patients when compared with healthy elderly controls, but also increases with age in both controls and patients. As a result of the overlap in retention between diagnostic groups and the age-dependent increase present also in controls, 18 F-AV-1451 PET might not reliably distinguish individual patients with PSP from controls. However, further studies are needed to evaluate whether 18 F-AV-1451 PET might be useful as a progression marker in clinical PSP trials. © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Accumulation of cortical and subcortical tau pathology is the primary pathological substrate for progressive supranuclear palsy (PSP). 18 F-AV-1451, a radiotracer that binds to the pathological tau protein, may be helpful for in vivo visualization and quantitation of tau pathology in PSP.Objectives: The objectives of this study were to investigate cortical and subcortical 18 F-AV-1451 binding patterns in patients with PSP.Methods: We recruited 14 PSP patients and compared their cortical and subcortical binding patterns in 18 F-AV-1451 positron emission tomography (PET) studies with those of 15 Parkinson's disease (PD) patients and 15 healthy controls.Results: In both the PD and PSP groups, subcortical 18 F-AV-1451 binding did not correlate with the severity of motor dysfunctions, and cortical binding did not differ between the controls and each patient group. However, the PSP patients showed greater 18 F-AV-1451 binding in the putamen, globus pallidus, subthalamic nucleus, and dentate nucleus when compared with the controls, whereas the PD patients showed lower 18 F-AV-1451 binding in the substantia nigra than controls.Conclusions: The PSP and PD patients showed distinct subcortical 18 F-AV-1451 binding patterns reflecting subcortical tau pathology in PSP and reduced nigral neuromelanin in PD. However, there was no correlation with the severity of motor dysfunction, no cortical regions with increased binding in PSP patients, and variable degrees of subcortical binding even in the controls. Therefore, the 18 F-AV-1451 PET may be less than ideal for assessing tau pathology in PSP. Further studies will be required to validate the clinical correlation and to understand the clinical utility of 18 F-AV-1451 PET for PSP patients. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Subcortical functions for language capacities are poorly defined, but may be investigated in the context of deep brain stimulation. Here, we studied event-related potentials recorded from electrodes in the subthalamic nucleus (STN) and the thalamic ventral intermediate nucleus (VIM) together with surface-EEG. Participants completed a lexical decision task (LDT), which required the differentiation of acoustically presented words from pseudo-words by button press. Target stimuli were preceded by prime-words. In recordings from VIM, a slow potential shift apparent at the lower electrode contacts persisted during target stimulus presentation (equally for words and pseudo-words). In contrast, recordings from STN electrodes showed a short local activation on prime-words but not target-stimuli. In both depth-recording regions, further components related to contralateral motor responses to target words were evident. On scalp level, mid-central activations on (pseudo)lexical stimuli were obtained, in line with the expression of N400 potentials. The prolonged activity recorded from VIM, exclusively accompanying the relevant LDT phase, is in line with the idea of thalamic 'selective engagement' for supporting the realization of the behavioral focus demanded by the task. In contrast, the phasic prime related activity rather indicates 'procedural' STN functions, for example, for trial sequencing or readiness inhibition of prepared target reactions. Hum Brain Mapp 38:370-383, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a neurodegenerative disorder characterized by changes to dopaminergic function in the striatum and a range of cognitive and motor deficits. Neuroimaging studies have repeatedly shown differences in activation and functional connectivity patterns of the striatum between symptomatic individuals with Parkinson's disease and healthy controls. However, the presence and severity of cognitive and motor symptoms seem to differ dramatically among individuals with Parkinson's disease at the early-stages. To investigate the neural basis of such heterogeneity, we examined the resting state functional connectivity patterns of caudate and putamen subdivisions in relation to cognitive and motor impairments among 62 early-stage individuals with Parkinson's disease (21 females, 23 drug naive, ages 39-77 years, average UPDRS motor scores off medication = 18.56, average H&Y stage = 1.66). We also explored how changes in striatal connectivity relate to changes in symptomatology over a year. There are two main findings. First, higher motor deficit rating was associated with weaker coupling between anterior putamen and midbrain including substantia nigra. Intriguingly, steeper declines in functional connectivity between these regions were associated with greater declines in motor function over the course of 1 year. Second, decline in cognitive function, particularly in the memory and visuospatial domains, was associated with stronger coupling between the dorsal caudate and the rostral anterior cingulate cortex. These findings remained significant after controlling for age, medication, gender, and education. In sum, our findings suggest that cognitive decline and motor deficit are each associated with a differentiable pattern of functional connectivity of striatal subregions. Hum Brain Mapp 37:648-662, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The ventral premotor cortex ( PMv), occupying the ventral aspect of area 6 in the frontal lobe, has been implicated in action planning and execution based on visual signals. Although the PMv has been characterized by cortico-cortical connections with specific subregions of the parietal and prefrontal cortical areas, a topographical input/output organization between the PMv and the basal ganglia ( BG) still remains elusive. In the present study, retrograde transneuronal labelling with the rabies virus was employed to identify the origins of multisynaptic projections from the BG to the PMv. The virus was injected into the forelimb region of the PMv, identified in the ventral aspect of the genu of the arcuate sulcus, in macaque monkeys. The survival time after the virus injection was set to allow either the second- or third-order neuron labelling across two or three synapses. The second-order neurons were observed in the ventral portion (primary motor territory) and the caudodorsal portion (higher-order motor territory) of the internal segment of the globus pallidus. Subsequently, the third-order neurons were distributed in the putamen caudal to the anterior commissure, including both the primary and the higher-order motor territories, and in the ventral striatum (limbic territory). In addition, they were found in the dorsolateral portion (motor territory) and ventromedial portion (limbic territory) of the subthalamic nucleus, and in the external segment of the globus pallidus including both the limbic and motor territories. These findings indicate that the PMv receives diverse signals from the primary motor, higher-order motor and limbic territories of the BG. [ABSTRACT FROM AUTHOR]

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is recognized as an effective treatment for the motor symptoms of Parkinson's disease (PD), but its mechanisms, particularly as concern dopaminergic transmission, remain unclear. The aim of this study was to evaluate changes in the expression of dopaminergic receptors (D1, D2, and D3 receptors) after prolonged (4 h) unilateral STN-HFS in anesthetized intact rats and rats with total dopaminergic denervation. We used [(3)H]SCH 23390, [(125)I]iodosulpride, and [(125)I]OH-PIPAT to assess the densities of D1R, D2R, and D3R, respectively, within different areas of the striatum-a major input structure of the basal ganglia-including the nucleus accumbens. We found that STN-HFS increased D1 R levels in almost all of the striatal areas examined, in both intact and denervated rats. By contrast, STN-HFS led to a large decrease in D2 R and D3R levels, limited to the nucleus accumbens and independent of the dopaminergic state of the animals. These data suggest that the influence of STN-HFS on striatal D1 R expression may contribute to its therapeutic effects on motor symptoms, whereas its impact on D2R/D3 R levels in the nucleus accumbens may account for the neuropsychiatric side effects often observed in stimulated PD patients, such as postoperative apathy. [ABSTRACT FROM AUTHOR]

Awareness of its rich structural pathways has earned the external segment of the globus pallidus (GPe) recognition as a central figure within the basal ganglia circuitry. Interestingly, GPe neurons are uniquely identified by the presence of prominent pauses interspersed among a high-frequency discharge rate of 50-80 spikes/s. These pauses have an average pause duration of 620 ms with a frequency of 13/min, yielding an average pause activity (probability of a GPe neuron being in a pause) of (620 × 13)/(60 × 1000) = 0.13. Spontaneous pause activity has been found to be inversely related to arousal state. The relationship of pause activity with behavioural events remains to be elucidated. In the present study, we analysed the electrophysiological activity of 200 well-isolated GPe pauser cells recorded from four non-human primates ( Macaque fascicularis) while they were engaged in similar classical conditioning tasks. The isolation quality of the recorded activity and the pauses were determined with objective automatic methods. The results showed that the pause probability decreased by 9.09 and 10.0%, and the discharge rate increased by 2.96 and 1.95%, around cue and outcome presentation, respectively. Analysis of the linear relationship between the changes in pause activity and discharge rate showed r2 = 0.46 and r2 = 0.66 upon cue onset and outcome presentation, respectively. Thus, pause activity is a pertinent element in short-term encoding of relevant behavioural events, and has a significant, but not exclusive, role in the modulation of GPe discharge rate around these events. [ABSTRACT FROM AUTHOR]

Historically, Parkinson's disease (PD) was defined as a pure movement disorder. Currently, it is widely accepted that this disease is also characterized by nonmotor signs, such as depression, apathy, and anxiety. On the other hand, the consideration of Gilles de la Tourette syndrome (GTS) as a neuropsychiatric disorder has also been debated. In this review, we will focus on these two disorders, which combine both motor and behavioral features and in which dysfunction of cortical and subcortical regions was suggested. Anatomical, experimental, and clinical data are reported to support the involvement of basal ganglia (BG) in cognitive and motivational functions in addition to motor control. In PD, the nonmotor signs could result from the heterogeneity of dopaminergic lesions and excessive activation of the dopamine receptors, particularly within the limbic neuronal networks. Experimental results obtained on nonhuman primates using local disinhibition within functional territories of BG allowed the precise mapping of their motor and nonmotor functions. Thus, impairment of inhibitory control inside specific striatal territories induced behavioral disorders and abnormal movements, which had striking similarities to clinical expressions of GTS. Establishing such a relationship between BG subterritories and motor and behavioral disorders could potentially be helpful for future target choices for DBS in many neuropsychiatric disorders. Furthermore, it is also of great interest for therapeutic research and for the efficient targeting of symptom relief to determine the precise pharmacological effects of the two main modulators of BG function, which are dopamine and serotonin. [ABSTRACT FROM AUTHOR]

The subthalamic nucleus ( STN) has been argued to be an important component of reward-sensitive basal ganglia circuitry. This view is especially supported by the behavioral changes observed after STN inactivation, which could reflect impairments in the motivational control of action. However, it is still unclear how the STN integrates reward information and to what extent such integration correlates with behavior. In this study, the response properties of STN neurons in monkeys performing reaching movements with a cue predicting the identity of an upcoming liquid reward (juice or water) were investigated. Although the timing of movements reliably indicated that monkeys had greater motivation for juice than water, rarely did task-related changes in neuronal activity depend on the nature of the expected reward. Conversely, when presented with a choice of selecting a response that leads to juice or water delivery, animals showed a clear preference for juice and more than half of the neurons were differentially modulated dependent on the reward obtained, mostly after the monkeys's overt choice of action. Under such circumstances, an increase in activity specifically followed the action outcomes across the population of neurons when monkeys failed to choose the juice reward. These results indicate that STN neurons encode whether or not a preferred reward had been received when a choice between response alternatives is required. This differential neuronal activity might reflect the participation of the STN in evaluating the reward value of chosen actions, thus highlighting its contribution to decision-making processes. [ABSTRACT FROM AUTHOR]

Cervical dystonia is characterized by abnormal posturing of the head, often combined with tremor-like oscillatory head movements. The nature and source of these oscillatory head movements is controversial, so they were quantified to delineate their characteristics and develop a hypothetical model for their genesis. A magnetic search coil system was used to measure head movements in 14 subjects with cervical dystonia. Two distinct types of oscillatory head movements were detected for most subjects, even when they were not clinically evident. One type had a relatively large amplitude and jerky irregular pattern, and the other had smaller amplitude with a more regular and sinusoidal pattern. The kinematic properties of these two types of oscillatory head movements were distinct, although both were often combined in the same subject. Both had features suggestive of a defect in a central neural integrator. The combination of different types of oscillatory head movements in cervical dystonia helps to clarify some of the current debates regarding whether they should be considered as manifestations of dystonia or tremor and provides novel insights into their potential pathogenesis. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

While the research programs in early cognitive science and artificial intelligence aimed to articulate what cognition was in ideal terms, much research in contemporary computational neuroscience looks at how and why brains fail to function as they should ideally. This focus on impairment affects how we understand David Marr's hypothesized three levels of understanding. In this essay, we suggest some refinements to Marr's distinctions using a population activity model of cortico-striatal circuitry exploring impulsivity and behavioral inhibition as a case study. In particular, we urge that Marr's computational level should be redefined to include a description of how systems break down. We also underscore that feed-forward processing, cognition disconnected from behavioral context, and representations do not always drive cognition in the way that Marr originally assumed. [ABSTRACT FROM AUTHOR]

The brainstem and basal ganglia are important in the pathophysiology of Parkinson's disease (PD). Reliable and sensitive detection of neural activity changes in these regions should be helpful in scientific and clinical research on PD. In this study, we used resting state functional MRI and amplitude of low frequency fluctuation (ALFF) methods to examine spontaneous neural activity in 109 patients with PD. We examined activity in two frequency bands, slow-4 (between 0.027 and 0.073 Hz) and slow-5 (0.010-0.027 Hz). Patients had decreased ALFF in the striatum and increased ALFF in the midbrain, and changes were more significant in slow-4. Additionally, changes in slow-4 in both basal ganglia and midbrain correlated with the severity of the parkinsonism. The ALFF in the caudate nucleus positively correlated with the dose of levodopa, while the ALFF in the putamen negatively correlated with the disease duration in both slow-4 and slow-5 bands. In addition, the ALFF in the rostral supplementary motor area negatively correlated with bradykinesia subscale scores. Our findings show that with a large cohort of patients and distinguishing frequency bands, neural modulations in the brainstem and striatum in PD can be detected and may have clinical relevance. The physiological interpretation of these changes needs to be determined. Hum Brain Mapp 35:5815-5833, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by widespread neural interactions in cortico-basal-ganglia networks primarily in beta oscillations (approx. 10-30 Hz), as suggested by previous findings of levodopa-modulated interhemispheric coherence between the bilateral subthalamic nuclei (STN) in local field potential recordings (LFPs). However, due to confounding effects of volume conduction the existence of 'genuine' interhemispheric subcortical coherence remains an open question. To address this issue we utilized the imaginary part of coherency (iCOH) which, in contrast to the standard coherence, is not susceptible to volume conduction. LFPs were recorded from eight patients with PD during wakeful rest before and after levodopa administration. We demonstrated genuine coherence between the bilateral STN in both 10-20 and 21-30 Hz oscillations, as revealed by a non-zero iCOH. Crucially, increased iCOH in 10-20 Hz oscillations positively correlated with the worsening of motor symptoms in the OFF medication condition across patients, which was not the case for standard coherence. Furthermore, across patients iCOH was increased after levodopa administration in 21-30 Hz oscillations. These results suggest a functional distinction between low and high beta oscillations in STN-LFP in line with previous studies. Furthermore, the observed functional coupling between the bilateral STN might contribute to the understanding of bilateral effects of unilateral deep brain stimulation. In conclusion, the present results imply a significant contribution of time-delayed neural interactions to interhemispheric coherence, and the clinical relevance of long-distance neural interactions between bilateral STN for motor symptoms in PD. [ABSTRACT FROM AUTHOR]

Aims Since the first description of the classical presentation of progressive supranuclear palsy ( PSP) in 1963, now known as Richardson's syndrome ( PSP-RS), several distinct clinical syndromes have been associated with PSP-tau pathology. Like other neurodegenerative disorders, the severity and distribution of phosphorylated tau pathology are closely associated with the clinical heterogeneity of PSP variants. PSP with corticobasal syndrome presentation ( PSP-CBS) was reported to have more tau load in the mid-frontal and inferior-parietal cortices than in PSP-RS. However, it is uncertain if differences exist in the distribution of tau pathology in other brain regions or if the overall tau load is increased in the brains of PSP-CBS. Methods We sought to compare the clinical and pathological features of PSP-CBS and PSP-RS including quantitative assessment of tau load in 15 cortical, basal ganglia and cerebellar regions. Results In addition to the similar age of onset and disease duration, we demonstrated that the overall severity of tau pathology was the same between PSP-CBS and PSP-RS. We identified that there was a shift of tau burden towards the cortical regions away from the basal ganglia; supporting the notion that PSP-CBS is a 'cortical' PSP variant. PSP-CBS also had less severe neuronal loss in the dorsolateral and ventrolateral subregions of the substantia nigra and more severe microglial response in the corticospinal tract than in PSP-RS; however, neuronal loss in subthalamic nucleus was equally severe in both groups. Conclusions A better understanding of the factors that influence the selective pathological vulnerability in different PSP variants will provide further insights into the neurodegenerative process underlying tauopathies. [ABSTRACT FROM AUTHOR]

ABSTRACT Diffusion tensor imaging could be useful in characterizing movement disorders because it noninvasively examines multiple brain regions simultaneously. We report a multitarget imaging approach focused on the basal ganglia and cerebellum in Parkinson's disease, parkinsonian variant of multiple system atrophy, progressive supranuclear palsy, and essential tremor and in healthy controls. Seventy-two subjects were studied with a diffusion tensor imaging protocol at 3 Tesla. Receiver operating characteristic analysis was performed to directly compare groups. Sensitivity and specificity values were quantified for control versus movement disorder (92% sensitivity, 88% specificity), control versus parkinsonism (93% sensitivity, 91% specificity), Parkinson's disease versus atypical parkinsonism (90% sensitivity, 100% specificity), Parkinson's disease versus multiple system atrophy (94% sensitivity, 100% specificity), Parkinson's disease versus progressive supranuclear palsy (87% sensitivity, 100% specificity), multiple system atrophy versus progressive supranuclear palsy (90% sensitivity, 100% specificity), and Parkinson's disease versus essential tremor (92% sensitivity, 87% specificity). The brain targets varied for each comparison, but the substantia nigra, putamen, caudate, and middle cerebellar peduncle were the most frequently selected brain regions across classifications. These results indicate that using diffusion tensor imaging of the basal ganglia and cerebellum accurately classifies subjects diagnosed with Parkinson's disease, atypical parkinsonism, and essential tremor and clearly distinguishes them from control subjects. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Neuroanatomical studies using transneuronal virus tracers in macaque monkeys recently demonstrated that substantial interactions exist between basal ganglia and the cerebellum. To what extent these interactions are present in the human brain remains unclear; however, these connections are thought to provide an important framework for understanding cerebellar contributions to the manifestation of basal ganglia disorders, especially with respect to tremor genesis in movement disorders such as Parkinson's disease. Here, we tested the feasibility of assessing these connections in vivo and non-invasively in the human brain with diffusion magnetic resonance imaging and tractography. After developing a standardized protocol for manual segmentation of basal ganglia and cerebellar structures, masks for diffusion tractography were defined based on structural magnetic resonance images. We tested intra- and inter-observer stability and carried out tractography for dentato-pallidal and subthalamo-cerebellar projections. After robustly achieving connection probabilities per tract, the connectivity values and connectional fingerprints were calculated in a group of healthy volunteers. Probabilistic diffusion tractography was applicable to probe the inter-connection of the cerebellum and basal ganglia. Our data confirmed that dentato-thalamo-striato-pallidal and subthalamo-cerebellar connections also exist in the human brain at a level similar to those that were recently suggested by transneuronal tracing studies in non-human primates. Standardized segmentation protocols made these findings reproducible with high stability. We have demonstrated that diffusion tractography in humans in vivo is capable of revealing the structural bases of cerebellar networks with the basal ganglia. These findings support the role of the cerebellum as a satellite system of established cortico-basal ganglia networks in humans. [ABSTRACT FROM AUTHOR]

Visuomotor adaptation is often driven by error-based ( EB) learning in which signed errors update motor commands. There are, however, visuomotor tasks where signed errors are unavailable or cannot be mapped onto appropriate motor command changes, rendering EB learning ineffective; and yet, healthy subjects can learn in these EB learning-free conditions. While EB learning depends on cerebellar integrity, the neural bases of EB-independent learning are poorly understood. As basal ganglia are involved in learning mechanisms that are independent of signed error feedback, here we tested whether patients with basal ganglia lesions, including those with Huntington's disease and Parkinson's disease, would show impairments in a visuomotor learning task that prevents the use of EB learning. We employed two visuomotor throwing tasks that were similar, but were profoundly different in the resulting visual feedback. This difference was implemented through the introduction of either a lateral displacement of the visual field via a wedge prism ( EB learning) or a horizontal reversal of the visual field via a dove prism (non- EB learning). Our results show that patients with basal ganglia degeneration had normal EB learning in the wedge prism task, but were profoundly impaired in the reversing prism task that does not depend on the signed error signal feedback. These results represent the first evidence that human visuomotor learning in the absence of EB feedback depends on the integrity of the basal ganglia. [ABSTRACT FROM AUTHOR]

Motor stereotypy is a key symptom of various neurological or neuropsychiatric disorders. Neuroleptics or the promising treatment using deep brain stimulation stops stereotypies but the mechanisms underlying their actions are unclear. In rat, motor stereotypies are linked to an imbalance between prefrontal and sensorimotor cortico-basal ganglia circuits. Indeed, cortico-nigral transmission was reduced in the prefrontal but not sensorimotor basal ganglia circuits and dopamine and acetylcholine release was altered in the prefrontal but not sensorimotor territory of the dorsal striatum. Furthermore, cholinergic transmission in the prefrontal territory of the dorsal striatum plays a crucial role in the arrest of motor stereotypy. Here we found that, as previously observed for raclopride, high-frequency stimulation of the subthalamic nucleus (HFS STN) rapidly stopped cocaine-induced motor stereotypies in rat. Importantly, raclopride and HFS STN exerted a strong effect on cocaine-induced alterations in prefrontal basal ganglia circuits. Raclopride restored the cholinergic transmission in the prefrontal territory of the dorsal striatum and the cortico-nigral information transmissions in the prefrontal basal ganglia circuits. HFS STN also restored the N-methyl- d-aspartic-acid-evoked release of acetylcholine and dopamine in the prefrontal territory of the dorsal striatum. However, in contrast to raclopride, HFS STN did not restore the cortico-substantia nigra pars reticulata transmissions but exerted strong inhibitory and excitatory effects on neuronal activity in the prefrontal subdivision of the substantia nigra pars reticulata. Thus, both raclopride and HFS STN stop cocaine-induced motor stereotypy, but exert different effects on the related alterations in the prefrontal basal ganglia circuits. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2012) 122, 812-822. Abstract Neuronal protein α-synuclein (α-syn) is an essential player in the development of neurodegenerative diseases called synucleinopathies. A spontaneous autosomal recessive rat model for neurodegeneration was developed in our laboratory. These rats demonstrate progressive increases in α-syn in the brain mesencephalon followed by loss of dopaminergic terminals in the basal ganglia (BG) and motor impairments. The severity of pathology is directly related to the overexpression of α-syn and parallel decrease in dopamine (DA) level in the striatum (ST) of affected rats. The neurodegeneration in this model is characterized by the presence of perikarya and neurites Lewis bodies (LB) and diffuse marked accumulation of perikaryal α-syn in the substantia nigra (SN), brain stem (BS), and striatum (ST) along with neuronal loss. Light and ultrastructural analyses revealed that the process of neuronal degeneration is a 'dying back' type. The disease process is accompanied by gliosis and release of inflammatory cytokines. This neurodegeneration is a multisystemic disease and implicate α-syn as a major factor in the pathogenesis of this inherited autosomal recessive animal model. Decrease dopamine (DA) and overexpression of α-syn in the brain mesencephalon may provide a naturally occurring animal model for Parkinson's disease (PD) and other synucleinopathies that reproduces significant pathological, neurochemical, and behavioral features of the human disease. [ABSTRACT FROM AUTHOR]

The availability of suitable animal models and the opportunity to record electrophysiologic data in movement disorder patients undergoing neurosurgical procedures has allowed researchers to investigate parkinsonism-related changes in neuronal firing patterns in the basal ganglia and associated areas of the thalamus and cortex. These studies have shown that parkinsonism is associated with increased activity in the basal ganglia output nuclei, along with increases in burst discharges, oscillatory firing and synchronous firing patterns throughout the basal ganglia. Computational approaches have the potential to play an important role in the interpretation of these data. Such efforts can provide a formalized view of neuronal interactions in the network of connections between the basal ganglia, thalamus, and cortex, allow for the exploration of possible contributions of particular network components to parkinsonism, and potentially result in new conceptual frameworks and hypotheses that can be subjected to biological testing. It has proven very difficult, however, to integrate the wealth of the experimental findings into coherent models of the disease. In this review, we provide an overview of the abnormalities in neuronal activity that have been associated with parkinsonism. Subsequently, we discuss some particular efforts to model the pathophysiologic mechanisms that may link abnormal basal ganglia activity to the cardinal parkinsonian motor signs and may help to explain the mechanisms underlying the therapeutic efficacy of deep brain stimulation for Parkinson's disease. We emphasize the logical structure of these computational studies, making clear the assumptions from which they proceed and the consequences and predictions that follow from these assumptions. [ABSTRACT FROM AUTHOR]

Summary Purpose: Patients with juvenile myoclonic epilepsy (JME) show evidence of microstructural white matter (WM) damage of thalamocortical fiber tracts and changes of blood oxygen level dependent (BOLD) signal in a striatothalamocortical network. The objective of the present study was to investigate microstructural and volumetric alterations of the putamen in patients with JME using diffusion tensor imaging (DTI) and conventional magnetic resonance imaging (MRI). Methods: We performed DTI and MRI for 10 patients with JME and 59 age-matched neurologically healthy volunteers. Evaluation of microstructural damage was investigated using calculation of mean fractional anisotropy (FA) values in a priori regions of interest (ROIs) for the putamen, frontal lobe, and a thalamocortical region, after application of an improved eddy current correction method and a new statistical parametric mapping (SPM)-compatible toolbox incorporating intensive multicontrast FA image registration. Stereologic analysis on MRI was performed to estimate macroscopic volume of the putamen in both cerebral hemispheres for all subjects. Key Findings: Relative to controls, patients had significantly reduced FA in the frontal lobe (p = 0.01) and thalamocortical fiber WM (p < 0.001). In contrast, putamen FA was bilaterally increased (p = 0.01) and correlated with decreasing putamen volume (r2 = −0.63, p = 0.004) in patients only. Putamen FA correlated negatively with onset of JME (total: r2 = −0.50, p = 0.01), duration of JME (r2 = 0.52, p = 0.01), and thalamocortical fiber FA (r2 = −0.47, p = 0.01). Significance: This is the first evidence of combined microstructural and macrostructural putamen abnormalities in patients with JME, with early age of onset and a longer duration of epilepsy being significant predictors for greater architectural alterations. These findings are consistent with studies indicating neurophysiologic abnormalities of frontostriatal networks in patients with JME, and may contribute to explain the frequent presentation of executive dysfunction in these patients. Confirmation and further exploration of the increase in putamen FA in patients with JME is required in larger samples. [ABSTRACT FROM AUTHOR]

Most of the human behaviors are executed automatically under familiar circumstances. These behaviors are prepotent in that they take precedence over any other potential alternatives. Yet, humans are also capable of engaging cognitive resources to inhibit such a prepotent behavior and replace it with an alternative controlled behavior in response to an unforeseen situation. This remarkable capability to switch behaviors in a short period of time is the hallmark of executive functions. In this article, we first argue that the prepotent automaticity could emerge at least in three different domains - innate, habitual and motivational. We then review neurophysiological findings on how the brain might realize its switching functions in each domain, primarily by focusing on the monkey oculomotor system as the experimental model. Emerging evidence now suggests that multiple neuronal populations in the shared cortico-basal ganglia network contribute to overriding prepotent eye movement, be its origin innate, habitual or motivational. This consideration suggests the general versatility of the cortico-basal ganglia network as the neural mechanism whereby humans and other animals keep themselves from becoming subservient to reflex, habit and motivational impulses. [ABSTRACT FROM AUTHOR]

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

Abstract: Restricted repetitive behaviors (stereotypy, compulsions, rituals) are diagnostic for autism spectrum disorder and common in related neurodevelopmental disorders. Despite their prevalence in clinical populations, underlying mechanisms associated with the development of these behaviors remain poorly understood. We examined the role of the indirect basal ganglia pathway in the development of stereotypy using deer mice. We measured neuronal metabolic activity in the subthalamic nucleus (STN) and other relevant brain regions using cytochrome oxidase (CO) histochemistry at three developmental time-points. Although no differences were observed in STN across development, significant differences were found when mice were grouped by developmental trajectory. At 6 weeks post-weaning, significantly lower CO activity in STN was found in those trajectory groups that developed high levels of repetitive behavior versus the trajectory group that did not, suggesting the development of stereotypy is associated with decreased indirect basal ganglia pathway activity. In addition, we tested the hypothesis that preferential activation of striatal striosomes relative to surrounding matrix would be associated with the development of stereotypy. No differences in the relative activation of these striatal compartments were observed across development or among trajectory groups. Our results point to dynamic changes in the indirect pathway associated with the development of repetitive behavior and extends our prior work linking reduced indirect pathway activation to stereotypy in adult deer mice. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

We examined the organization of multisynaptic projections from the basal ganglia (BG) to the dorsal premotor area in macaques. After injection of the rabies virus into the rostral sector of the caudal aspect of the dorsal premotor area (F2r) and the caudal sector of the caudal aspect of the dorsal premotor area (F2c), second-order neuron labeling occurred in the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). Labeled GPi neurons were found in the caudoventral portion after F2c injection, and in the dorsal portion at the rostrocaudal middle level after F2r injection. In the SNr, F2c and F2r injections led to labeling in the caudal or rostral part, respectively. Subsequently, third-order neuron labeling was observed in the external segment of the globus pallidus (GPe), the subthalamic nucleus (STN), and the striatum. After F2c injection, labeled neurons were observed over a broad territory in the GPe, whereas after F2r injection, labeled neurons tended to be restricted to the rostral and dorsal portions. In the STN, F2c injection resulted in extensive labeling over the nucleus, whereas F2r injection resulted in labeling in the ventral portion only. After both F2r and F2c injections, labeled neurons in the striatum were widely observed in the striatal cell bridge region and neighboring areas, as well as in the ventral striatum. The present results revealed that the origins of multisynaptic projections to F2c and F2r in the BG are segregated in the output stations of the BG, whereas intermingling rather than segregation is evident with respect to their input station. [ABSTRACT FROM AUTHOR]