Single gene,two diseases,and multiple clinical presentations: Biotin–thiamine-responsive basal ganglia disease

AimTo present seven new genetically confirmed cases of biotin–thiamin-responsive basal ganglia disease (BTBGD) with different clinical and brain magnetic resonance imaging (MRI) characteristics.Material and methodsGenetic variants, clinical presentations, brain MRI findings, treatment response, and prognosis of seven selected patients with BTBGD, diagnosed with SLC19A3 mutations were described.ResultsAmong seven patients diagnosed with BTBGD, two had early infantile form, four had classic childhood form, and one was asymptomatic. Four different homozygous variants were found in the SLC19A3. Two patients with early infantile form presented with encephalopathy, dystonia, and refractory seizure in the neonatal period and have different variants. Their MRI findings were similar and pathognomonic for the early infantile form. Three siblings had same variants: one presented seizure and encephalopathy at the age of 4 months, one presented seizure at 14 years, and another was asymptomatic at 20 years. Only one of them had normal MRI findings, and the others MRI findings were similar and suggestive of the classic form. Other two siblings; one of them presented with developmental delay, seizure, and dystonia at 18 months and the other presented with subacute encephalopathy and ataxia at 20 months. Their MRI findings were also similar and suggestive of the classic form.ConclusionBTBGD may present with dissimilar clinical characteristics or remain asymptomatic for a long time period even in a family or patients with same variants. Brain MRI patterns may be important for the early diagnosis of BTBGD that would save children’s lives.     

What are the computations of the cerebellum,the basal ganglia and the cerebral cortex?

The classical notion that the cerebellum and the basal ganglia are dedicated to motor control is under dispute given increasing evidence of their involvement in non-motor functions. Is it then impossible to characterize the functions of the cerebellum, the basal ganglia and the cerebral cortex in a simplistic manner? This paper presents a novel view that their computational roles can be characterized not by asking what are the “goals” of their computation, such as motor or sensory, but by asking what are the “methods” of their computation, specifically, their learning algorithms. There is currently enough anatomical, physiological, and theoretical evidence to support the hypotheses that the cerebellum is a specialized organism for supervised learning, the basal ganglia are for reinforcement learning, and the cerebral cortex is for unsupervised learning.This paper investigates how the learning modules specialized for these three kinds of learning can be assembled into goal-oriented behaving systems. In general, supervised learning modules in the cerebellum can be utilized as “internal models” of the environment. Reinforcement learning modules in the basal ganglia enable action selection by an “evaluation” of environmental states. Unsupervised learning modules in the cerebral cortex can provide statistically efficient representation of the states of the environment and the behaving system. Two basic action selection architectures are shown, namely, reactive action selection and predictive action selection. They can be implemented within the anatomical constraint of the network linking these structures. Furthermore, the use of the cerebellar supervised learning modules for state estimation, behavioral simulation, and encapsulation of learned skill is considered. Finally, the usefulness of such theoretical frameworks in interpreting brain imaging data is demonstrated in the paradigm of procedural learning.     

Mental retardation,spasticity, basal ganglia calcification,cerebral white matter lesions,multiple endocrine defects,telangiectasia and atrophic skin: A new syndrome?

We report on an 8-year-old boy with mental retardation and spastic tetraparesis associated with atrophic skin on the face and extremities, telangiectasia, and severe dental caries. Basal ganglia calcification and multiple lesions in the subcortical white matter have been present since infancy. The patient has complications of liver dysfunction, multiple endocrine defects, and elevation of blood/cerebrospinal fluid lactate. Extensive laboratory examinations, including skin and muscle biopsies, and UV- and mitomycin C-sensitivity tests on fibroblasts, provided no evidence of a specific disease entity. No deterioration was noted, and supplementation of riboflavin and other vitamins had no apparent effect on the neurodevelopmental status of this patient. This patient may represent a novel disease entity, with unclear pathogenesis.     

How do the basal ganglia contribute to categorization? Their roles in generalization, response selection, and learning via feedback

This article examines how independent corticostriatal loops linking basal ganglia with cerebral cortex contribute to visual categorization. The first aspect of categorization discussed is the role of the visual corticostriatal loop, which connects the visual cortex and the body/tail of the caudate, in mapping visual stimuli to categories, including evaluating the degree to which this loop may generalize across individual category members. The second aspect of categorization discussed is the selection of appropriate actions or behaviors on the basis of category membership, and the role of the visual corticostriatal loop output and the motor corticostriatal loop, which connects motor planning areas with the putamen, in action selection. The third aspect of categorization discussed is how categories are learned with the aid of feedback linked dopaminergic projections to the basal ganglia. These projections underlie corticostriatal synaptic plasticity across the basal ganglia, and also serve as input to the executive and motivational corticostriatal loops that play a role in strategic use of feedback.     

Is Broca's area part of a basal ganglia thalamocortical circuit?

The cortex constituting Broca's area does not exist in isolation. Rather, like other cortical regions, Broca's area is connected to other brain structures, which likely play closely related functional roles. This paper focuses on the basal ganglia, a set of subcortical structures that project through topographically organized "channels" via the thalamus to different frontal regions. It is hypothesized that the basal ganglia project to Broca's area. This circuitry is further posited to encompass at least two channels. One channel can be characterized as subserving procedural memory, while the other underlies the retrieval of knowledge from declarative memory. These hypotheses are supported by both anatomical and functional evidence. Implications and issues for further investigation are discussed.     

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

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

Characteristics of basal ganglia aphasia after stroke and the rehabilitative interventions

OBJECTIVE: To introduce the characteristics of basal ganglia aphasia after stroke and the rehabilitative interventions. DATA SOURCES: Articles related to stroke, subcortical aphasia, basal ganglia aphasia and language rehabilitation published in Chinese from January 1988 to December 2005 were searched in Chinese journal full-text database (CJFD) using the Keywords of "stroke, basal ganglia aphasia, language rehabilitation" in Chinese. Meanwhile, English articles about aphasia published from January 1982 to December 2005 were searched in and Pubmed database. Besides, several books associated with the contents were looked through manually. STUDY SELECTION: The data were checked primarily, the articles about the pathomechanism and neurolinguistic characteristics of basal ganglia aphasia, diagnostic methods of aphasia and language rehabilitation were selected, and those had no obvious relation with the above contents were excluded. Inclusive criteria: literatures explain the clinical characteristics of basal ganglia aphasia, neurolinguistic pathogenesis and methods of rehabilitation therapy in details. The repetitive studies were excluded. DATA EXTRACTION: Totally 95 literatures about basal ganglia aphasia were collected, including 31 about the clinical characteristics of basal ganglia aphasia, 45 about its neurolinguistic pathogenesis, 5 about the evaluation and classification of aphasia, and 14 about its rehabilitation therapy. Thirty accorded with the inclusive criteria were used for review, and the other 65 were excluded. DATA SYNTHESIS: Concisely introduced the definition, past investigation of basal ganglia aphasia after stroke, then dwelled on the multiplicity neurolinguistics characteristics. Aphasia evaluation was dependent upon clinical aphasic symptoms. The relationship between symptom and focus of infection was explored, and the mechanism of pathosis language behavior on basal ganglia aphasia patients was understood to provide consequence data that could authenticate the processing of language in brain. On the other hand, the method of rehabilitation on basal ganglia aphasia after stroke was explained. CONCLUSION: Basal ganglia aphasia is manifested as atypical aphasic symptom, the mechanism for the structure of basal ganglia in the speech formation should be further confirmed. It is effective to select pertinent language rehabilitation for basal ganglia aphasia after stroke.     

The habenula as an evolutionary conserved link between basal ganglia,limbic, and sensory systems—A phylogenetic comparison based on anuran amphibians

Based on anatomical and functional data, the habenula—a phylogenetically old brain structure present in all vertebrates—takes part in the integration of limbic, sensory, and basal ganglia information to guide effective response strategies appropriate to environmental conditions. In the present study, we investigated the connections of the habenular nuclei of the oriental fire-bellied toad, Bombina orientalis, and compared them with published data from lampreys, chondrichthyes, teleosts, reptiles, birds, and mammals. During phylogenetic development, the primordial habenula circuitry underwent various evolutionary adaptations and in the tetrapod line, the circuit complexity increased. The habenula circuitry of anuran amphibians, decedents of the first land-living tetrapods, seem to exhibit a mix of ancient as well as modern features. The anuran medial and lateral habenula homologs receive differential input from the septum, nucleus of the diagonal band of Broca, preoptic area, hypothalamus, rostral pallium, nucleus accumbens, ventral pallidum, and bed nucleus of the stria terminalis. Additional input arises from a border region in the ventral prethalamus, here discussed as a putative homolog of the entopeduncular nucleus of rodents. The habenular subnuclei also differentially innervate the interpeduncular nucleus, raphe nuclei, substantia nigra pars compacta and ventral tegmental area homologs, superficial mamillary area, laterodorsal tegmental nucleus, locus coeruleus, inferior and superior colliculus homologs, hypothalamus, preoptic area, septum, nucleus of the diagonal band of Broca, and main olfactory bulb. It seems likely that the main connectivity between the habenula and the basal ganglia, limbic, and sensory systems was already present in the common tetrapod ancestor.     

Basal ganglia network by constrained spherical deconvolution: A possible cortico-pallidal pathway?

In the recent past, basal ganglia circuitry was simplified as represented by the direct and indirect pathways and by hyperdirect pathways. Based on data from animal studies, we hypothesized a fourth pathway, the cortico-pallidal, pathway, that complements the hyperdirect pathway to the subthalamus. Ten normal brains were analyzed by using the high angular resolution diffusion imaging—constrained spherical deconvolution (CSD)-based technique. The study was performed with a 3T magnetic resonance imaging (MRI) scanner (Achieva, Philips Healthcare, Best, Netherlands); by using a 32-channel SENSE head coil. We showed that CSD is a powerful technique that allows a fine evaluation of both the long and small tracts between cortex and basal ganglia, including direct, indirect, and hyperdirect pathways. In addition, a pathway directly connecting the cortex to the globus pallidus was seen. Our results confirm that the CSD tractography is a valuable technique allowing a reliable reconstruction of small- and long-fiber pathways in brain regions with multiple fiber orientations, such as basal ganglia. This could open a future scenario in which CSD could be used to focally target with deep brain stimulation (DBS) the small bundles within the basal ganglia loops. © 2014 International Parkinson and Movement Disorder Society     

A selective role for right insula—basal ganglia circuits in appetitive stimulus processing

Hemispheric lateralization of hedonic evaluation (‘liking’) and incentive motivation (‘wanting’) in neural networks connecting the basal ganglia and insula (BG-I) in humans was examined. Participants with brain damage restricted to the BG-I of the right (n = 5) or left (n = 5) hemisphere, and 26 healthy participants matched on age, sex and intelligence quotient were tested on positively and negatively valenced pictures drawn from varied stimulus categories (Vijayaraghavan et al., 2008). Liking was assessed with explicit ratings of pleasantness using a nine-point Likert scale. Wanting was quantified as the amount of work (via repeated keypresses) that participants expended to increase (approach) or decrease (withdraw) viewing time. Right-lesion patients showed abnormally low viewing times and liking ratings for positive images. For a subset of positive images depicting sexual content, right-lesion patients exhibited active withdrawal, while the other two groups approached such stimuli. These results suggest that the right basal ganglia–insula complex plays a greater role than the left in supporting hedonic evaluation and motivational approach to positively valenced stimuli. The finding that active avoidance of stimuli that were not ‘liked’ was spared in both right- and left-sided lesion subjects suggests that unilateral damage to insula/basal ganglia circuits may not be sufficient to affect general incentive motivation independent of preference.     

Basal ganglia volume and clinical correlates in ‘preclinical’ Huntington’s disease

Abstract Objective   To establish differences in basal ganglia and thalamic volume between preclinical carriers and non-carriers of the Huntington’s disease (HD) gene and to link the volume to motor, cognitive and behavioural characteristics in carriers. Methods   Sixteen HD gene carriers without overt clinical motor signs and 14 non-gene carriers underwent clinical evaluation and a MRI scan. Volumes of the caudate nucleus, putamen, gobus pallidus and thalamus were measured using T1-weighted MR images. Motor, cognitive and behavioural functioning was assessed using the Unified Huntington’s Disease Rating Scale (UHDRS), cognitive testing and the Beck Depression Inventory (BDI-II). Results   Volumes of the caudate nucleus, putamen and globus pallidus were significantly smaller in carriers than in non-carriers while no differences between groups were found on clinical evaluation. In gene carriers smaller globus pallidus volume was associated with more motor abnormalities. A smaller putamen volume correlated significantly with worse psychomotor function on the Symbol Digit Modalities Task and the Trail Making Test B. Conclusions   In line with previous research we demonstrated that basal ganglia abnormalities precede overt disease manifestation of HD. Besides we showed that smaller basal ganglia volumes are related to subtle motor abnormalities and worse psychomotor performance in gene carriers without clinical diagnosis. Motor and psychomotor measures may be suitable clinical markers in future neuroprotective trials when combined with volumetric imaging.     

α-Synuclein-immunoreactive structure formation is enhanced in sympathetic ganglia of patients with multiple system atrophy

We immunohistochemically examined the sympathetic ganglia (SG) and brains of 26 patients with multiple system atrophy (MSA), 19 age-matched controls, and 25 patients with amyotrophic lateral sclerosis (ALS). -Synuclein-immunoreactive structures were found in the neuronal cytoplasm and processes of the SG in 11 of the 26 MSA cases (42.3%) and 1 of the 25 ALS cases (4%), but not in the 19 controls. No -synuclein-immunoreactive structures were found in Schwann cells or the neuronal nucleus. Mean disease duration of MSA cases with -synuclein-immunoreactive structures was significantly longer than that of MSA cases without -synuclein-immunoreactive structures. -Synuclein-immunoreactive structures in 4 cases proved to be Lewy bodies (LB) based on hematoxylin-eosin staining. A few LB were also found in the brains of 3 of these 4 cases. In the other 7 MSA cases, diffuse or focal neuronal cytoplasmic aggregates and swollen neurites were detected with -synuclein immunostaining, but not with hematoxylin-eosin staining. However, a few LB-like structures with ring-like staining were observed in those aggregates, which suggested those aggregates had progressed to form LB. Immunoelectron microscopically, those aggregates were composed of filaments and granular materials which closely resembled the ultrastructural features of LB. We inferred that -synuclein aggregates found in the SG in our study evidenced LB-related pathologies. MSA, a type of synucleinopathy, is characterized by glial cytoplasmic inclusions in oligodendrocytes, but also frequently develops LB pathology in the late stage, especially in the SG.     

Dopaminergic dysbalance in distinct basal ganglia neurocircuits: Implications for the pathophysiology of parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder

The basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system is also involved in the pathophysiology of ADHD. The most convincing evidence comes from the demonstration of the efficacy of psychostimulants such as the dopamine transporter (DAT) blocker methylphenidate in the symptomatic treatment of ADHD. Genetic studies have shown an association between ADHD and genes involved in dopaminergic neurotransmission (for example the dopamine receptor genes DRD4 and DRD5, and the DAT gene DAT1). DAT knockout mice display a phenotype with increased locomotor activity, which is normalized by psychostimulant treatment. Finally, imaging studies demonstrated an increased density of DAT in the striatum of ADHD patients. Which system is disturbed and whether this system is hyper- or hypoactive is not unambiguously known yet.     

Prolonged morphine treatment selectively increases membrane recruitment of δ-opioid receptors in mouse basal ganglia

In recent years, we demonstrated that prolonged (48-h) treatment of rats or mice with selective m-opioid receptor ((mu)OR) agonists induced a translocation of delta-opioid receptors ((delta)ORs) from intracellular compartments to neuronal plasma membranes in the dorsal horn of the spinal cord. It remained to be determined whether this phenomenon also occurred in the brain. To resolve this issue, we analyzed by immunogold histochemistry the subcellular distribution of (delta)ORs in the nucleus accumbens, dorsal neostriatum, and frontal cortex in mice treated or not with morphine (48 h). We observed that prolonged treatment with morphine induced a translocation of (delta)ORs from intracellular to subplasmalemmal and membrane compartments in dendrites from both the nucleus accumbens and the dorsal neostriatum but not from the frontal cortex. We propose that this (mu)OR-(delta)OR interaction might prolong and modulate the sensitivity of neurons to opiates in specific target regions.