Postmortem neuropathology in early Huntington disease.

Two aspects of the neuropathology of early Huntington disease (HD) are examined. Neurons of the neostriatum are counted to determine relative loss in striosomes versus matrix at early stages, including for the first time in preclinical cases. An immunohistochemical procedure is described that tentatively distinguishes early HD from HD mimic disorders in postmortem brains. Counts of striatal projection neurons (SPNs) in striosomes defined by calbindin immunohistochemistry versus counts in the surrounding matrix are reported for 8 Vonsattel grade 0 (including 5 premanifest), 8 grade 1, 2 grade 2 HD, and for 8 control postmortem brains. Mean counts of striosome and matrix SPNs were significantly lower in premanifest grade 0 versus controls, with striosome counts significantly lower than matrix. In 8 grade 1 and 2 grade 2 brains, no striosomes with higher SPN counts than in the surrounding matrix were observed. Comparing dorsal versus ventral neostriatum, SPNs in dorsal striosomes and matrix declined more than ventral, making clear the importance of the dorsoventral site of tissue selection for research studies. A characteristic pattern of expanded polyglutamine-immunopositive inclusions was seen in all HD cases. Inclusions were always present in some SPNs and some pontine nucleus neurons and were absent in Purkinje cells, which showed no obvious cell loss.

Reversible inhibition of the basal ganglia prolongs repetitive vocalization but only weakly affects sequencing at branch points in songbirds.

Although vocal signals, including languages and songbird syllables, are composed of a finite number of acoustic elements, diverse vocal sequences are composed of a combination of these elements, which are linked together by syntactic rules. However, the neural basis of syntactic vocalization generation remains poorly understood. Here, we report that inhibition using tetrodotoxin (TTX) and manipulations of gamma-aminobutyric acid (GABA) receptors within the basal ganglia Area X or lateral magnocellular nucleus of the anterior neostriatum (LMAN) alter and prolong repetitive vocalization in Bengalese finches (Lonchura striata var. domestica). These results suggest that repetitive vocalizations are modulated by the basal ganglia and not solely by higher motor cortical neurons. These data highlight the importance of neural circuits, including the basal ganglia, in the production of stereotyped repetitive vocalizations and demonstrate that dynamic disturbances within the basal ganglia circuitry can differentially affect the repetitive temporal features of songs.

Quantitative analysis of the Golgi impregnated human (neo)striatal neurons: Observation of the morphological characteristics followed by an emphasis on the functional diversity of cells.

BACKGROUND: The (neo)striatum is the major input structure of the basal nuclei, which is involved in the execution of voluntary movements, but also in controlling the processes that lead to the movement, such as motivation and cognition. The striatum provides its function through an interaction between projection neurons and interneurons. The aim of this study was to quantify the morphological properties of neurons in the precommissural putamen and precommissural caudate nucleus head and to evaluate whether there is a difference in cell morphology between different cell groups within one part and between the same cell groups within different parts of the striatum. METHODS: A total of 652 neuronal images of human striatum were observed. The features of the neuronal morphology (soma size, dendritic field size, shape of neuronal image, dendritic curviness, dendritic branching complexity) were observed by determining appropriate parameters of digital images of neurons. RESULTS: According to the presence of spines on the soma and/or dendrites, neurons were qualitatively classified into 446 spiny and 206 aspiny cells. The analysis of the distribution of the dendritic field area shows that spiny and aspiny neurons from both parts of the neostriatum can be decomposed into two distributions, which means that they can be classified into subgroups. A quantitative analysis of the spiny/aspiny neurons in the human putamen or caudate nucleus head has shown that there is a statistically significant difference between them. By comparing the morphology of neurons of the same group between different parts of the human neostriatum (putamen and caudate nucleus), it was also determined that there is a statistically significant difference. CONCLUSION: Since the morphology and function of neurons are in close correlation, it can be assumed that different groups of neurons in the human striatum might support functional diversity of the studied area.

The neostriatum in polyglutamine diseases: preferential decreases in large neurons in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease and in small neurons in Huntington disease.

The presence of polyglutamine-immunoreactive deposits in neurons of the neostriatum has been reported in dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and Huntington disease (HD). However, among these diseases, precise quantitative investigations on neurons have been performed only for HD. Changes in the number of neurons and the immunohistological features of polyglutamine deposits in the caudate head and putamen were examined in six patients with DRPLA, three with MJD, and four with HD. In the neostriatum in DRPLA, the numbers of large and small neurons were reduced to 33-38% and 48-68% relative to controls, respectively, whereas the corresponding figures in MJD were 19-26% and 65-76%, respectively, and those in HD were 34-35% and 12-16%, respectively. In DRPLA, 2-55% of neurons remaining in the neostriatum showed diffuse nuclear accumulation of polyglutamine, in contrast to 3-20% in MJD and a few percent in HD. These findings indicate that, in the neostriatum, a decrease in the number of small neurons is predominant in HD, whereas a decrease in the number of large neurons is predominant in DRPLA and MJD. Thus, it is suggested that disease processs differ among polyglutamine diseases.

Behavioral features in child and adolescent huntingtin gene-mutation carriers.

INTRODUCTION: We compared neuropsychiatric symptoms between child and adolescent huntingtin gene-mutation carriers and noncarriers. Given previous evidence of atypical striatal development in carriers, we also assessed the relationship between neuropsychiatric traits and striatal development. METHODS: Participants between 6 and 18 years old were recruited from families affected by Huntington's disease and tested for the huntingtin gene expansion. Neuropsychiatric traits were assessed using the Pediatric Behavior Scale and the Behavior Rating Inventory of Executive Function. Striatal volumes were extracted from 3T neuro-anatomical images. Multivariable linear regression models were conducted to evaluate the impact of group (i.e., gene nonexpanded [GNE] or gene expanded [GE]), age, and trajectory of striatal growth on neuropsychiatric symptoms. RESULTS: There were no group differences in any behavioral measure with the exception of depression/anxiety score, which was higher in the GNE group compared to the GE group (estimate = 4.58, t(129) = 2.52, FDR = 0.051). The growth trajectory of striatal volume predicted depression scores (estimate = 0.429, 95% CI 0.15:0.71, p = .0029), where a negative slope of striatal volume over time was associated with lower depression/anxiety. CONCLUSIONS: The current findings show that GE children may have lower depression/anxiety compared to their peers. Previously, we observed a unique pattern of early striatal hypertrophy and continued decrement in volume over time among GE children and adolescents. In contrast, GNE individuals largely show striatal volume growth. These findings suggest that the lower scores of depression and anxiety seen in GE children and adolescents may be associated with differential growth of the striatum.

Transient compartmentalization and accelerated volume growth coincide with the expected development of cortical afferents in the human neostriatum.

The neostriatum plays a central role in cortico-subcortical circuitry underlying goal-directed behavior. The adult mammalian neostriatum shows chemical and cytoarchitectonic compartmentalization in line with the connectivity. However, it is poorly understood how and when fetal compartmentalization (AChE-rich islands, nonreactive matrix) switches to adult (AChE-poor striosomes, reactive matrix) and how this relates to the ingrowth of corticostriatal afferents. Here, we analyze neostriatal compartments on postmortem human brains from 9 postconceptional week (PCW) to 18 postnatal months (PM), using Nissl staining, histochemical techniques (AChE, PAS-Alcian), immunohistochemistry, stereology, and comparing data with volume-growth of in vivo and in vitro MRI. We find that compartmentalization (C) follows a two-compartment (2-C) pattern around 10PCW and is transformed into a midgestational labyrinth-like 3-C pattern (patches, AChE-nonreactive perimeters, matrix), peaking between 22 and 28PCW during accelerated volume-growth. Finally, compartmentalization resolves perinatally, by the decrease in transient "AChE-clumping," disappearance of AChE-nonreactive, ECM-rich perimeters, and an increase in matrix reactivity. The initial "mature" pattern appears around 9 PM. Therefore, transient, a 3-C pattern and accelerated neostriatal growth coincide with the expected timing of the nonhomogeneous distribution of corticostriatal afferents. The decrease in growth-related AChE activity and transfiguration of corticostriatal terminals are putative mechanisms underlying fetal compartments reorganization. Our findings serve as normative for studying neurodevelopmental disorders.

Spatiotemporal Up-Regulation of Mu Opioid Receptor 1 in Striatum of Mouse Model of Huntington's Disease Differentially Affecting Caudal and Striosomal Regions.

The striatum of humans and other mammals is divided into macroscopic compartments made up of a labyrinthine striosome compartment embedded in a much larger surrounding matrix compartment. Anatomical and snRNA-Seq studies of the Huntington's disease (HD) postmortem striatum suggest a preferential decline of some striosomal markers, and mRNAs studies of HD model mice concur. Here, by immunohistochemical methods, we examined the distribution of the canonical striosomal marker, mu-opioid receptor 1 (MOR1), in the striatum of the Q175 knock-in mouse model of HD in a postnatal time series extending from 3 to 19 months. We demonstrate that, contrary to the loss of many markers for striosomes, there is a pronounced up-regulation of MOR1 in these Q175 knock-in mice. We show that in heterozygous Q175 knock-in model mice [~192 cytosine-adenine-guanine (CAG) repeats], this MOR1 up-regulation progressed with advancing age and disease progression, and was particularly remarkable at caudal levels of the striatum. Given the known importance of MOR1 in basal ganglia signaling, our findings, though in mice, should offer clues to the pathogenesis of psychiatric features, especially depression, reinforcement sensitivity, and involuntary movements in HD.

Biological Sex and Sex Hormone Impacts on Deficits in Episodic-Like Memory in a Rat Model of Early, Pre-motor Stages of Parkinson's Disease.

Episodic memory deficits are among the earliest appearing and most commonly occurring examples of cognitive impairment in Parkinson's disease (PD). These enduring features can also predict a clinical course of rapid motor decline, significant cognitive deterioration, and the development of PD-related dementia. The lack of effective means to treat these deficits underscores the need to better understand their neurobiological bases. The prominent sex differences that characterize episodic memory in health, aging and in schizophrenia and Alzheimer's disease suggest that neuroendocrine factors may also influence episodic memory dysfunction in PD. However, while sex differences have been well-documented for many facets of PD, sex differences in, and sex hormone influences on associated episodic memory impairments have been less extensively studied and have never been examined in preclinical PD models. Accordingly, we paired bilateral neostriatal 6-hydroxydopamine (6-OHDA) lesions with behavioral testing using the What-Where-When Episodic-Like Memory (ELM) Task in adult rats to first determine whether episodic-like memory is impaired in this model. We further compared outcomes in gonadally intact female and male subjects, and in male rats that had undergone gonadectomy-with and without hormone replacement, to determine whether biological sex and/or sex hormones influenced the expression of dopamine lesioned-induced memory deficits. These studies showed that 6-OHDA lesions profoundly impaired recall for all memory domains in male and female rats. They also showed that in males, circulating gonadal hormones powerfully modulated the negative impacts of 6-OHDA lesions on What, Where, and When discriminations in domain-specific ways. Specifically, the absence of androgens was shown to fully attenuate 6-OHDA lesion-induced deficits in ELM for "Where" and to partially protect against lesion-induced deficits in ELM for "What." In sum, these findings show that 6-OHDA lesions in rats recapitulate the vulnerability of episodic memory seen in early PD. Together with similar evidence recently obtained for spatial working memory, the present findings also showed that diminished androgen levels provide powerful, highly selective protections against the harmful effects that 6-OHDA lesions have on memory functions in male rats.

Parkinson's Disease Diagnosis Using Neostriatum Radiomic Features Based on T2-Weighted Magnetic Resonance Imaging.

Background: Parkinson's disease (PD) is a neurodegenerative disease in which the neostriatum, including the caudate nucleus (CN) and putamen (PU), has an important role in the pathophysiology. However, conventional magnetic resonance imaging (MRI) lacks sufficient specificity to diagnose PD. Therefore, the study's aim was to investigate the feasibility of using a radiomics approach to distinguish PD patients from healthy controls on T2-weighted images of the neostriatum and provide a basis for the clinical diagnosis of PD. Methods: T2-weighted images from 69 PD patients and 69 age- and sex-matched healthy controls were obtained on the same 3.0T MRI scanner. Regions of interest (ROIs) were manually placed at the CN and PU on the slices showing the largest respective sizes of the CN and PU. We extracted 274 texture features from each ROI and then used the least absolute shrinkage and selection operator regression to perform feature selection and radiomics signature building to identify the CN and PU radiomics signatures consisting of optimal features. We used a receiver operating characteristic curve analysis to assess the diagnostic performance of two radiomics signatures in a training group and estimate the generalization performance in the test group. Results: There were no significant differences in the demographic and clinical characteristics between the PD patients and healthy controls. The CN and PU radiomics signatures were built using 12 and 7 optimal features, respectively. The performance of the two radiomics signatures to distinguish PD patients from healthy controls was good. In the training and test groups, the AUCs of the CN radiomics signatures were 0.9410 (95% confidence interval [CI]: 0.8986-0.9833) and 0.7732 (95% CI: 0.6292-0.9173), respectively, and the AUCs of the PU radiomics signature were 0.8767 (95% CI: 0.8066-0.9469) and 0.7143 (95% CI: 0.5540-0.8746), respectively. Vertl_GlevNonU_R appeared simultaneously in both the CN and PU radiomics signatures as an optimal feature. A t-test analysis revealed significantly higher levels of texture values of the CN and PU in the PD patients than healthy controls (P < 0.05). Conclusion: Neostriatum radiomics signatures achieved good diagnostic performance for PD and potentially could serve as a basis for the clinical diagnosis of PD.

Assistive technology: Visual mapping combined with mobile software can enhance quality of life and ability to carry out activities of daily living in individuals with impaired memory.

BACKGROUND: There is growing evidence that assistive digital technology can enhance quality of life (QOL) for individuals with various forms of cognitive impairment, including dementia. OBJECTIVE: Assess whether the use of a visual mapping software program to manage activities of daily living would have a positive impact on QOL scores and on cognitive scores in a group of dementia residents in an adult living community. METHODS: We compared quality-of-life scores and cognitive function scores before and after using the assistive technology for three months. RESULTS: 1. QOL scores significantly improved in the memory impaired residents, as measured by a self-report questionnaire. 2. Caregivers also reported significantly improved QOL scores in the residents, and the caregivers reported more improved scores than the residents did. 3. Net Promoter Scores for residents and caregivers showed that using visual maps was highly satisfying; they would continue using this technology. 4. Memory-impaired residents showed significantly improved scores in cognitive areas reflecting improved ability to focus and pay attention. CONCLUSIONS: In addition to the positive findings in QOL and cognition, assistive technologies applied to dementia care are easy to access, easy to use, have little risk of side effects, and are relatively low in cost.

Striatal morphology and neurocognitive dysfunction in Huntington disease: The IMAGE-HD study.

We aimed to investigate the relationship between striatal morphology in Huntington disease (HD) and measures of motor and cognitive dysfunction. MRI scans, from the IMAGE-HD study, were obtained from 36 individuals with pre-symptomatic HD (pre-HD), 37 with early symptomatic HD (symp-HD), and 36 healthy matched controls. The neostriatum was manually segmented and a surface-based parametric mapping protocol derived two pointwise shape measures: thickness and surface dilation ratio. Significant shape differences were detected between all groups. Negative associations were detected between lower thickness and surface area shape measure and CAG repeats, disease burden score, and UHDRS total motor score. In symp-HD, UPSIT scores were correlated with higher thickness in left caudate tail and surface dilation ratio in left posterior putamen; Stroop scores were positively correlated with the thickness of left putamen head and body. Self-paced tapping (slow) was correlated with higher thickness and surface dilation ratio in the right caudate in symp-HD and with bilateral putamen in pre-HD. Self-paced tapping (fast) was correlated with higher surface dilation ratio in the right anterior putamen in symp-HD. Shape changes correlated with functional measures subserved by corticostriatal circuits, suggesting that the neostriatum is a potentially useful structural basis for characterisation of endophenotypes of HD.

Awareness and current knowledge of Parkinson's disease: a neurodegenerative disorder.

CONTEXT: Parkinson's disease (PD) is the second common progressive neurodegenerative disease, distressing older men and is prevalent Worldwide. OBJECTIVES: This article is aimed to review the epidemiology, etiology, pathogenesis, clinical manifestation, diagnosis and management of PD. METHODS: A google search was performed to recognise studies that review the characteristics of PD. Search terms included 'Parkinson's disease', 'epidemiology', 'etiology', 'pathogenesis', 'clinical manifestations', 'diagnosis' and 'management of Parkinson disease'. RESULTS: PD is linked to factors such as environmental chemicals, aging, family history and pesticide exposure such as the use of synthetic heroin. PD is characterised clinically by tremors at rest, postural instability, expressionless countenance, lead pipe rigidity and less commonly cognitive impairment. After 60 years of age, PD is commonly prevalent in 1-% of the population, no racial differences are apparent, but the prevalence of PD is more common in men than women. There has also been a better understanding that the disorder may be linked with major non-motor trouble in addition to the additional generally recognised motor complications. There are various management options for the timely management of PD. As the ailment advances, further management strategies are existing; however, the management of non-motor manifestations and late stage motor complications remains mainly testing and will advantage from additional clinical studies. CONCLUSIONS: In this article, we have discussed current progress in the understanding of the epidemiology, clinical manifestations, pathogenesis and management strategies of the disease.

The Tiny Drosophila Melanogaster for the Biggest Answers in Huntington's Disease.

The average life expectancy for humans has increased over the last years. However, the quality of the later stages of life is low and is considered a public health issue of global importance. Late adulthood and the transition into the later stage of life occasionally leads to neurodegenerative diseases that selectively affect different types of neurons and brain regions, producing motor dysfunctions, cognitive impairment, and psychiatric disorders that are progressive, irreversible, without remission periods, and incurable. Huntington's disease (HD) is a common neurodegenerative disorder. In the 25 years since the mutation of the huntingtin (HTT) gene was identified as the molecule responsible for this neural disorder, a variety of animal models, including the fruit fly, have been used to study the disease. Here, we review recent research that used Drosophila as an experimental tool for improving knowledge about the molecular and cellular mechanisms underpinning HD.

Blockade of synaptic activity in the neostriatum and activation of striatal efferent pathways produce opposite effects on panic attack-like defensive behaviours evoked by GABAergic disinhibition in the deep layers of the superior colliculus.

The dorsal periaqueductal grey matter (dPAG) and the deep layers of the superior colliculus (dlSC) have been implicated in the organisation of innate fear-related defensive behaviours. Furthermore, GABAergic neurons from the substantia nigra pars reticulata (SNpr) connected to the dlSC and dPAG receive convergent disinhibitory inputs from the caudate-putamen (CPu), comprising the neostriatum, and modulate defence responses elicited by midbrain tectum stimulation. The purpose of this work was to study the effect of either excitatory cortico-neostriatal input blockade or neostriato-nigral GABAergic disinhibitory output activation on the responsivity of GABAergic nigro-collicular tonic inhibitory pathways during the elicitation of panic attack-like defensive responses produced by bicuculline administration into the dlSC. Thus, we investigated the effects of microinjection of either the synaptic activity blocker cobalt chloride (CoCl2) or the NMDA receptor agonist N-methyl-D-aspartic acid in the CPu on the elaboration of the defensive behaviour elicited by the selective blockade of GABAA receptors in the dlSC. Our findings showed that pretreatment of the neostriatum with CoCl2 caused clear anxiolytic and panicolytic-like effects, reducing the incidence and duration of alertness and diminishing defensive immobility and explosive escape responses. On the other hand, pretreatment of the neostriatum with NMDA (40 nmol) caused a pro-aversive effect, enhancing running and jumping responses elicited by GABAergic disinhibition in the dlSC. We conclude from the data that the neostriato-nigral disinhibitory and nigro-collicular inhibitory GABAergic pathways modulate innate fear and panic attack-like responses organised by dlSC neurons.

Striatal changes in Parkinson disease: An investigation of morphology, functional connectivity and their relationship to clinical symptoms.

We sought to investigate morphological and resting state functional connectivity changes to the striatal nuclei in Parkinson disease (PD) and examine whether changes were associated with measures of clinical function. Striatal nuclei were manually segmented on 3T-T1 weighted MRI scans of 74 PD participants and 27 control subjects, quantitatively analysed for volume, shape and also functional connectivity using functional MRI data. Bilateral caudate nuclei and putamen volumes were significantly reduced in the PD cohort compared to controls. When looking at left and right hemispheres, the PD cohort had significantly smaller left caudate nucleus and right putamen volumes compared to controls. A significant correlation was found between greater atrophy of the caudate nucleus and poorer cognitive function, and between greater atrophy of the putamen and more severe motor symptoms. Resting-state functional MRI analysis revealed altered functional connectivity of the striatal structures in the PD group. This research demonstrates that PD involves atrophic changes to the caudate nucleus and putamen that are linked to clinical dysfunction. Our work reveals important information about a key structure-function relationship in the brain and provides support for caudate nucleus and putamen atrophy as neuroimaging biomeasures in PD.

Striatal and Hippocampal Atrophy in Idiopathic Parkinson's Disease Patients without Dementia: A Morphometric Analysis.

BACKGROUND: Analyses of subcortical gray structure volumes in non-demented idiopathic Parkinson's disease (PD) often, but not always, show volume loss of the putamen, caudate nucleus, nucleus accumbens, and hippocampus. There is building evidence that structure morphometry might be more sensitive to disease-related processes than volume. OBJECTIVE: To assess morphometric differences of subcortical structures (putamen, caudate nucleus, thalamus, globus pallidus, nucleus accumbens, and amygdala) as well as the hippocampus in non-demented individuals with PD relative to age and education matched non-PD peers. METHODS: Prospective recruitment of idiopathic no-dementia PD and non-PD peers as part of a federally funded investigation. T1-weighted isovoxel metrics acquired via 3-T Siemens Verio for all individuals [PD n = 72 (left side onset n = 27, right side onset n = 45); non-PD n = 48]. FIRST (FMRIB Software Library) applications provided volumetric and vertex analyses on group differences for structure size and morphometry. RESULTS: Group volume differences were observed only for putamen and hippocampi (PD < non-PD) with hippocampal volume significantly associating with disease duration. Group shape differences were observed for bilateral putamen, caudate nucleus, and hippocampus with greater striatal atrophy contralateral to side of motor symptom onset. Hippocampal shape differences disappeared when removing the effects of volume. CONCLUSION: The putamen was the primary structure to show both volume and shape differences in PD, indicating that the putamen is the predominant site of basal ganglia atrophy in early- to mid-stage PD. Side of PD symptom onset associates with contralateral striatal atrophy. Left-onset PD might experience more extensive striatal atrophy than right-onset PD. Hippocampus morphometric results suggest possible primary atrophy of CA3/4 and dentate gyrus.

Effect of normal aging on the structure of marginal division of neostriatum as measured by MR phase imaging and diffusion tensor imaging.

PURPOSE: To investigate the structural changes of marginal division (MrD) which is the high intensity zone between globus pallidus and putamen on phase image in the human brain. MATERIALS AND METHODS: The structural changes of MrD were investigated based on MR phase imaging and diffusion tensor imaging (DTI) data at 3.0 Tesla (T) MR scanner in 72 volunteers. Phase value, including high iron components (HIC), low iron components (LIC), LIC ratio, and average iron components (AIC), were obtained using histogram analysis about the head of caudate nucleus (CA), globus pallidus (GP), putamen (PU), and MrD. The structural measurement of MrD was applied on corrected phase images (CPIs). Average apparent diffusion coefficient (ADC) values and fractional anisotropy (FA) values were calculated based on DTI data. RESULTS: MrD showed negative correlation for LIC with aging, with the highest HIC (left/right 2149.3 ± 19.6/2155.9 ± 17.9) and LIC (left/right 1996.6 ± 18.2/1999.6 ± 20.7), the lowest LIC ratio (left/right 21.5% ± 7.9%/19.4% ± 8.0%), and the highest AIC (left/right 2116.4 ± 21.4/2124.7 ± 21.0). The width (Head: left/right 2.01 ± 0.41 mm/1.86 ± 0.36 mm; Body: left/right 1.84 ± 0.38 mm/1.49 ± 0.29 mm; Tail: left/right 1.17 ± 0.36 mm/1.05 ± 0.23 mm) and area (left/right 49.44 ± 9.71 mm2 /42.75 ± 8.80 mm2 ) of MrD showed negative correlation with aging, presenting gradually narrower pattern based on CPIs. Average ADC value (left/right 0.69 ± 0.04 10-3 mm2 /s / 0.71 ± 0.03 10-3 mm2 /s) revealed negative correlation, while FA value (left/right 0.19 ± 0.03/0.22 ± 0.03) revealed positive correlation with aging. CONCLUSION: The findings suggested that the structure measurements based on CPIs and DTI could provide a simple and effective tool for the evaluation of MrD in vivo in the human brain and for the assessment of the changes seen with aging. LEVEL OF EVIDENCE: 1 J. MAGN. RESON. IMAGING 2017;45:1343-1351.

GABAρ selective antagonist TPMPA partially inhibits GABA-mediated currents recorded from neurones and astrocytes in mouse striatum.

The neostriatum plays a central role in motor coordination where nerve cells operate neuronal inhibition through GABAergic transmission. The neostriatum expresses a wide range of GABA-A subunits, including GABAρ1 and ρ2 which are restricted to a fraction of GABAergic interneurons and astrocytes. Spontaneous postsynaptic currents (sPSCs) evoked by 4-aminopyridine (4-AP) were recorded from neurones of the dorsal neostriatum, and their frequency was reduced > 50% by the selective GABAρ antagonist (1,2,5,6-Tetrahydropyridine-4-yl) methylphosphinic acid (TPMPA). Additionally, we recorded GABA evoked currents from astrocytes in vitro and in situ. Astrocytes in vitro showed modulation by pentobarbital and desensitization upon consecutive applications of GABA. However, modulation by pentobarbital was absent and no significant desensitization was detected from astrocytes in situ. Moreover, TPMPA-sensitive GABA-currents that were insensitive to bicuculline were also recorded from astrocytes in situ, consistent with our previous study where GABAρ expression was demonstrated. Finally, we assessed the mRNA expression of GABAρ3, through different stages of postnatal development; double immunofluorescence disclosed GABAρ3 expression in calretinin-positive interneurons as well as in astrocytes (>70%). These results add new information about the participation of GABAρ subunits in neostriatal interneurons and astrocytes.

Neostriatal Neuronal Activity Correlates Better with Movement Kinematics under Certain Rewards.

This study investigated how the activity of neostriatal neurons is related to the kinematics of movement when monkeys performed visually and vibratory cued wrist extensions and flexions. Single-unit recordings of 142/236 neostriatal neurons showed pre-movement activity (PMA) in a reaction time task with unpredictable reward. Monkeys were pseudo-randomly (75%) rewarded for correct performance. A regression model was used to determine whether the correlation between neostriatal neuronal activity and the kinematic variables (position, velocity, and acceleration) of wrist movement changes as a function of reward contingency, sensory cues, and movement direction. The coefficients of determination (CoD) representing the proportion of the variance in neuronal activity explained by the regression model on a trial by trial basis, together with their temporal occurrences (time of best regression/correlation, ToC) were compared across sensory modality, movement direction, and reward contingency. The best relationship (correlation) between neuronal activity and movement kinematic variables, given by the average coefficient of determination (CoD), was: (a) greater during trials in which rewards were certain, called "A" trials, as compared with those in which reward was uncertain called ("R") trials, (b) greater during flexion (Flex) trials as compared with extension (Ext) trials, and (c) greater during visual (VIS) cued trials than during vibratory (VIB) cued trials, for the same type of trial and the same movement direction. These results are consistent with the hypothesis that predictability of reward for correct performance is accompanied by faster linkage between neostriatal PMA and the vigor of wrist movement kinematics. Furthermore, the results provide valuable insights for building an upper-limb neuroprosthesis.

Altered functional connectivity of the marginal division in migraine: a resting-state fMRI study.

BACKGROUND: The marginal division of neostriatum (MrD) is a flat, pan-shaped zone between the neostriatum and the globus pallidus, and previous documents demonstrated that it was involved in the modulation of pain. The aim of this study is to investigate the roles of the MrD of the human brain in the chronicization migraine using resting state functional magnetic resonance imaging (rs-fMRI). METHODS: Conventional MRI, 3D structure images, and rs-fMRI were performed in 18 patients with episodic migraines (EM), 16 patients with chronic migraine (CM), 44 patients with medication overuse headache plus chronic migraine (MOH + CM), and 32 normal controls (NC). MrD was defined using manual delineation on structural images, and was selected as the seed to calculate the functional connectivity (FC). RESULTS: Compared with the NC group, the decreased FC of MrD was observed in the EM and CM groups, and increased FC of MrD was demonstrated in all patient groups. Compared with the EM group, the decreased FC of MrD was revealed in the CM and MOH + CM groups, and the increased FC occurred only in the CM group. Increased FC of MrD alone was observed in the MOH + CM group compared with that in the CM group. CONCLUSION: This study confirmed the double neuromodulation network of MrD in pain modulation and migraine chronicization; however, the mechanism requires further investigation.