MRI-Visible Anatomy of the Basal Ganglia and Thalamus.

Conventional MR imaging does not discriminate basal ganglia and thalamic internal anatomy well. Radiology reports describe anatomic locations but not specific functional structures. Functional neurosurgery uses indirect targeting based on commissural coordinates or atlases that do not fully account for individual variability. We describe innovative MR imaging sequences that improve the visualization of normal anatomy in this complex brain region and may increase our understanding of basal ganglia and thalamic function. Better visualization also may improve treatments for movement disorders and other emerging functional neurosurgery targets. We aim to provide an accessible review of the most clinically-relevant neuroanatomy within the thalamus and basal ganglia.

High-resolution mapping and digital atlas of subcortical regions in the macaque monkey based on matched MAP-MRI and histology.

Subcortical nuclei and other deep brain structures are known to play an important role in the regulation of the central and peripheral nervous systems. It can be difficult to identify and delineate many of these nuclei and their finer subdivisions in conventional MRI due to their small size, buried location, and often subtle contrast compared to neighboring tissue. To address this problem, we applied a multi-modal approach in ex vivo non-human primate (NHP) brain that includes high-resolution mean apparent propagator (MAP)-MRI and five different histological stains imaged with high-resolution microscopy in the brain of the same subject. By registering these high-dimensional MRI data to high-resolution histology data, we can map the location, boundaries, subdivisions, and micro-architectural features of subcortical gray matter regions in the macaque monkey brain. At high spatial resolution, diffusion MRI in general, and MAP-MRI in particular, can distinguish a large number of deep brain structures, including the larger and smaller white matter fiber tracts as well as architectonic features within various nuclei. Correlation with histology from the same brain enables a thorough validation of the structures identified with MAP-MRI. Moreover, anatomical details that are evident in images of MAP-MRI parameters are not visible in conventional T1-weighted images. We also derived subcortical template "SC21" from segmented MRI slices in three-dimensions and registered this volume to a previously published anatomical template with cortical parcellation (Reveley et al., 2017; Saleem and Logothetis, 2012), thereby integrating the 3D segmentation of both cortical and subcortical regions into the same volume. This newly updated three-dimensional D99 digital brain atlas (V2.0) is intended for use as a reference standard for macaque neuroanatomical, functional, and connectional imaging studies, involving both cortical and subcortical targets. The SC21 and D99 digital templates are available as volumes and surfaces in standard NIFTI and GIFTI formats.

The mouse cortico-basal ganglia-thalamic network.

The cortico-basal ganglia-thalamo-cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1-4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico-basal ganglia-thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.

Implicit associative learning relates to basal ganglia gray matter microstructure in young and older adults.

Older adults are impaired at implicit associative learning (IAL), or the learning of relationships between stimuli in the environment without conscious awareness. These age effects have been attributed to differential engagement of the basal ganglia (e.g. caudate, globus pallidus) and hippocampus throughout learning. However, no studies have examined gray matter diffusion relations with IAL, which can reveal microstructural properties that vary with age and contribute to learning. In this study, young (18-29 years) and older (65-87 years) adults completed the Triplet Learning Task, in which participants implicitly learn that the location of cues predict the target location on some trials (high frequency triplets). Diffusion imaging was also acquired and multicompartment diffusion metrics were calculated using neurite orientation dispersion and density imaging (NODDI). As expected, results revealed age deficits in IAL (smaller differences in performance to high versus low frequency triplets in the late learning stage) and age-related differences in basal ganglia and hippocampus free, hindered, and restricted diffusion. Significant correlations were seen between restricted caudate diffusion and early IAL and between hindered globus pallidus diffusion and late IAL, which were not moderated by age group. These findings indicate that individual differences in basal ganglia, but not hippocampal, gray matter microstructure contribute to learning, independent of age, further supporting basal ganglia involvement in IAL.

MRI-visible dilated perivascular spaces in healthy young adults: A twin heritability study.

We investigated the narrow-sense heritability of MRI-visible dilated perivascular spaces (dPVS) in healthy young adult twins and nontwin siblings (138 monozygotic, 79 dizygotic twin pairs, and 133 nontwin sibling pairs; 28.7 ± 3.6 years) from the Human Connectome Project. dPVS volumes within basal ganglia (BGdPVS) and white matter (WMdPVS) were automatically calculated on three-dimensional T2-weighted MRI. In univariate analysis, heritability estimates of BGdPVS and WMdPVS after age and sex adjustment were 65.8% and 90.2%. In bivariate analysis, both BGdPVS and WMdPVS showed low to moderate genetic correlations (.30-.43) but high shared heritabilities (71.8-99.9%) with corresponding regional volumes, intracranial volumes, and other regional dPVS volumes. Older age was significantly associated with larger dPVS volume in both regions even after adjusting for clinical and volumetric variables, while blood pressure was not associated with dPVS volume although there was weak genetic correlation. dPVS volume, particularly WMdPVS, was highly heritable in healthy young adults, adding evidence of a substantial genetic contribution in dPVS development and differential effect by location. Age affects dPVS volume even in young adults, while blood pressure might have limited role in dPVS development in its normal range.

Mapping tracts in the human subthalamic area by 11.7T ex vivo diffusion tensor imaging.

The cortico-basal ganglia-thalamo-cortical feedback loops that consist of distinct white matter pathways are important for understanding in vivo imaging studies of functional and anatomical connectivity, and for localizing subthalamic white matter structures in surgical approaches for movement disorders, such as Parkinson's disease. Connectomic analysis in animals has identified fiber connections between the basal ganglia and thalamus, which pass through the fields of Forel, where other fiber pathways related to motor, sensory, and cognitive functions co-exist. We now report these pathways in the human brain on ex vivo mesoscopic (250 µm) diffusion tensor imaging and on tractography. The locations of the tracts were identified relative to the adjacent gray matter structures, such as the internal and external segments of the globus pallidus; the zona incerta; the subthalamic nucleus; the substantia nigra pars reticulata and compacta; and the thalamus. The connectome atlas of the human subthalamic region may serve as a resource for imaging studies and for neurosurgical planning.

Cumulative Blood Pressure Exposure, Basal Ganglia, and Thalamic Morphology in Midlife.

High blood pressure (BP) negatively affects brain structure and function. Hypertension is associated with white matter hyperintensities, cognitive and mobility impairment in late-life. However, the impact of BP exposure from young adulthood on brain structure and function in mid-life is unclear. Identifying early brain structural changes associated with BP exposure, before clinical onset of cognitive dysfunction and mobility impairment, is essential for understanding mechanisms and developing interventions. We examined the effect of cumulative BP exposure from young adulthood on brain structure in a substudy of 144 (61 female) individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study. At year 30 (Y30, ninth visit), participants (56±4 years old) completed brain magnetic resonance imaging and gait measures (pace, rhythm, and postural control). Cumulative systolic and diastolic BP (cumulative systolic blood pressure, cDBP) over 9 visits were calculated, multiplying mean values between 2 consecutive visits by years between visits. Surface-based analysis of basal ganglia and thalamus was achieved using FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping. Morphometric changes were regressed onto cumulative BP to localize regions of shape variation. Y30 white matter hyperintensity volumes were small and positively correlated with cumulative BP but not gait. Negative morphometric associations with cumulative systolic blood pressure were seen in the caudate, putamen, nucleus accumbens, pallidum, and thalamus. A concave right medial putamen shape mediated the relationship between cumulative systolic blood pressure and stride width. Basal ganglia and thalamic morphometric changes, rather than volumes, may be earlier manifestation of gray matter structural signatures of BP exposure that impact midlife gait.

The Caudate Nucleus: Its Connections, Surgical Implications, and Related Complications.

BACKGROUND: The caudate nucleus is a C-shaped structure that is located in the center of the brain and is divided into 3 parts: the head, body, and tail. METHODS: We detail the anatomic connections, relationships with other basal ganglia structures, and clinical implications of injury to the caudate nucleus. RESULTS: Anatomically, the most inferior transcapsular gray matter is the lentiform peduncle, which is the connection between the lentiform nucleus and caudate nucleus as well as the amygdala. The border between the tail and body of the caudate nucleus is the posterior insular point. The tail of the caudate nucleus is extraependymal in some parts and intraependymal in some parts of the roof of the temporal horn of the lateral ventricle. The tail of the caudate nucleus crosses the inferior limiting sulcus (temporal stem), and section of the tail during approaches to lesions involving the temporal stem may cause motor apraxia. The mean distance from the temporal limen point, which is the junction of the limen insula and inferior limiting sulcus, to the tail of the caudate nucleus in the temporal stem is 15.87 ± 3.10 mm. CONCLUSIONS: Understanding of the functional anatomy and connections of the distinct parts of the caudate nucleus is essential for deciding the extent of resection of lesions involving the caudate nucleus and the types of deficits that may be found postoperatively.

Feasibility and performance of a frameless stereotactic system for targeting subcortical nuclei in nonhuman primates.

OBJECTIVE: Deep brain stimulation (DBS) is an effective therapy for different neurological diseases, despite the lack of comprehension of its mechanism of action. The use of nonhuman primates (NHPs) has been historically important in advancing this field and presents a unique opportunity to uncover the therapeutic mechanisms of DBS, opening the way for optimization of current applications and the development of new ones. To be informative, research using NHPs should make use of appropriate electrode implantation tools. In the present work, the authors report on the feasibility and accuracy of targeting different deep brain regions in NHPs using a commercially available frameless stereotactic system (microTargeting platform). METHODS: Seven NHPs were implanted with DBS electrodes, either in the subthalamic nucleus or in the cerebellar dentate nucleus. A microTargeting platform was designed for each animal and used to guide implantation of the electrode. Imaging studies were acquired preoperatively for each animal, and were subsequently analyzed by two independent evaluators to estimate the electrode placement error (EPE). The interobserver variability was assessed as well. RESULTS: The radial and vector components of the EPE were estimated separately. The magnitude of the vector of EPE was 1.29 ± 0.41 mm and the mean radial EPE was 0.96 ± 0.63 mm. The interobserver variability was considered negligible. CONCLUSIONS: These results reveal the suitability of this commercial system to enhance the surgical insertion of DBS leads in the primate brain, in comparison to rigid traditional frames. Furthermore, our results open up the possibility of performing frameless stereotaxy in primates without the necessity of relying on expensive methods based on intraoperative imaging.

The Anatomy and Physiology of Claustrum-Cortex Interactions.

The claustrum is one of the most widely connected regions of the forebrain, yet its function has remained obscure, largely due to the experimentally challenging nature of targeting this small, thin, and elongated brain area. However, recent advances in molecular techniques have enabled the anatomy and physiology of the claustrum to be studied with the spatiotemporal and cell type-specific precision required to eventually converge on what this area does. Here we review early anatomical and electrophysiological results from cats and primates, as well as recent work in the rodent, identifying the connectivity, cell types, and physiological circuit mechanisms underlying the communication between the claustrum and the cortex. The emerging picture is one in which the rodent claustrum is closely tied to frontal/limbic regions and plays a role in processes, such as attention, that are associated with these areas.

Localising movement disorders in childhood.

The diagnosis and management of movement disorders in children can be improved by understanding the pathways, neurons, ion channels, and receptors involved in motor learning and control. In this Review, we use a localisation approach to examine the anatomy, physiology, and circuitry of the basal ganglia and highlight the mechanisms that underlie some of the major movement disorders in children. We review the connections between the basal ganglia and the thalamus and cortex, address the basic clinical definitions of movement disorders, and then place diseases within an anatomical or physiological framework that highlights basal ganglia function. We discuss how new pharmacological, behavioural, and electrophysiological approaches might benefit children with movement disorders by modifying synaptic function. A better understanding of the mechanisms underlying movement disorders allows improved diagnostic and treatment decisions.

An open cortico-basal ganglia loop allows limbic control over motor output via the nigrothalamic pathway.

Cortico-basal ganglia-thalamocortical loops are largely conceived as parallel circuits that process limbic, associative, and sensorimotor information separately. Whether and how these functionally distinct loops interact remains unclear. Combining genetic and viral approaches, we systemically mapped the limbic and motor cortico-basal ganglia-thalamocortical loops in rodents. Despite largely closed loops within each functional domain, we discovered a unidirectional influence of the limbic over the motor loop via ventral striatum-substantia nigra (SNr)-motor thalamus circuitry. Slice electrophysiology verifies that the projection from ventral striatum functionally inhibits nigro-thalamic SNr neurons. In vivo optogenetic stimulation of ventral or dorsolateral striatum to SNr pathway modulates activity in medial prefrontal cortex (mPFC) and motor cortex (M1), respectively. However, whereas the dorsolateral striatum-SNr pathway exerts little impact on mPFC, activation of the ventral striatum-SNr pathway effectively alters M1 activity. These results demonstrate an open cortico-basal ganglia loop whereby limbic information could modulate motor output through ventral striatum control of M1.

Hand preference and local asymmetry in cerebral cortex, basal ganglia, and cerebellar white matter.

Hand preference is a striking example of functional lateralization, with 90% of the population preferentially using their right hand. However, the search for brain structural correlates of this lateralization has produced inconsistent results. While large-scale neuroimaging studies using automated methods have largely failed to find local anatomical asymmetries associated with hand preference, other studies identifying specific motor regions have been able to find local morphological and functional differences. The present study looked at brain asymmetries in the brain's motor system using established cortical landmarks to identify the somatomotor hand region and extracted regional volumes of subcortical and cerebellar regions. Our results showed a strong left-right asymmetry in the cortical hand region, with weaker asymmetries appearing in the striatum and cerebellar white matter. Such asymmetries were much more pronounced in right-handers, whereas much weaker or absent lateralizing effects were observed in left-handed subjects. This study demonstrates the importance of local landmarks in studying individual anatomical differences. More generally, establishing structural correlates of hand preference is important, as this could further establish the origins of cerebral lateralization.

Previous contraceptive treatment relates to grey matter volumes in the hippocampus and basal ganglia.

Oral contraceptive (OC) effects on the brain have gained increasing interest, but are highly controversial. Previous studies suggest that OC users have larger hippocampi, parahippocampi, fusiform gyri and Cerebelli. Preliminary evidence from one of those studies even suggests an effect of previous contraceptive use on the hippocampi of women who are not current users of OCs. Furthermore, more recent studies postulate an involvement of previous OC treatment in later development of mood disorders. To address the question whether previous OC treatment affects women's brain structure later in life, high resolution structural images were obtained from 131 naturally cycling women. Among them, 52 women had never used OC before, 52 had previously used one OC for a continuous time period and 27 had previously used multiple contraceptives. The groups did not differ in gray matter volumes. Since endogenous sex hormones modulate gray matter volumes of the hippocampus and basal ganglia along the menstrual cycle, we hypothesize effects of OC use on these areas. Specifically, we hypothesize that a longer duration of previous OC treatment is related to larger hippocampi and larger basal ganglia. Indeed we found the duration of previous OC use to be positively correlated to hippocampal and basal ganglia volumes bilaterally. For the hippocampus, but not for the basal ganglia, this association disappeared after controlling for the time since discontinuation. These results suggest that for the hippocampus, but not for the basal ganglia, effects of previous contraceptive treatment are reversed after a time period comparable to treatment duration. These data question the immediate reversibility of OC effects on brain structure. Accordingly, some changes in the brain due to long-term contraceptive use, while subtle, may be long-lasting.

Structural covariability hubs in old age.

Studies have shown that inter-individual differences in grey matter, as measured by voxel-based morphometry, are coordinated between voxels. This has been done by studying covariance maps based on a limited number of seed regions. Here, we used GPU-based (Graphics Processing Unit) accelerated computing to calculate, for the first time, the aggregated map of the total structural topographical organisation in the brain on voxel level in a large sample of 960 healthy individuals in the age range 68-83 years. This map describes for each voxel the number of significant correlations with all other grey matter voxels in the brain. Voxels that correlate significantly with many other voxels are called hubs. A majority of these hubs were found in the basal ganglia, the thalamus, the brainstem, and the cerebellum; subcortical regions that have been preserved through vertebrate evolution, interact with large portions of the neocortex and play fundamental roles for the control of a wide range of behaviours. No significant difference in the level of covariability could be found with increasing age or between men and women in these hubs.

Topographic precision in sensory and motor corticostriatal projections varies across cell type and cortical area.

The striatum shows general topographic organization and regional differences in behavioral functions. How corticostriatal topography differs across cortical areas and cell types to support these distinct functions is unclear. This study contrasted corticostriatal projections from two layer 5 cell types, intratelencephalic (IT-type) and pyramidal tract (PT-type) neurons, using viral vectors expressing fluorescent reporters in Cre-driver mice. Corticostriatal projections from sensory and motor cortex are somatotopic, with a decreasing topographic specificity as injection sites move from sensory to motor and frontal areas. Topographic organization differs between IT-type and PT-type neurons, including injections in the same site, with IT-type neurons having higher topographic stereotypy than PT-type neurons. Furthermore, IT-type projections from interconnected cortical areas have stronger correlations in corticostriatal targeting than PT-type projections do. As predicted by a longstanding model, corticostriatal projections of interconnected cortical areas form parallel circuits in the basal ganglia.

Dystonia.

Dystonia is a neurological condition characterized by abnormal involuntary movements or postures owing to sustained or intermittent muscle contractions. Dystonia can be the manifesting neurological sign of many disorders, either in isolation (isolated dystonia) or with additional signs (combined dystonia). The main focus of this Primer is forms of isolated dystonia of idiopathic or genetic aetiology. These disorders differ in manifestations and severity but can affect all age groups and lead to substantial disability and impaired quality of life. The discovery of genes underlying the mendelian forms of isolated or combined dystonia has led to a better understanding of its pathophysiology. In some of the most common genetic dystonias, such as those caused by TOR1A, THAP1, GCH1 and KMT2B mutations, and idiopathic dystonia, these mechanisms include abnormalities in transcriptional regulation, striatal dopaminergic signalling and synaptic plasticity and a loss of inhibition at neuronal circuits. The diagnosis of dystonia is largely based on clinical signs, and the diagnosis and aetiological definition of this disorder remain a challenge. Effective symptomatic treatments with pharmacological therapy (anticholinergics), intramuscular botulinum toxin injection and deep brain stimulation are available; however, future research will hopefully lead to reliable biomarkers, better treatments and cure of this disorder.

Cortical and Subcortical Projections from Granular Insular Cortex Receiving Orofacial Proprioception.

We have recently revealed that the proprioceptive signal from jaw-closing muscle spindles (JCMSs) is conveyed to the dorsal part of granular insular cortex rostroventrally adjacent to the rostralmost part of secondary somatosensory cortex (dGIrvs2) via the caudo-ventromedial edge (VPMcvm) of ventral posteromedial thalamic nucleus (VPM) in rats. However, it remains unclear to which cortical or subcortical structures the JCMS proprioceptive information is subsequently conveyed from the dGIrvs2. To test this issue, we injected an anterograde tracer, biotinylated dextranamine, into the electophysiologically identified dGIrvs2, and analyzed the resultant distribution profiles of labeled axon terminals in rats. Labeled terminals were distributed with an ipsilateral predominance. In the cerebral cortex, they were seen in the primary and secondary somatosensory cortices, lateral and medial agranular cortices and dorsolateral orbital cortex. In the basal ganglia, they were found in the caudate putamen, core part of accumbens nucleus, lateral globus pallidus, subthalamic nucleus, and substantia nigra pars compacta and pars reticulata. They were also observed in the central amygdaloid nucleus and extended amygdala (the interstitial nucleus of posterior limb of anterior commissure and the juxtacapsular part of lateral division of bed nucleus of stria terminalis). In the thalamus, they were seen in the reticular nucleus, ventromedial nucleus, core VPM, parvicellular part of ventral posterior nucleus, oval paracentral nucleus, medial and triangular parts of posterior nucleus, and zona incerta as well as the VPMcvm. These data suggest that the JCMS proprioceptive information through the dGIrvs2 is transmitted to the emotional 'limbic' regions as well as sensorimotor regions.

Subcortical structural connectivity of insular subregions.

Hidden beneath the Sylvian fissure and sometimes considered as the fifth lobe of the brain, the insula plays a multi-modal role from its strategic location. Previous structural studies have reported cortico-cortical connections with the frontal, temporal, parietal and occipital lobes, but only a few have looked at its connections with subcortical structures. The insular cortex plays a role in a wide range of functions including processing of visceral and somatosensory inputs, olfaction, audition, language, motivation, craving, addiction and emotions such as pain, empathy and disgust. These functions implicate numerous subcortical structures, as suggested by various functional studies. Based on these premises, we explored the structural connectivity of insular ROIs with the thalamus, amygdala, hippocampus, putamen, globus pallidus, caudate nucleus and nucleus accumbens. More precisely, we were interested in unraveling the specific areas of the insula connected to these subcortical structures. By using state-of-the-art HARDI tractography algorithm, we explored here the subcortical connectivity of the insula.

Anatomy, Physiology, and Clinical Syndromes of the Basal Ganglia: A Brief Review.

Movement disorders typically arise from dysfunction of the basal ganglia (BG), cerebellum, or both. The BG-a group of deep, subcortical structures-form complex circuits that shape motor control and motor learning, as well as limbic and associative functions. In this article, we summarize the anatomy and physiology of the BG and cerebellum, and briefly highlight the clinical syndromes that may arise in the context of their injury or dysfunction.