Neuroanatomical considerations for optimizing thalamic deep brain stimulation in Tourette syndrome.

OBJECTIVE: Deep brain stimulation (DBS) of the centromedian thalamic nucleus has been reportedly used to treat severe Tourette syndrome, yielding promising outcomes. However, it remains unclear how DBS electrode position and stimulation parameters modulate the specific area and related networks. The authors aimed to evaluate the relationships between the anatomical location of stimulation fields and clinical responses, including therapeutic and side effects. METHODS: The authors collected data from 8 patients with Tourette syndrome who were treated with DBS. The authors selected the active contact following threshold tests of acute side effects and gradually increased the stimulation intensity within the therapeutic window such that acute and chronic side effects could be avoided at each programming session. The patients were carefully interviewed, and stimulation-induced side effects were recorded. Clinical outcomes were evaluated using the Yale Global Tic Severity Scale, the Yale-Brown Obsessive-Compulsive Scale, and the Hamilton Depression Rating Scale. The DBS lead location was evaluated in the normalized brain space by using a 3D atlas. The volume of tissue activated was determined, and the associated normative connective analyses were performed to link the stimulation field with the therapeutic and side effects. RESULTS: The mean follow-up period was 10.9 ± 3.9 months. All clinical scales showed significant improvement. Whereas the volume of tissue activated associated with therapeutic effects covers the centromedian and ventrolateral nuclei and showed an association with motor networks, those associated with paresthesia and dizziness were associated with stimulation of the ventralis caudalis and red nucleus, respectively. Depressed mood was associated with the spread of stimulation current to the mediodorsal nucleus and showed an association with limbic networks. CONCLUSIONS: This study addresses the importance of accurate implantation of DBS electrodes for obtaining standardized clinical outcomes and suggests that meticulous programming with careful monitoring of clinical symptoms may improve outcomes.

Development of thalamus mediates paternal age effect on offspring reading: A preliminary investigation.

The importance of (inherited) genetic impact in reading development is well established. De novo mutation is another important contributor that is recently gathering interest as a major liability of neurodevelopmental disorders, but has been neglected in reading research to date. Paternal age at childbirth (PatAGE) is known as the most prominent risk factor for de novo mutation, which has been repeatedly shown by molecular genetic studies. As one of the first efforts, we performed a preliminary investigation of the relationship between PatAGE, offspring's reading, and brain structure in a longitudinal neuroimaging study following 51 children from kindergarten through third grade. The results showed that greater PatAGE was significantly associated with worse reading, explaining an additional 9.5% of the variance after controlling for a number of confounds-including familial factors and cognitive-linguistic reading precursors. Moreover, this effect was mediated by volumetric maturation of the left posterior thalamus from ages 5 to 8. Complementary analyses indicated the PatAGE-related thalamic region was most likely located in the pulvinar nuclei and related to the dorsal attention network by using brain atlases, public datasets, and offspring's diffusion imaging data. Altogether, these findings provide novel insights into neurocognitive mechanisms underlying the PatAGE effect on reading acquisition during its earliest phase and suggest promising areas of future research.

Age-related differences in network structure and dynamic synchrony of cognitive control.

Cognitive trajectories vary greatly across older individuals, and the neural mechanisms underlying these differences remain poorly understood. Here, we investigate the cognitive variability in older adults by linking the influence of white matter microstructure on the task-related organization of fast and effective communications between brain regions. Using diffusion tensor imaging and electroencephalography, we show that individual differences in white matter network organization are associated with network clustering and efficiency in the alpha and high-gamma bands, and that functional network dynamics partly explain individual differences in cognitive control performance in older adults. We show that older individuals with high versus low structural network clustering differ in task-related network dynamics and cognitive performance. These findings were corroborated by investigating magnetoencephalography networks in an independent dataset. This multimodal (fMRI and biological markers) brain connectivity framework of individual differences provides a holistic account of how differences in white matter microstructure underlie age-related variability in dynamic network organization and cognitive performance.

The superior parietal lobule of primates: a sensory-motor hub for interaction with the environment.

The superior parietal lobule of the macaque monkey occupies the postero-medial part of the parietal lobe and plays a crucial role in the integration of different sources of information (from visual, motor and somatosensory brain regions) for the purpose of high-level cognitive functions, as perception for action. This region encompasses the intraparietal sulcus and the parieto-occipital sulcus and includes also the precuneate cortex in the mesial surface of the hemisphere. It hosts several areas extensively studied in the macaque: PE, PEip, PEci anteriorly and PEc, MIP, PGm and V6A posteriorly. Recently studies based on functional MRI have suggested putative human homologue of some of the areas of the macaque superior parietal lobule. Here we review the anatomical subdivision, the cortico-cortical and thalamo-cortical connections of the macaque superior parietal lobule compared with their functional properties and the homology with human organization in physiological and lesioned situations. The knowledge of this part of the macaque brain could help in understanding pathological conditions that in humans affect the normal behaviour of arm-reaching actions and can inspire brain computer interfaces performing in more accurate ways the sensorimotor transformations needed to interact with the surrounding environment.

Multiple Visuotopically Organized Subdivisions of the Lateral Pulvinar/Central Lateral Inferior Pulvinar Project into Thin and Thick Stripe Compartments of V2 in Macaques.

The lateral and central lateral inferior pulvinar (PL/PIcl) of primates has been implicated in playing an important role in visual processing, but its physiological and anatomical characteristics remain to be elucidated. It has been suggested that there are two complete visuotopic maps in the PL/PIcl, each of which sends afferents into V2 and V4 in primates. Given that functionally distinct thin and thick stripes of V2 both receive inputs from the PL/PIcl, this raises the possibility of a presence of parallel segregated pathways within the PL/PIcl. To address this question, we selectively injected three types of retrograde tracers (CTB-488, CTB-555, and BDA) into thin or thick stripes in V2 and examined labeling in the PL/PIcl in macaques. As a result, we found that every cluster of retrograde labeling in the PL/PIcl included all three types of signals next to each other, suggesting that thin stripe- and thick stripe-projecting compartments are not segregated into domains. Unexpectedly, we found at least five topographically organized retrograde labeling clusters in the PL/PIcl, indicating the presence of more than two V2-projecting maps. Our results suggest that the PL/PIcl exhibits greater compartmentalization than previously thought. They may be functionally similar but participate in multiple cortico-pulvinar-cortical loops.

An increase in dendritic plateau potentials is associated with experience-dependent cortical map reorganization.

The organization of sensory maps in the cerebral cortex depends on experience, which drives homeostatic and long-term synaptic plasticity of cortico-cortical circuits. In the mouse primary somatosensory cortex (S1) afferents from the higher-order, posterior medial thalamic nucleus (POm) gate synaptic plasticity in layer (L) 2/3 pyramidal neurons via disinhibition and the production of dendritic plateau potentials. Here we address whether these thalamocortically mediated responses play a role in whisker map plasticity in S1. We find that trimming all but two whiskers causes a partial fusion of the representations of the two spared whiskers, concomitantly with an increase in the occurrence of POm-driven N-methyl-D-aspartate receptor-dependent plateau potentials. Blocking the plateau potentials restores the archetypical organization of the sensory map. Our results reveal a mechanism for experience-dependent cortical map plasticity in which higher-order thalamocortically mediated plateau potentials facilitate the fusion of normally segregated cortical representations.

Functional organization and connectivity of the dorsal column nuclei complex reveals a sensorimotor integration and distribution hub.

The dorsal column nuclei complex (DCN-complex) includes the dorsal column nuclei (DCN, referring to the gracile and cuneate nuclei collectively), external cuneate, X, and Z nuclei, and the median accessory nucleus. The DCN are organized by both somatotopy and modality, and have a diverse range of afferent inputs and projection targets. The functional organization and connectivity of the DCN implicate them in a variety of sensorimotor functions, beyond their commonly accepted role in processing and transmitting somatosensory information to the thalamus, yet this is largely underappreciated in the literature. To consolidate insights into their sensorimotor functions, this review examines the morphology, organization, and connectivity of the DCN and their associated nuclei. First, we briefly discuss the receptors, afferent fibers, and pathways involved in conveying tactile and proprioceptive information to the DCN. Next, we review the modality and somatotopic arrangements of the remaining constituents of the DCN-complex. Finally, we examine and discuss the functional implications of the myriad of DCN-complex projection targets throughout the diencephalon, midbrain, and hindbrain, in addition to their modulatory inputs from the cortex. The organization and connectivity of the DCN-complex suggest that these nuclei should be considered a complex integration and distribution hub for sensorimotor information.

The topology of higher-order complexes associated with brain hubs in human connectomes.

Higher-order connectivity in complex systems described by simplexes of different orders provides a geometry for simplex-based dynamical variables and interactions. Simplicial complexes that constitute a functional geometry of the human connectome can be crucial for the brain complex dynamics. In this context, the best-connected brain areas, designated as hub nodes, play a central role in supporting integrated brain function. Here, we study the structure of simplicial complexes attached to eight global hubs in the female and male connectomes and identify the core networks among the affected brain regions. These eight hubs (Putamen, Caudate, Hippocampus and Thalamus-Proper in the left and right cerebral hemisphere) are the highest-ranking according to their topological dimension, defined as the number of simplexes of all orders in which the node participates. Furthermore, we analyse the weight-dependent heterogeneity of simplexes. We demonstrate changes in the structure of identified core networks and topological entropy when the threshold weight is gradually increased. These results highlight the role of higher-order interactions in human brain networks and provide additional evidence for (dis)similarity between the female and male connectomes.

Spatially coherent and topographically organized pathways of the human globus pallidus.

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.

Functional differentiation in the human ventromedial frontal lobe: A data-driven parcellation.

Ventromedial regions of the frontal lobe (vmFL) are thought to play a key role in decision-making and emotional regulation. However, aspects of this area's functional organization, including the presence of a multiple subregions, their functional and anatomical connectivity, and the cross-species homologies of these subregions with those of other species, remain poorly understood. To address this uncertainty, we employed a two-stage parcellation of the region to identify six distinct structures within the region on the basis of data-driven classification of functional connectivity patterns obtained using the meta-analytic connectivity modeling (MACM) approach. From anterior to posterior, the derived subregions included two lateralized posterior regions, an intermediate posterior region, a dorsal and ventral central region, and a single anterior region. The regions were characterized further by functional connectivity derived using resting-state fMRI and functional decoding using the Brain Map database. In general, the regions could be differentiated on the basis of different patterns of functional connectivity with canonical "default mode network" regions and/or subcortical regions such as the striatum. Together, the findings suggest the presence of functionally distinct neural structures within vmFL, consistent with data from experimental animals as well prior demonstrations of anatomical differences within the region. Detailed correspondence with the anterior cingulate, medial orbitofrontal cortex, and rostroventral prefrontal cortex, as well as specific animal homologs are discussed. The findings may suggest future directions for resolving potential functional and structural correspondence of subregions within the frontal lobe across behavioral contexts, and across mammalian species.

Creative music therapy to promote brain function and brain structure in preterm infants: A randomized controlled pilot study.

Cognitive and neurobehavioral problems are among the most severe adverse outcomes in very preterm infants. Such neurodevelopmental impairments may be mitigated through nonpharmacological interventions such as creative music therapy (CMT), an interactive, resource- and needs-oriented approach that provides individual social contact and musical stimulation. The aim was to test the feasibility of a study investigating the role of CMT and to measure the short- and medium-term effects of CMT on structural and functional brain connectivity with MRI. In this randomized, controlled clinical pilot feasibility trial, 82 infants were randomized to either CMT or standard care. A specially trained music therapist provided CMT via infant-directed humming and singing in lullaby style. To test the short-term effects of CMT on brain structure and function, diffusion tensor imaging data and resting-state functional imaging data were acquired. Clinical feasibility was achieved despite moderate parental refusal mainly in the control group after randomization. 40 infants remained as final cohort for the MRI analysis. Structural brain connectivity appears to be moderately affected by CMT, structural connectomic analysis revealed increased integration in the posterior cingulate cortex only. Lagged resting-state MRI analysis showed lower thalamocortical processing delay, stronger functional networks, and higher functional integration in predominantly left prefrontal, supplementary motor, and inferior temporal brain regions in infants treated with CMT. This trial provides unique evidence that CMT has beneficial effects on functional brain activity and connectivity in networks underlying higher-order cognitive, socio-emotional, and motor functions in preterm infants. Our results indicate the potential of CMT to improve long-term neurodevelopmental outcomes in children born very preterm.

The interrelationship of body mass index with gray matter volume and resting-state functional connectivity of the hypothalamus.

BACKGROUND: The hypothalamus plays an important role in regulating body weight through its interactions with multiple brain circuits involved in distinct aspects of feeding behavior. Yet, how hypothalamic gray matter volume (GMV) and connectivity may be related to individual differences in body weight remains unclear. We tested the hypothesis that the hypothalamus shows enhanced resting-state functional connectivity (rsFC) with regions of the reward, motivation, and motor circuits in positive correlation with body mass index (BMI) and the opposite with those associated with inhibitory control. We further examined the interdependent relationships between hypothalamic GMV, connectivity, and body weight. METHODS: Using seed-based rsFC and voxel-based morphometry analyses, we examined the relationship between the rsFC and GMV of the hypothalamus and BMI in 105 healthy humans. Additionally, we employed mediation analyses to characterize the inter-relationships between hypothalamic connectivity, GMV, and BMI. RESULTS: A whole-brain multiple regression showed that BMI was positively correlated with hypothalamic rsFC with the insula, thalamus, globus pallidus, and cerebellum, and negatively correlated with hypothalamic rsFC with the superior parietal lobule. Thus, higher BMI was associated with enhanced hypothalamic connectivity with regions involved in motivated feeding and reduced connectivity with those in support of cognitive control of food intake. A second whole-brain multiple regression revealed a positive correlation between hypothalamic GMV and the hypothalamus-posterior insula connectivity. Finally, the relationship between hypothalamic GMV and BMI was significantly and bidirectionally mediated by the hypothalamus-posterior insula connectivity. CONCLUSIONS: The current findings suggest that the hypothalamus differentially interacts with the motivation, motor, and control circuits to regulate BMI. We further found evidence for the interdependence of hypothalamic structure, function, and body weight, which provides potential insights into the brain mechanisms of obesity.

Linking the impact of aging on visual short-term memory capacity with changes in the structural connectivity of posterior thalamus to occipital cortices.

Aging impacts both visual short-term memory (vSTM) capacity and thalamo-cortical connectivity. According to the Neural Theory of Visual Attention, vSTM depends on the structural connectivity between posterior thalamus and visual occipital cortices (PT-OC). We tested whether aging modifies the association between vSTM capacity and PT-OC structural connectivity. To do so, 66 individuals aged 20-77 years were assessed by diffusion-weighted imaging used for probabilistic tractography and performed a psychophysical whole-report task of briefly presented letter arrays, from which vSTM capacity estimates were derived. We found reduced vSTM capacity, and aberrant PT-OC connection probability in aging. Critically, age modified the relationship between vSTM capacity and PT-OC connection probability: in younger adults, vSTM capacity was negatively correlated with PT-OC connection probability while in older adults, this association was positive. Furthermore, age modified the microstructure of PT-OC tracts suggesting that the inversion of the association between PT-OC connection probability and vSTM capacity with aging might reflect age-related changes in white-matter properties. Accordingly, our results demonstrate that age-related differences in vSTM capacity links with the microstructure and connectivity of PT-OC tracts.

The white matter architecture underlying semantic processing: A systematic review.

From a holistic point of view, semantic processes are subserved by large-scale subcortico-cortical networks. The dynamic routing of information between grey matter structures depends on the integrity of subcortical white matter pathways. Nonetheless, controversy remains on which of these pathways support semantic processing. Therefore, a systematic review of the literature was performed with a focus on anatomo-functional correlations obtained from direct electrostimulation during awake tumor surgery, and conducted between diffusion tensor imaging metrics and behavioral semantic performance in healthy and aphasic individuals. The 43 included studies suggest that the left inferior fronto-occipital fasciculus contributes to the essential connectivity that allows semantic processing. However, it remains uncertain whether its contributive role is limited to the organization of semantic knowledge or extends to the level of semantic control. Moreover, the functionality of the left uncinate fasciculus, inferior longitudinal fasciculus and the posterior segment of the indirect arcuate fasciculus in semantic processing has to be confirmed by future research.

Central taste anatomy and physiology.

The gustatory system contributes to the flavor of foods and beverages and communicates information about nutrients and poisons. This system has evolved to detect and ultimately respond to hydrophilic molecules dissolved in saliva. Taste receptor cells, located in taste buds and distributed throughout the oral cavity, activate nerve afferents that project to the brainstem. From here, information propagates to thalamic, subcortical, and cortical areas, where it is integrated with information from other sensory systems and with homeostatic, visceral, and affective processes. There is considerable divergence, as well as convergence, of information between multiple regions of the central nervous system that interact with the taste pathways, with reciprocal connections occurring between the involved regions. These widespread interactions among multiple systems are crucial for the perception of food. For example, memory, hunger, satiety, and visceral changes can directly affect and can be affected by the experience of tasting. In this chapter, we review the literature on the central processing of taste with a specific focus on the anatomic and physiologic responses of single neurons. Emphasis is placed on how information is distributed along multiple systems with the goal of better understanding how the rich and complex sensations associated with flavor emerge from large-scale, systems-wide, interactions.

Shifting brain circuits in pain chronicity.

The evaluation of brain changes to a specific pain condition in pediatric and adult patients allows for insights into potential mechanisms of pain chronicity and possibly long-term brain changes. Here we focused on the primary somatosensory system (SS) involved in pain processing, namely the ventroposterolateral thalamus (VPL) and the primary somatosensory cortex (SI). We evaluated, using MRI, three specific processes: (a) somatotopy of changes in the SS for different pain origins (viz., foot vs. arm); (b) differences in acute (ankle sprain versus complex regional pain syndrome-CRPS); and (c) differences of the effects of CRPS on SS in pediatric versus adult patients. In all cases, age- and sex-matched individuals were used as controls. Our results suggest a shift in concurrent gray matter density (GMD) and resting functional connectivity strengths (rFC) across pediatric and adult CRPS with (a) differential patterns of GMD (VPL) and rFC (SI) on SS in pediatric vs. adult patterns that are consistent with upper and lower limb somatotopical organization; and (b) widespread GMD alterations in pediatric CRPS from sensory, emotional and descending modulatory processes to more confined sensory-emotional changes in adult CRPS and rFC patterns from sensory-sensory alterations in pediatric populations to a sensory-emotional change in adult populations. These results support the idea that pediatric and adult CRPS are differentially represented and may reflect underlying differences in pain chronification across age groups that may contribute to the well-known differences between child and adult pain vulnerability and resilience.

Structure-function multi-scale connectomics reveals a major role of the fronto-striato-thalamic circuit in brain aging.

Physiological aging affects brain structure and function impacting morphology, connectivity, and performance. However, whether some brain connectivity metrics might reflect the age of an individual is still unclear. Here, we collected brain images from healthy participants (N = 155) ranging from 10 to 80 years to build functional (resting state) and structural (tractography) connectivity matrices, both data sets combined to obtain different connectivity features. We then calculated the brain connectome age-an age estimator resulting from a multi-scale methodology applied to the structure-function connectome, and compared it to the chronological age (ChA). Our results were twofold. First, we found that aging widely affects the connectivity of multiple structures, such as anterior cingulate and medial prefrontal cortices, basal ganglia, thalamus, insula, cingulum, hippocampus, parahippocampus, occipital cortex, fusiform, precuneus, and temporal pole. Second, we found that the connectivity between basal ganglia and thalamus to frontal areas, also known as the fronto-striato-thalamic (FST) circuit, makes the major contribution to age estimation. In conclusion, our results highlight the key role played by the FST circuit in the process of healthy aging. Notably, the same methodology can be generally applied to identify the structural-functional connectivity patterns correlating to other biomarkers than ChA.

EEG Signatures of Dynamic Functional Network Connectivity States.

The human brain operates by dynamically modulating different neural populations to enable goal directed behavior. The synchrony or lack thereof between different brain regions is thought to correspond to observed functional connectivity dynamics in resting state brain imaging data. In a large sample of healthy human adult subjects and utilizing a sliding windowed correlation method on functional imaging data, earlier we demonstrated the presence of seven distinct functional connectivity states/patterns between different brain networks that reliably occur across time and subjects. Whether these connectivity states correspond to meaningful electrophysiological signatures was not clear. In this study, using a dataset with concurrent EEG and resting state functional imaging data acquired during eyes open and eyes closed states, we demonstrate the replicability of previous findings in an independent sample, and identify EEG spectral signatures associated with these functional network connectivity changes. Eyes open and eyes closed conditions show common and different connectivity patterns that are associated with distinct EEG spectral signatures. Certain connectivity states are more prevalent in the eyes open case and some occur only in eyes closed state. Both conditions exhibit a state of increased thalamocortical anticorrelation associated with reduced EEG spectral alpha power and increased delta and theta power possibly reflecting drowsiness. This state occurs more frequently in the eyes closed state. In summary, we find a link between dynamic connectivity in fMRI data and concurrently collected EEG data, including a large effect of vigilance on functional connectivity. As demonstrated with EEG and fMRI, the stationarity of connectivity cannot be assumed, even for relatively short periods.

Mapping cortical mesoscopic networks of single spiking cortical or sub-cortical neurons.

Understanding the basis of brain function requires knowledge of cortical operations over wide-spatial scales, but also within the context of single neurons. In vivo, wide-field GCaMP imaging and sub-cortical/cortical cellular electrophysiology were used in mice to investigate relationships between spontaneous single neuron spiking and mesoscopic cortical activity. We make use of a rich set of cortical activity motifs that are present in spontaneous activity in anesthetized and awake animals. A mesoscale spike-triggered averaging procedure allowed the identification of motifs that are preferentially linked to individual spiking neurons by employing genetically targeted indicators of neuronal activity. Thalamic neurons predicted and reported specific cycles of wide-scale cortical inhibition/excitation. In contrast, spike-triggered maps derived from single cortical neurons yielded spatio-temporal maps expected for regional cortical consensus function. This approach can define network relationships between any point source of neuronal spiking and mesoscale cortical maps.

Essential Subcortical Tracts in Language and Reading. 3D-Tractography for Clinical Practice and Anatomic Correlation with Intraoperative Subcortical Electrostimulation.

Diffusion tensor imaging (DTI) and tractography provide the neurosurgeon with a valid 3D view of the white matter tracts of the brain for the presurgical planning of the treatment of lesions close to eloquent areas, this being one of the principal clinical applications of this technique. In this article, we describe through practical cases the anatomic relationships of white matter tracts that are essential for language and reading, based on DTI studies and the excellent anatomic correlation with the intraoperative subcortical map.