Corticopontine Research Articles

Associations between white matter integrity and postural control in adults with traumatic brain injury.

Abnormalities of postural sway have been extensively reported in traumatic brain injury (TBI). However, the underlying neural correlates of balance disturbances in TBI remain to be elucidated. Studies in children with TBI have reported associations between the Sensory Organization Test (SOT) and measures of white matter (WM) integrity with diffusion tensor imaging (DTI) in brain areas responsible for multisensory integration. This study seeks to replicate those associations in adults as well as explore relationships between DTI and the Limits of Stability (LOS) Test. Fifty-six participants (43±17 years old) with a history of TBI were tested 30 days to 5 years post-TBI. This study confirmed results in children for associations between the SOT and the medial lemniscus as well as middle cerebellar peduncle, and revealed additional associations with the posterior thalamic radiation. Additionally, this study found significant correlations between abnormal LOS scores and impaired WM integrity in the cingulum, corpus callosum, corticopontine and corticospinal tracts, fronto-occipital fasciculi, longitudinal fasciculi, medial lemniscus, optic tracts and thalamic radiations. Our findings indicate the involvement of a broad range of WM tracts in the control of posture, and demonstrate the impact of TBI on balance via disruptions to WM integrity.

The Infratrigeminal Suprafloccular Approach to Intrapontine Lesions: An Anatomical Overview and Relevance for the Approach to Intrapontine Lesions.

Background and objectives Brainstem lesions have long been considered complex pathologies that may lead to permanent deficits or life-threatening complications, posing significant challenges for surgical removal. Among these lesions, intrapontine lesions are particularly challenging in the field of neurosurgery. However, with advancements in microsurgical anatomy knowledge and technology, these lesions have become more amenable to surgical treatment. In this study, the authors examine an infratrigeminal suprafloccular approach, which has been shown to be a safe surgical route, resulting in fewer postoperative complications, while evaluating the anatomical nuances of the approach and route. Methods Twenty cadaveric brainstem specimens were analyzed to assess the anatomy, focusing on the lateral aspect of the pons as a potential safe entry zone for intrapontine lesions. The authors consistently analyzed twenty brainstem specimens, carefully examining the pontine microsurgical anatomy. A triangular area of entrance was measured, with three sides or walls (X, Y, and Z) aiming to identify the safe zone that would spare the distinct pontine nuclei, ascending sensory pathways, corticospinal, corticonuclear, and corticopontine tracts of the brainstem. An illustrative case was adapted to the described safe entry zone for corroboration purposes. Results The authors measured three distinct lines on the lateral surface of the pons, named X, Y, and Z, forming a triangle in shape. Line X extended from the midpoint anteroposteriorly of the flocculus of the cerebellum to the apparent trigeminal exit in the lateral aspect of the pons. Line Y ran from the trigeminal exit in the pons to the apparent exit of the facial-vestibulocochlear complex in the far lateral aspect of the pontomedullary sulcus in the cerebellopontine fissure. Line Z represented the measurement from the vestibulocochlear complex to the midpoint anteroposteriorly of the flocculus of the cerebellum. The mean measurements were as follows: X = 14.41mm (range: 10mm to 20mm), Y = 13.1mm (range: 10mm to 21mm), and Z = 3mm (range: 2mm to 5mm). The mean surface area of the analyzed specimens within the triangle (formed by X, Y, and Z) was 20.1mm² (range: 10mm² to 40mm²). This area was identified as a safe zone for the entry of microsurgical approaches to intrapontine lesions, involving less retraction of the anterior pons and potentially sparing critical structures, such as the corticospinal tracts, pontine perforating arteries, tegmentum pontis, cranial nerve nuclei, substantia reticulata dorsally, and transverse pontine fibers. Microsurgical anatomical findings, combined with intraoperative monitoring in an illustrative case, consistently demonstrated that this entry area predicted less functional instability of the analyzed tracts and resulted in fewer postoperative complications. Conclusion Deep-seated pontine lesions present a complex range of pathologies with a high potential for devastating outcomes, particularly those involving hemorrhage. This study identifies and describes a presumed safe entry zone that allows for the creation of a surgical corridor for biopsy or microsurgical resection of these lesions, reducing morbidity in a previously considered impenetrable region.

Disrupted structural connectivity and less efficient network system in patients with the treatment-naive adult attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder whose primary symptoms are hyperactivity, impulsivity, and inattention. Historically, ADHD was recognized as a disease of childhood and adolescence. However, many patients are known to have persistent symptoms into adulthood. Many researchers consider the neuropathology of ADHD to be based on abnormalities in multiple parallel and intersecting pathways rather than a single anatomical area, but such alterations remain to be clarified. Using diffusion tensor imaging, we investigated differences in the global network metrics estimated by graph theory and the degree of connectivity between adjacent voxels within a white matter (WM) fascicle defined by the density of the diffusing spins (connectometry) between 19 drug-naive Japanese patients with adult ADHD and 19 matched healthy controls (HCs). In adult patients with ADHD, we examined the relationships between the symptomatology of ADHD and global network metrics and WM abnormalities. Compared with HCs, adult patients with ADHD showed a reduced rich-club coefficient and decreased connectivity in widely distributed WMs such as the corpus callosum, the forceps, and the cingulum bundle. Correlational analyses demonstrated that the general severity of ADHD symptoms was associated with several global network metrics, such as lower global efficiency, clustering coefficient, small worldness, and longer characteristic path length. The connectometry revealed that the severity of hyperactive/impulsive symptoms was associated with overconnectivity in the corticostriatal, corticospinal, and corticopontine tracts, the inferior fronto-occipital fasciculus, and the extreme capsule but dysconnectivity in the cerebellum. The severity of inattentive symptoms was associated with dysconnectivity in the intracerebellar circuit and some other fibers. The results of the present study indicated that patients with treatment-naive adult ADHD showed disrupted structural connectivity, which contributes to less efficient information transfer in the ADHD brain and pathophysiology of ADHD. UMIN Clinical Trials Registry (UMIN-CTR) UMIN000025183, Registered: 5 January 2017.

The language-related cerebro-cerebellar pathway in humans: a diffusion imaging-based tractographic study.

The cerebellum and cerebral cortex form the most important cortico-cerebellar system in the brain. However, diffusion magnetic resonance imaging (MRI)-based tractography of the connecting white matter between the cerebellum and cerebral cortex, which support language function, has not been extensively reported on. This work aims to serve as a guideline for facilitating the analysis of white matter tracts along the language-related cerebro-cerebellar pathway (LRCCP), which includes the corticopontine, pontocerebellar, corticorubral, rubroolivary, olivocerebellar, and dentatorubrothalamic tracts. The LRCCP templates were developed via processing the high-resolution, population-averaged atlas available in the Human Connectome Project (HCP)-1065 dataset (2017 Q4, 1,200-subject release) in DSI Studio. The deterministic tracking was performed with the manually selected regions of interest (ROIs) on this atlas according to prior anatomic knowledge. Templates were then applied to the MRI datasets of 30 health participants acquired from a single hospital to verify the practicability of the tracking. The diffusion tensor and shape analysis metrics were calculated for all LRCCP tracts. Differences in the tracking metrics between the left and right hemispheres were compared, and the related white matter asymmetry was discussed. The LRCCP templates were successfully created and applied to healthy participants for quantitative analysis. Significantly higher mean fractional anisotropy (FA) values were discovered on the left (L) corticorubral tract [L, 0.43±0.02 vs. right (R), 0.41±0.02; P<0.01] and left dentatorubrothalamic tract (L, 0.47±0.02 vs. R, 0.46±0.02; P<0.01). Significant differences in tract volume and streamline number were observed between the corticopontine, corticorubral, and dentatorubrothalamic tracts. The size of the right corticopontine and corticorubral tracts were smaller, and both had smaller streamline numbers and innervation areas when compared with the contralateral sides. The R dentatorubrothalamic tract showed a larger volume (R, 23,582.47±4,160.71 mm3 vs. L, 19,821.27±2,983.91 mm3; P<0.01) and innervation area (R, 2,117.37±433.98 mm2 vs. L, 1,610.00±356.19 mm2; P<0.01) than did the L side. No significant differences were observed in the rubroolivary tracts. This work suggests the feasibility of applying tractography templates of the LRCCP to quantitatively evaluate white matter properties associated with language function. Lateralized diffusion metrics were observed in preliminary experiments. LRCCP tractography-based research may provide a potential quantitative method to better understanding neuroplasticity.

Examining The Effects Of Mild Traumatic Brain Injury On Brainstem Integrity

Concussion-related brainstem injuries have received little attention in research, yet concussion-related symptoms, e.g. headache and postural instability, share a common neurological origin within the brainstem. As advanced neuroimaging techniques evolve, so do opportunities to better examine the underlying damage in the brainstem and its related white matter (WM) circuitry following an mTBI. PURPOSE: To examine the brainstem integrity in mTBI patients using advanced neuroimaging techniques. METHODS: T1-weighted and diffiusion-weighted MRI scans were performed on 13 mTBI participants within 14 days of their injuries and 3 individuals without history of brain injury. Diffusion images were acquired using a multishell high-definition fiber tracking sequence. The data were reconstructed using generalized q-sampling imaging, then a deterministic fiber tracking algorithm was applied to generate WM tract profiles indicating the quantitative anisotropy (QA) for the bilateral frontal, parietal, and occipital corticopontine tracts (CPT), the corticospinal tracts (CST), the corticoreticular tracts (CRT), and the middle cerebellar peduncle (MCP). Volumes of the midbrain, pons, medulla oblongata, and superior cerebellar peduncle were determined using Freesurfer v6. A two-sample t-test was used to determine between-group differences in the segmented brainstem structures. One-dimensional statistical parametric mapping was performed to compare WM tracts, and Hedge’s g was calculated to determine between-group effect size.RESULTS: QA values for the first 5% (caudal end) of the left CPT-F was significantly lower in the mTBI group (p = .021). Large effect sizes were found when comparing mTBI to control groups for overall tract QA for the right CPT-O and CPT-F, left and right CPT-P, CST, CRT, and MCP (g > 0.8), with the largest effect for the left CPT-F tract (g = 1.64). There were no significant differences between groups in the segmented brainstem volumes. CONCLUSION: Lower QA values in the caudal portion of the CPT-F indicate that WM near the brainstem may be susceptible to mTBI-related change despite a lack of effect on brainstem volume. Further research should investigate the brainstem after mTBI. Supported by NIH Grant R21 12973518

Endoscopic Anatomy of Transcallosal Hemispherotomy: Laboratory Study with Advanced Three-Dimensional Modeling

Epilepsy surgery has an important role in the treatment of patients with medically intractable seizures. Various authors have proposed an endoscopic technique to perform disconnective procedures. A detailed description of intracerebral anatomy seen through an endoscopic transcallosal corridor has not been reported. The aim of this study was to present a cadaveric step-by-step anatomical demonstration of endoscopic transcallosalhemispherotomy using a dedicated three-dimensional model. Anatomical dissections were performed on 6 cadaveric heads (12 hemispheres), and the disconnective procedure was performed using an endoscopic transcallosal approach. A dedicated three-dimensional model was used to better illustrate each step. A simulation of the disconnective procedure was performed by recreating the surgical steps on a subject from the Human Connectome Project dataset, and a calculation of the fiber tracts intersected was performed. Analyzing data extracted from the three-dimensional model and tractography simulation, 100% of the fibers (streamlines) of corpus callosum, corticopontine tracts, corticospinal tract, and inferior fronto-occipital fascicle were transected. Moreover, a satisfactory number of fibers (>95%) of the thalamocortical tracts, corticostriatal tracts, corona radiata, fornix, and uncinate fascicle were disconnected. This anatomical study described the relevant neurovascular structures to enable prediction of feasibility and control of the surgical procedure using the endoscopic transcallosal approach. The quantitative analysis permitted estimation of the theoretical efficacy of the procedure, confirming its relevant role in disconnective surgery.

Sex-Specific Patterns of Body Mass Index Relationship with White Matter Connectivity.

Background:Obesity is an increasingly recognized modifiable risk factor for Alzheimer’s disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity.Objective:We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity.Methods:A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm.Results:We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status.Conclusion:BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

Diffusion spectrum imaging of patients with middle cerebral artery stenosis

ObjectiveWe aimed to detect microstructural changes in the brains of patients with unilateral middle cerebral artery (MCA) stenosis and to assess the integrity of the fiber structure and the small-world networks using diffusion spectrum imaging (DSI). MethodsA total of 21 healthy controls and 48 patients with unilateral MCA stenosis underwent 3.0 T MRI examination using DSI technique. Differential tractography, diffusion connectometry, and structural networks were performed by using DSI software. The correlation between the stenosis and quantitative anisotropy (QA) were analyzed using multiple regression models in the correlation tractography. ResultsDifferential tractography analysis showed that the left or right MCA stenosis group had decreased fiber connectivity in the brain network compared with the control group. The correlation tractography analysis of the patients with MCA stenosis showed that QA was negatively correlated with stenosis in the bilateral arcuate fasciculus, bilateral corticostriatal and corticothalamic pathway, bilateral corticopontine and corticospinal tract, right superior longitudinal fasciculus, right cingulum, corpus callosum, and left frontal aslant tract. Statistically significant differences were shown between the MCA stenosis groups and control group in graph density, global efficiency, network path length, and rich club coefficient. ConclusionDSI revealed that stroke-free patients with unilateral MCA stenosis have a disrupted structural network and damaged white matter fibers. Furthermore, the fiber connection disruption is more severe in the ipsilateral hemisphere and less prominent in the contralateral hemisphere in patients with unilateral MCA stenosis. Therefore, microstructural impairment has happened to patients with unilateral MCA stenosis even at a subclinical stage.

Body mass index predicts lower connectivity in associational fibers of the temporal lobe in older men

Increased body mass index (BMI) is related to changes in white matter (WM) connectivity1 . We investigated whether WM connectivity patterns as a function of BMI varies across sex differences.We enrolled 289 individuals (58 CDR=0 & 231 CDR=0.5) from the Knight Alzheimer Disease Research Center (ADRC) (Table 1). Participants were included if they had a physical evaluation within 12 months of a diffusion MRI scan and excluded if they had clinical dementia. Connectome analyses were performed using the DSI Studio software (http://dsi-studio.labsolver.org/). Diffusion data were reconstructed in the MNI space using q-space diffeomorphic reconstruction (QSDR)2 . The quantitative anisotropy was extracted as the local connectome fingerprint. A multi-regression model were used to derive the correlation and a false discovery rate threshold of 0.05 was adopted to select tracts using a deterministic fiber tracking algorithm.A positive association between connectivity in the left arcuate fasciculus (AF) and the left middle cerebellar peduncle in men did not survive regression for age (Figure 1-A). Men also showed a statistically significant negative association between connectivity in the bilateral inferior longitudinal fasciculi (ILF), right inferior fronto-occipital fasciculus (IFOF), the frontoparietal and parahippocampal parts of the right cingulum, the tapetum part of the corpus callosum (CC), right fornix and right corticospinal, corticostriatal, and corticopontine tracts. All of these relationships persisted when co-varying for age (Figure 1-B). Results in women revealed a significant positive correlation between connectivity of the right IFOF, right superior longitudinal fasciculus (SLF), right corticopontine, corticospinal tracts, bilateral reticulospinal tracts, and left arcuate fasciculus (AF) (Figure 2-A) even when controlling for age. Connectivity in the bilateral ILF, right IFOF and the tapetum part of the CC showed an inverse correlation with BMI in women (Figure 2-B).Increased BMI is related to lower structural connectivity in important associational WM fibers of the temporal lobe, particularly in older men.

Anatomy and white-matter connections of the precuneus.

Purpose Advances in neuroimaging have provided an understanding of the precuneus'(PCu) involvement in functions such as visuospatial processing and cognition. While the PCu has been previously determined to be apart of a higher-order default mode network (DMN), recent studies suggest the presence of possible dissociations from this model in order to explain the diverse functions the PCu facilitates, such as in episodic memory. An improved structural model of the white-matter anatomy of the PCu can demonstrate its unique cerebral connections with adjacent regions which can provide additional clarity on its role in integrating information across higher-order cerebral networks like the DMN. Furthermore, this information can provide clinically actionable anatomic information that can support clinical decision making to improve neurologic outcomes such as during cerebral surgery. Here, we sought to derive the relationship between the precuneus and underlying major white-mater bundles by characterizing its macroscopic connectivity. Methods Structural tractography was performed on twenty healthy adult controls from the Human Connectome Project (HCP) utilizing previously demonstrated methodology. All precuneus connections were mapped in both cerebral hemispheres and inter-hemispheric differences in resultant tract volumes were compared with an unpaired, corrected Mann-Whitney U test and a laterality index(LI) was completed. Ten postmortem dissections were then performed to serve as ground truth by using a modified Klingler technique with careful preservation of relevant white matter bundles. Results The precuneus is a heterogenous cortical region with five major types of connections that were present bilaterally. (1) Short association fibers connect the gyri of the precuneus and connect the precuneus to the superior parietal lobule and the occipital cortex. (2) Four distinct parts of the cingulum bundle connect the precuneus to the frontal lobe and the temporal lobe. (3) The middle longitudinal fasciculus from the precuneus connects to the superior temporal gyrus and the dorsolateral temporal pole. (4) Parietopontine fibers travel as part of the corticopontine fibers to connect the precuneus to pontine regions. (5) An extensive commissural bundle connects the precuneus bilaterally. Conclusion We present a summary of the anatomic connections of the precuneus as part of an effort to understand the function of the precuneus and highlight key white-matter pathways to inform surgical decision-making. Our findings support recent models suggesting unique fiber connections integrating at the precuneus which may suggest finer subsystems of the DMN or unique networks, but further study is necessary to refine our model in greater quantitative detail.

Sex Differences are Reflected in Microstructural White Matter Alterations of Musical Sophistication: A Diffusion MRI Study.

Background: The human-specified ability to engage with different kinds of music in sophisticated ways is named “Musical Sophistication.” Herein, we investigated specific white matter (WM) tracts that are associated with musical sophistication and musicality in both genders, separately, using Diffusion MRI connectometry approach. We specifically aimed to explore potential sex differences regarding WM alterations correlated with musical sophistication.Methods: 123 healthy participants [70 (56.9%) were male, mean age = 36.80 ± 18.86 year], who were evaluated for musical sophistication using Goldsmiths Musical Sophistication Index (Gold-MSI) self-assessment instrument from the LEMON database, were recruited in this study. The WM correlates of two Gold-MSI subscales (active engagement and music training) were analyzed. Images were prepared and analyzed with diffusion connectometry to construct the local connectome. Multiple regression models were then fitted to address the correlation of local connectomes with Gold-MSI components with the covariates of age and handedness.Results: a significant positive correlation between WM integrity in the corpus callosum (CC), right corticospinal tract (CST), cingulum, middle cerebellar peduncle (MCP), bilateral parieto-pontine tract, bilateral cerebellum, and left arcuate fasciculus (AF) and both active engagement [false discovery rate (FDR) = 0.008] and music training (FDR = 0.057) was detected in males. However, WM integrity in the body of CC, MCP, and cerebellum in females showed an inverse association with active engagement (FDR = 0.046) and music training (FDR = 0.032).Conclusion: WM microstructures with functional connection with motor and somatosensory areas (CST, cortico-pontine tracts, CC, cerebellum, cingulum, and MCP) and language processing area (AF) have significant correlation with music engagement and training. Our findings show that these associations are different between males and females, which could potentially account for distinctive mechanisms related to musical perception and musical abilities across genders.

Pyramidal weakness: Is it time to retire the term?

Pyramidal weakness, that is, the weakness that preferentially spares the antigravity muscles, is considered an integral part of the upper motor neuron syndrome. Despite its name, pyramidal weakness has very little to do with the pyramidal tract, and preeminent texts on neurology, neuroanatomy, and clinical examination differ considerably in their descriptions and localization of this enigmatic finding. Evidence from human and nonhuman primate studies demonstrates that lesions confined only to the corticospinal (pyramidal) tract cause significant deficits in fine motor control of the hand, but do not cause posturing or patterned weakness of the extremities. Lesioning of the corticofugal fibers, particularly the corticoreticular and corticopontine tracts, leads to dysbalanced output from reticulospinal, and vestibulospinal systems, which along with changes in rubrospinal tract output balance, probably accounts for the pyramidal weakness pattern. Importantly, this would delineate that pyramidal weakness could only be incited by lesions above the brainstem. It has also been suggested that the inherently greater strength of the antigravity musculature is the substrate for pyramidal weakness, independent of any preferential motor innervation. These hypotheses require further testing in myometric studies with carefully selected participants.

Structural and Functional Brain Abnormalities in Human Immunodeficiency Virus Disease Revealed by Multimodal Magnetic Resonance Imaging Fusion: Association With Cognitive Function.

Human immunodeficiency virus (HIV)-associated neurocognitive impairment remains a prevalent comorbidity that impacts daily functioning and increases morbidity. While HIV infection is known to cause widespread disruptions in the brain, different magnetic resonance imaging (MRI) modalities have not been effectively integrated. In this study, we applied 3-way supervised fusion to investigate how structural and functional coalterations affect cognitive function. Participants (59 people living with HIV and 58 without HIV) completed comprehensive neuropsychological testing and multimodal MRI scanning to acquire high-resolution anatomical, diffusion-weighted, and resting-state functional images. Preprocessed data were reduced using voxel-based morphometry, probabilistic tractography, and regional homogeneity, respectively. We applied multimodal canonical correlation analysis with reference plus joint independent component analysis using global cognitive functioning as the reference. Compared with controls, participants living with HIV had lower global cognitive functioning. One joint component was both group discriminating and correlated with cognitive function. This component included the following covarying regions: fractional anisotropy in the corpus callosum, short and long association fiber tracts, and corticopontine fibers; gray matter volume in the thalamus, prefrontal cortex, precuneus, posterior parietal regions, and occipital lobe; and functional connectivity in frontoparietal and visual processing regions. Component loadings for fractional anisotropy also correlated with immunosuppression. These results suggest that coalterations in brain structure and function can distinguish people with and without HIV and may drive cognitive impairment. As MRI becomes more commonplace in HIV care, multimodal fusion may provide neural biomarkers to support diagnosis and treatment of cognitive impairment.

A Reproducible New Model of Focal Ischemic Injury in the Marmoset Monkey: MRI and Behavioural Follow-Up.

Ischemic stroke mostly affects the primary motor cortex and descending motor fibres, with consequent motor impairment. Pre-clinical models of stroke with reproducible and long-lasting sensorimotor deficits in higher-order animals are lacking. We describe a new method to induce focal brain damage targeting the motor cortex to study damage to the descending motor tracts in the non-human primate. Stereotaxic injection of malonate into the primary motor cortex produced a focal lesion in middle-aged marmosets (Callithrix jacchus). Assessment of sensorimotor function using a neurological scale and testing of forelimb dexterity and strength lasted a minimum of 12weeks. Lesion evolution was followed by magnetic resonance imaging (MRI) at 24h, 1 week, 4 and 12 weeks post-injury and before sacrifice for immunohistochemistry. Our model produced consistent lesions of the motor cortex, subcortical white matter and caudate nucleus. All animals displayed partial spontaneous recovery with long lasting motor deficits of force (54% loss) and dexterity (≈ 70% loss). Clearly visible T2 hypointensity in the white matter was observed with MRI and corresponded to areas of chronic gliosis in the internal capsule and lenticular fasciculus. We describe a straightforward procedure to reproducibly injure the motor cortex in the marmoset monkey, causing long-lasting motor deficits. The MRI signature reflects Wallerian degeneration and remote injury of corticospinal and corticopontine tracts, as well as subcortical motor loops. Our model may be suitable for the testing of therapies for post-stroke recovery, particularly in the chronic phase.

Identifying and characterizing projections from the subthalamic nucleus to the cerebellum in humans

A connection between the subthalamic nucleus (STN) and the cerebellum which has been shown to exist in non-human primates, was recently identified in humans. However, its anatomical features, network properties and function have yet to be elucidated in humans. In the present study, we quantified the STN-cerebellum pathway in humans and explored its function based on structural observations. Anatomical features and asymmetry index (AI) were explored using high definition fiber tractography data of 30 individuals from the Massachusetts General Hospital – Human Connectome Project adult diffusion database. Pearson’s correlation analysis was performed to determine the interrelationship between the subdivisions of the STN-cerebellum and the global cortical-STN connections. The pathway was visualized bilaterally in all the subjects. Typically, after setting out from the STN, the STN-cerebellum projections incorporated into the nearby corticopontine tracts, passing through the cerebral peduncle, mediated by the pontine nucleus and then connecting in two opposite directions to join the bilateral middle cerebellar peduncle. On the group averaged level, 78.03% and 62.54% of fibers from the right and left STN respectively, distributed to Crus I in the cerebellum, part of the remaining fibers projected to Crus II, with most of the fibers crossing contralaterally. According to the AI evaluation, 60% of the participants were right STN dominant, 23% were left STN dominant, and 17% were relatively symmetric. Pearson’s correlation analysis further indicated that the number of pathways from mesial Brodmann area 8 to the STN (hyperdirect pathway associated with decision making) was positively correlated with the number of fibers from the right STN to Crus I. The insertion and termination, the right-side dominance, and the positive correlation with the hyperdirect pathway all suggest that the STN-cerebellum pathway might be involved in decision-making processes.

Network reorganisation following anterior temporal lobe resection and relation with post-surgery seizure relapse: A longitudinal study

ObjectiveTo characterise temporal lobe epilepsy (TLE) surgery-induced changes in brain network properties, as measured using diffusion weighted MRI, and investigate their association with postoperative seizure-freedom. MethodsFor 48 patients who underwent anterior temporal lobe resection, diffusion weighted MRI was acquired pre-operatively, 3–4 months post-operatively (N = 48), and again 12 months post-operatively (N = 13). Data for 17 controls were also acquired over the same period. After registering all subjects to a common space, we performed two complementary analyses of the subjects’ quantitative anisotropy (QA) maps. 1) A connectometry analysis which is sensitive to changes in subsections of fasciculi. 2) A graph theory approach which integrates connectivity information across the wider brain network. ResultsWe found significant postoperative alterations in QA in patients relative to controls measured over the same period. Reductions were primarily located in the uncinate fasciculus and inferior fronto-occipital fasciculus ipsilaterally for all patients. Larger reductions were associated with postoperative seizure-freedom in left TLE. Increased QA was mainly located in corona radiata and corticopontine tracts. Graph theoretic analysis revealed widespread increases in nodal betweenness centrality, which were not associated with patient outcomes. ConclusionSubstantial alterations in QA occur in the months after epilepsy surgery, suggesting Wallerian degeneration and strengthening of specific white matter tracts. Greater reductions in QA were related to postoperative seizure freedom in left TLE.

Control of excitatory hierarchical circuits by parvalbumin-FS basket cells in layer 5 of the frontal cortex: insights for cortical oscillations.

The cortex contains multiple neuron types with specific connectivity and functions. Recent progress has provided a better understanding of the interactions of these neuron types as well as their output organization particularly for the frontal cortex, with implications for the circuit mechanisms underlying cortical oscillations that have cognitive functions. Layer 5 pyramidal cells (PCs) in the frontal cortex comprise two major subtypes: crossed-corticostriatal (CCS) and corticopontine (CPn) cells. Functionally, CCS and CPn cells exhibit similar phase-dependent firing during gamma waves but participate in two distinct subnetworks that are linked unidirectionally from CCS to CPn cells. GABAergic parvalbumin-expressing fast-spiking (PV-FS) cells, necessary for gamma oscillation, innervate PCs, with stronger and global inhibition to somata and weaker and localized inhibitions to dendritic shafts/spines. While PV-FS cells form reciprocal connections with both CCS and CPn cells, the excitation from CPn to PV-FS cells exhibits short-term synaptic dynamics conducive for oscillation induction. The electrical coupling between PV-FS cells facilitates spike synchronization among PV-FS cells receiving common excitatory inputs from local PCs and inhibits other PV-FS cells via electrically communicated spike afterhyperpolarizations. These connectivity characteristics can promote synchronous firing in the local networks of CPn cells and firing of some CCS cells by anode-break excitation. Thus subsets of L5 CCS and CPn cells within different levels of connection hierarchy exhibit coordinated activity via their common connections with PV-FS cells, and the resulting PC output drives diverse neuronal targets in cortical layer 1 and the striatum with specific temporal precision, expanding the computational power of the cortical network.

Preferential cholinergic excitation of corticopontine neurons.

Phasic activation of M1 muscarinic receptors generates transient inhibition followed by longer lasting excitation in neocortical pyramidal neurons. Corticopontine neurons in the mouse prefrontal cortex exhibit weaker cholinergic inhibition, but more robust and longer lasting excitation, than neighbouring callosal projection neurons. Optogenetic release of endogenous ACh in response to single flashes of light (5ms) preferentially enhances the excitability of corticopontine neurons for many tens of seconds. Cholinergic excitation of corticopontine neurons involves at least three ionic mechanisms: suppression of KV 7 currents, activation of the calcium-dependent non-specific cation conductance underlying afterdepolarizations, and activation of what appears to be a calcium-sensitive but calcium-permeable non-specific cation conductance. Preferential cholinergic excitation of prefrontal corticopontine neurons may facilitate top-down attentional processes and behaviours. Pyramidal neurons in layer 5 of the neocortex comprise two broad classes of projection neurons: corticofugal neurons, including corticopontine (CPn) neurons, and intratelencephalic neurons, including commissural/callosal (COM) neurons. These non-overlapping neuron subpopulations represent discrete cortical output channels contributing to perception, decision making and behaviour. CPn and COM neurons have distinct morphological and physiological characteristics, and divergent responses to modulatory transmitters such as serotonin and acetylcholine (ACh). To better understand how ACh regulates cortical output, in slices of mouse prefrontal cortex (PFC) we compared the responsivity of CPn and COM neurons to transient exposure to exogenous or endogenous ACh. In both neuron subtypes, exogenous ACh generated qualitatively similar biphasic responses in which brief hyperpolarization was followed by longer lasting enhancement of excitability. However, cholinergic inhibition was more pronounced in COM neurons, while excitatory responses were larger and longer lasting in CPn neurons. Similarly, optically triggered release of endogenous ACh from cholinergic terminals preferentially and persistently (for ∼40s) enhanced the excitability of CPn neurons, but had little impact on COM neurons. Cholinergic excitation of CPn neurons involved at least three distinct ionic mechanisms: suppression of KV 7 channels (the 'M-current'), activation of the calcium-dependent non-specific cation conductance underlying afterdepolarizations, and activation of what appears to be a calcium-sensitive but calcium-permeable non-specific cation conductance. Our findings demonstrate projection-specific selectivity in cholinergic signalling in the PFC, and suggest that transient release of ACh during behaviour will preferentially promote corticofugal output.

Segregated Excitatory-Inhibitory Recurrent Subnetworks in Layer 5 of the Rat Frontal Cortex.

A prominent feature of neocortical pyramidal cells (PCs) is their numerous projections to diverse brain areas. In layer 5 (L5) of the rat frontal cortex, there are 2 major subtypes of PCs that differ in their long-range axonal projections, corticopontine (CPn) cells and crossed corticostriatal (CCS) cells. The outputs of these L5 PCs can be regulated by feedback inhibition from neighboring cortical GABAergic cells. Two major subtypes of GABAergic cells are parvalbumin (PV)-positive and somatostatin (SOM)-positive cells. PV cells have a fast-spiking (FS) firing pattern, while SOM cells have a low threshold spike (LTS) and regular spiking. In this study, we found that the 2 PC subtypes in L5 selectively make recurrent connections with LTS cells. The connection patterns correlated with the morphological and physiological diversity of LTS cells. LTS cells with high input resistance (Ri) exhibited more compact dendrites and more rebound spikes than LTS cells with low Ri, which had vertically elongated dendrites. LTS subgroups differently inhibited the PC subtypes, although FS cells made nonselective connections with both projection subtypes. These results demonstrate a novel recurrent network of inhibitory and projection-specific excitatory neurons within the neocortex.

Pyramidal Cell Subtypes and Their Synaptic Connections in Layer 5 of Rat Frontal Cortex.

The frontal cortical areas make a coordinated response that generates appropriate behavior commands, using individual local circuits with corticostriatal and corticocortical connections in longer time scales than sensory areas. In secondary motor cortex (M2), situated between the prefrontal and primary motor areas, major subtypes of layer 5 corticostriatal cells are crossed-corticostriatal (CCS) cells innervating both sides of striatum, and corticopontine (CPn) cells projecting to the ipsilateral striatum and pontine nuclei. CCS cells innervate CPn cells unidirectionally: the former are therefore hierarchically higher than the latter among L5 corticostriatal cells. CCS cells project directly to both frontal and nonfrontal areas. On the other hand, CPn cells innervate the thalamus and layer 1a of frontal areas, where thalamic fibers relaying basal ganglia outputs are distributed. Thus, CCS cells can make activities of frontal areas in concert with those of nonfrontal area using corticocortical loops, whereas CPn cells are more involved in closed corticostriatal loops than CCS cells. Since reciprocal connections between CPn cells with facilitatory synapses may be related to persistent activity, CPn cells play a key role of longer time constant processes in corticostriatal as well as in corticocortical loops between the frontal areas.