Few studies have concentrated on pyramidal tract (PY) changes after brain stem hemorrhage (BSH). In this study, we used a diffusion tensor imaging (DTI) technique and histologic identification to investigate longitudinal PY changes on both the contralateral and ipsilateral sides after experimental BSH.

The aberrant pyramidal tract (APT) refers to the collateral pathway of the pyramidal tract (PT) through the medial lemniscus in the midbrain and pons. Using diffusion tensor tractography (DTT), we investigated the characteristics of the APT in comparison with the PT in the normal human brain.

Currently, comparative studies evaluating the quantification accuracy of pyramidal tracts (PT) and PT branches that were tracked based on four mainstream diffusion models are deficient. The present study aims to evaluate four mainstream models using the high-quality Human Connectome Project (HCP) dataset. Diffusion tensor imaging (DTI), diffusion spectral imaging (DSI), generalized Q-space sampling imaging (GQI), and Q-ball imaging (QBI) were used to construct the PT and PT branches in 50 healthy volunteers from the HCP. False and true PT fibers were identified based on anatomic information. One-way repeated measure analysis of variance and post hoc paired-sample t-test were performed to identify the best PT and PT branch quantification model. The number, percentage, and density of true fibers of PT obtained based on GQI and QBI were significantly larger than those based on DTI and DSI (all p < 0.0005, Bonferroni corrected), whereas false fibers yielded the opposite results (all p < 0.0005, Bonferroni corrected). More trunk branches (PTtrunk) were present in the four diffusion models compared with the upper limb (PTUlimb), lower limb (PTLlimb), and cranial (PTcranial) branches. In addition, significantly more true fibers were obtained in PTtrunk, PTUlimb, and PTLlimb based on the GQI and QBI compared with DTI and DSI (all p < 0.0005, Bonferroni corrected). Finally, GQI-based group probabilistic maps showed that the four PT branches exhibited relatively unique spatial distributions. Therefore, the GQI and QBI represent better diffusion models for the PT and PT branches. The group probabilistic maps of PT branches have been shared with the public to facilitate more precise studies on the plasticity of and the damage to the motor pathway.

We investigated the control of spinal interneurons by corticospinal and medial brain stem descending tracts in two macaque monkeys. Stimulating electrodes were implanted in the left pyramidal tract (PT), and the right medial longitudinal fasciculus (MLF), which contains reticulospinal, vestibulospinal, and some tectospinal fibers. Single unit discharge was recorded from 163 interneurons in the intermediate zone of the right spinal cord (segmental levels C(6)-C(8)) in the awake state; inputs from descending pathways were assessed from the responses to stimulation through the PT and MLF electrodes. Convergent input from both pathways was the most common finding (71/163 cells); responses to PT and MLF stimulation were of similar amplitude. Interneuron discharge was also recorded while the animal performed a reach and grasp task with the right hand; the output connections of the recorded cells were determined by delivering intraspinal microstimulation (ISMS) at the recording sites. Convergent input from MLF/PT stimulation was also common when analysis was restricted to cells that increased their rate during grasp (14/23 cells) or to cells recorded at sites where ISMS elicited finger or wrist movements (23/57 cells). We conclude that medial brain stem and corticospinal descending pathways have largely overlapping effects on spinal interneurons, including those involved in the control of the hand. This may imply a more important role for the brain stem in coordinating hand movements in primates than commonly assumed; brain stem pathways could contribute to the restoration of function seen after lesions to the corticospinal tract.

Injury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.Spinal cord injury can induce synaptic reorganization and remodeling in the brain. Here the authors study how severed distal axons signal back to the cell body to induce hyperexcitability, loss of inhibition and enhanced presynaptic release through netrin-1.

The aberrant pyramidal tract is the collateral pathway of the pyramidal tract through the medial lemniscus in the brainstem. A 21-year-old man presented with right hemiparesis due to a traumatic intracerebral hemorrhage in the left corona radiata. His motor function recovered almost to the normal state at 10 months after onset. Through diffusion tensor tractography, the pyramidal tract in the affected (left) hemisphere showed discontinuation at the pontine level at 13 months after onset. An aberrant pyramidal tract was observed, which originated from the primary motor cortex and the supplementary motor area and descended through the corona radiata, then through the posterior limb of the internal capsule and the medial lemniscus pathway from the midbrain to the pons, finally entered into the pyramidal tract area at the pontomedullary junction. It suggests that the motor functions of the right extremities in this patient had recovered by this aberrant pyramidal tract.

Repetitive transcranial magnetic stimulation (rTMS) has gained interest as a non-invasive treatment for stroke based on the data promoting its effects on functional recovery. However, the exact action mechanisms by which the rTMS exert beneficial effects in cellular and molecular aspect are largely unknown. To elucidate the effects of high- and low-frequency rTMS in the acute-ischemic brain, we examined how rTMS influences injury development, cerebral blood flow (CBF), DNA fragmentation, neuronal survival, pro- and anti-apoptotic protein activations after 30 and 90 min of focal cerebral ischemia. In addition, inflammation, angiogenesis, growth factors and axonal outgrowth related gene expressions, were analyzed. Furthermore, we have investigated the effects of rTMS on post-acute ischemic brain, particularly on spontaneous locomotor activity, perilesional tissue remodeling, axonal sprouting of corticobulbar tracts, glial scar formation and cell proliferation, in which rTMS was applied starting 3 days after the stroke onset for 28 days. In the high-frequency rTMS received animals reduced DNA fragmentation, infarct volume and improved CBF were observed, which were associated with increased Bcl-xL activity and reduced Bax, caspase-1, and caspase-3 activations. Moreover, increased angiogenesis, growth factors; and reduced inflammation and axonal sprouting related gene expressions were observed. These results correlated with reduced microglial activation, neuronal degeneration, glial scar formation and improved functional recovery, tissue remodeling, contralesional pyramidal tract plasticity and neurogenesis in the subacute rTMS treated animals. Overall, we propose that high-frequency rTMS in stroke patients can be used to promote functional recovery by inducing the endogenous repair and recovery mechanisms of the brain.

A role for endocannabinoid signaling in neuronal morphogenesis as the brain develops has recently been suggested. Here we used the developing somatosensory circuit as a model system to examine the role of endocannabinoid signaling in neural circuit formation. We first show that a deficiency in cannabinoid receptor type 1 (CB(1)R), but not G-protein-coupled receptor 55 (GPR55), leads to aberrant fasciculation and pathfinding in both corticothalamic and thalamocortical axons despite normal target recognition. Next, we localized CB(1)R expression to developing corticothalamic projections and found little if any expression in thalamocortical axons, using a newly established reporter mouse expressing GFP in thalamocortical projections. A similar thalamocortical projection phenotype was observed following removal of CB(1)R from cortical principal neurons, clearly demonstrating that CB(1)R in corticothalamic axons was required to instruct their complimentary connections, thalamocortical axons. When reciprocal thalamic and cortical connections meet, CB(1)R-containing corticothalamic axons are intimately associated with elongating thalamocortical projections containing DGLβ, a 2-arachidonoyl glycerol (2-AG) synthesizing enzyme. Thus, 2-AG produced in thalamocortical axons and acting at CB(1)Rs on corticothalamic axons is likely to modulate axonal patterning. The presence of monoglyceride lipase, a 2-AG degrading enzyme, in both thalamocortical and corticothalamic tracts probably serves to restrict 2-AG availability. In summary, our study provides strong evidence that endocannabinoids are a modulator for the proposed 'handshake' interactions between corticothalamic and thalamocortical axons, especially for fasciculation. These findings are important in understanding the long-term consequences of alterations in CB(1)R activity during development, a potential etiology for the mental health disorders linked to prenatal cannabis use.

Corticothalamic axons express Contactin-2 (CNTN2/TAG-1), a neuronal recognition molecule of the immunoglobulin superfamily involved in neurogenesis, neurite outgrowth, and fasciculation. TAG-1, which is expressed transiently by cortical pyramidal neurons during embryonic development, has been shown to be fundamental for axonal recognition, cellular migration, and neuronal proliferation in the developing cortex. Although Tag-1 -/- mice do not exhibit any obvious defects in the corticofugal system, the role of TAG-1+ neurons during the development of the cortex remains elusive. We have generated a mouse model expressing EGFP under the Tag-1 promoter and encompassing the coding sequence of Diptheria Toxin subunit A (DTA) under quiescence with no effect on the expression of endogenous Tag-1. We show that while the line recapitulates the expression pattern of the molecule, it highlights an extended expression in the forebrain, including multiple axonal tracts and neuronal populations, both spatially and temporally. Crossing these mice to the Emx1-Cre strain, we ablated the vast majority of TAG-1+ cortical neurons. Among the observed defects were a significantly smaller cortex, a reduction of corticothalamic axons as well as callosal and commissural defects. Such defects are common in neurodevelopmental disorders, thus this mouse could serve as a useful model to study physiological and pathophysiological cortical development.

In this study, we introduced a length-normalized parameterization method to establish anatomical correspondence of white matter fiber tracts across subjects and applied this method to investigate the presence of abnormal diffusion along the pyramidal tract (PYT) of relapsing neuromyelitis optica (RNMO) patients without visible brain lesions. In this approach, the part of the PYT between the lowest slice of the cerebral peduncle and the uppermost slice of the lateral ventricle was reconstructed to establish the anatomical correspondence across subjects using diffusion tensor tractography. Then it was parameterized by normalizing its length and dividing equally the normalized length into a certain number of segments, so that the comparability of each segment across subjects along the PYT was established. Tract-specific diffusion indices, including directionally averaged diffusivity (D(av)), fractional anisotropy (FA), primary diffusivity (lambda(1)) and transverse diffusivity (lambda(23)), were obtained from each segment. Thus, the distribution maps of these indices along the PYT were obtained. The distribution maps of D(av), FA, and lambda(23) of RNMO patients were significantly different from those of healthy controls, especially in the lower part of the PYT. The differences may be caused by secondary degeneration to lesions in the spinal cord. In conclusion, a length-normalized parameterization method is proposed to establish anatomical correspondence for the PYT. Compared with existed methods, a major merit of our method is to provide comparability across subjects along the PYT on the basis of diffusion tensor tractography and to make it possible for the quantitative analysis along the fiber tract. This method can also be used to quantitatively analyze other white matter fiber tracts between two definite anatomic landmarks in many neurological or psychiatric diseases.

Haemorrhagic stroke is one of the leading causes of death and the most common cause of long-term adult disability. An accurate estimation of prognosis is very important for haemorrhagic stroke patients. Impairment of motor function caused by pyramidal tract injury is common in these patients. In this study, we performed MR diffusion tensor tractography (DTT) to predict the impairment of motor function in patients with basal ganglion haemorrhage and explore its clinical value.

The current research aimed to analyze the alterations within the motor cortex and pyramidal pathways and their association with the degree of damage within the peripheral nerve fibers in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). To achieve that goal, we investigated the microstructural changes within the pyramidal white matter tracts using diffusion tensor imaging (DTI) parameters, evaluated metabolic alterations in both precentral gyri using magnetic resonance spectroscopy (MRS) ratios, and correlated them with the neurographic findings in patients with CIDP.

The L1 CAM family of cell adhesion molecules and the ankyrin family of spectrin-binding proteins are candidates to collaborate in transcellular complexes used in diverse contexts in nervous systems of vertebrates and invertebrates. This report presents evidence for functional coupling between L1 and 440-kD ankyrinB in premyelinated axons in the mouse nervous system. L1 and 440-kD ankyrinB are colocalized in premyelinated axon tracts in the developing nervous system and are both down-regulated after myelination. AnkyrinB (-/-) mice exhibit a phenotype similar to, but more severe, than L1 (-/-) mice and share features of human patients with L1 mutations. AnkyrinB (-/-) mice exhibit hypoplasia of the corpus callosum and pyramidal tracts, dilated ventricles, and extensive degeneration of the optic nerve, and they die by postnatal day 21. AnkyrinB (-/-) mice have reduced L1 in premyelinated axons of long fiber tracts, including the corpus callosum, fimbria, and internal capsule in the brain, and pyramidal tracts and lateral columns of the spinal cord. L1 was evident in the optic nerve at postnatal day 1 but disappeared by postnatal day 7 in mutant mice while NCAM was unchanged. Optic nerve axons of ankyrinB (-/-) mice become dilated with diameters up to eightfold greater than normal, and they degenerated by day 20. These findings provide the first evidence for a role of ankyrinB in the nervous system and support an interaction between 440-kD ankyrinB and L1 that is essential for maintenance of premyelinated axons in vivo.

ALS2 gene encoding for alsin protein is responsible for neurological disorders due to retrograde degeneration of the upper motor neurons of the pyramidal tracts, inherited in an autosomal recessive manner, and displaying a clinical continuum including the infantile ascending hereditary spastic paraplegiaidentified in three Spanish children presented here.

Nowadays, increasing longevity associated with declining cerebral nervous system functions, suggests the need for continued development of new imaging contrast mechanisms to support the differential diagnosis of age-related decline. In our previous papers, we developed a new imaging contrast metrics derived from anomalous diffusion signal representation and obtained from diffusion-weighted (DW) data collected by varying diffusion gradient strengths. Recently, we highlighted that the new metrics, named γ-metrics, depended on the local inhomogeneity due to differences in magnetic susceptibility between tissues and diffusion compartments in young healthy subjects, thus providing information about myelin orientation and iron content within cerebral regions. The major structural modifications occurring in brain aging are myelinated fibers damage in nerve fibers and iron accumulation in gray matter nuclei. Therefore, we investigated the potential of γ-metrics in relation to other conventional diffusion metrics such as DTI, DKI and NODDI in detecting age-related structural changes in white matter (WM) and subcortical gray matter (scGM). DW-images were acquired in 32 healthy subjects, adults and elderly (age range 20-77 years) using 3.0T and 12 b-values up to 5000 s/mm2. Association between diffusion metrics and subjects' age was assessed using linear regression. A decline in mean γ (Mγ) in the scGM and a complementary increase in radial γ (γ⊥) in frontal WM, genu of corpus callosum and anterior corona radiata with advancing age were found. We suggested that the increase in γ⊥ might reflect declined myelin density, and Mγ decrease might mirror iron accumulation. An increase in D// and a decrease in the orientation dispersion index (ODI) were associated with axonal loss in the pyramidal tracts, while their inverted trends within the thalamus were thought to be linked to reduced architectural complexity of nerve fibers. γ-metrics together with conventional diffusion-metrics can more comprehensively characterize the complex mechanisms underlining age-related changes than conventional diffusion techniques alone.

The basal ganglia is part of a complex system of neuronal circuits that play a key role in the integration and execution of motor, cognitive and emotional function in the human brain. Parkinson's disease is a progressive neurological disorder of the motor circuit characterized by tremor, rigidity, and slowness of movement. Deep brain stimulation (DBS) of the subthalamic nucleus and the globus pallidus pars interna provides an efficient treatment to reduce symptoms and levodopa-induced side effects in Parkinson's disease patients. While the underlying mechanism of action of DBS is still unknown, the potential modulation of white matter tracts connecting the surgical targets has become an active area of research. With the introduction of advanced diffusion MRI acquisition sequences and sophisticated post-processing techniques, the architecture of the human brain white matter can be explored in vivo. The goal of this study is to investigate the white matter connectivity between the subthalamic nucleus and the globus pallidus. Two multi-fiber tractography methods were used to reconstruct pallido-subthalamic, subthalamo-pallidal and pyramidal fibers in five healthy subjects datasets of the Human Connectome Project. The anatomical accuracy of the tracts was assessed by four judges with expertise in neuroanatomy, functional neurosurgery, and diffusion MRI. The variability among subjects was evaluated based on the fractional anisotropy and mean diffusivity of the tracts. Both multi-fiber approaches enabled the detection of complex fiber architecture in the basal ganglia. The qualitative evaluation by experts showed that the identified tracts were in agreement with the expected anatomy. Tract-derived measurements demonstrated relatively low variability among subjects. False-negative tracts demonstrated the current limitations of both methods for clinical decision-making. Multi-fiber tractography methods combined with state-of-the-art diffusion MRI data have the potential to help identify white matter tracts connecting DBS targets in functional neurosurgery intervention.

Using multimodal imaging, we tested the hypothesis that patients after hemispherotomy recruit non-primary motor areas and non-pyramidal descending motor fibers to restore motor function of the impaired limb.

Electrophysiological and neuroimaging studies suggest that the integrity of ipsilesional and inter-hemispheric motor circuits is important for motor recovery after stroke. However, the extent to which each of these tracts contributes to the variance in outcome remains unclear. We examined whether diffusion tensor imaging (DTI)-derived measures of corticospinal and transcallosal tracts predict motor improvement in an experimental neurorehabilitation trial. 15 chronic stroke patients received bihemispheric transcranial direct current stimulation and simultaneous physical/occupational therapy for five consecutive days. Motor impairment was assessed prior to and after the intervention. At baseline, the patients underwent DTI; probabilistic fiber tracking was used to reconstruct the pyramidal tract (PT), alternate descending motor fibers (aMF), and transcallosal fibers connecting primary motor cortices (M1-M1). Ipsilesional corticospinal tracts (PT, aMF) and M1-M1 showed significantly decreased fractional anisotropy (FA) and increased directional diffusivities when compared to age-matched healthy controls. Partial correlations revealed that greater gains in motor function were related to higher FA values and lower directional diffusivities of transcallosal and ipsilesional corticospinal tracts. M1-M1 diffusivity had the greatest predictive value. An additional slice-by-slice analysis of FA values along the corticospinal tracts demonstrated that the more the ipsilesional FA profiles of patients resembled those of healthy controls, the greater their functional improvement. In conclusion, our study shows that DTI-derived measures can be used to predict functional potential for subsequent motor recovery in chronic stroke patients. Diffusivity parameters of individual tracts and tract combinations may help in assessing a patient's individual recovery potential and in determining optimal neurorehabilitative interventions.

The relationship between brain structure, cortical physiology, and learning ability in older adults is of particular interest in understanding mechanisms of age-related cognitive decline. Only a few studies addressed this issue so far, yielding mixed results. Here, we used comprehensive multiple regression analyses to investigate associations between brain structure on the one hand, i.e., cortical thickness (CT), fractional anisotropy (FA) of the pyramidal tract and individual coil-to-cortex distance, and cortical physiology on the other hand, i.e. motor cortex excitability and long-term potentiation (LTP)-like cortical plasticity, in healthy older adults (mean age 64 years, 14 women). Additional exploratory analyses assessed correlations between cortical physiology and learning ability in the verbal domain. In the regression models, we found that cortical excitability could be best predicted by CT of the hand knob of the primary motor cortex (CT-M1HAND) and individual coil-to-cortex distance, while LTP-like cortical plasticity was predicted by CT-M1HAND and FA of the pyramidal tract. Exploratory analyses revealed a significant inverse correlation between cortical excitability and learning ability. In conclusion, higher cortical excitability was associated with lower CT and lower learning ability in a cohort of healthy older adults, in line with previous reports of increased cortical excitability in patients with cortical atrophy and cognitive deficits due to Alzheimer's Disease. Cortical excitability may thus be a parameter to identify individuals at risk for cognitive decline and gray matter atrophy, a hypothesis to be explored in future longitudinal studies.

Cervical spondylotic myelopathy (CSM) is caused by chronic compression of the spinal cord and is the most common cause of myelopathy in adults. No drug is currently available to mitigate CSM. Herein, we made a rat model of CSM by epidurally implanting an expanding water-absorbent polymer underneath the laminae compress the spinal cord. The CSM rats exhibited progressive motor impairments recapitulating human CSM. CSM rats had loss of spinal motor neurons, and increased lipid peroxidation in the spinal cord. Zonisamide (ZNS) is clinically used for epilepsy and Parkinson's disease. We previously reported that ZNS protected primary spinal motor neurons against oxidative stress. We thus examined the effects of ZNS on our rat CSM model. CSM rats with daily intragastric administration of 0.5% methylcellulose (n = 11) and ZNS (30 mg/kg/day) in 0.5% methylcellulose (n = 11). Oral administration of ZNS ameliorated the progression of motor impairments, spared the number of spinal motor neurons, and preserved myelination of the pyramidal tracts. In addition, ZNS increased gene expressions of cystine/glutamate exchange transporter (xCT) and metallothionein 2A in the spinal cord in CSM rats, and also in the primary astrocytes. ZNS increased the glutathione (GSH) level in the spinal motor neurons of CSM rats. ZNS potentially ameliorates loss of the spinal motor neurons and demyelination of the pyramidal tracts in patients with CSM.