Longitudinal Fascicle Research Articles

Temporal Profile of Endogenous Anatomical Repair and Functional Recovery following Spinal Cord Injury in Adult Zebrafish

Regenerated cerebrospinal axons are considered to be involved in the spontaneous recovery of swimming ability following a spinal cord injury in adult zebrafish. We employed behavioral analysis, neuronal tracing, and immunocytochemistry to determine the exact temporal relationship between swimming ability and regenerated cerebrospinal axon number in adult zebrafish with a complete spinal cord transection. Between two and eight weeks post-lesion, swimming gradually improved to 44% of sham-injured zebrafish. Neurons within the reticular formation, magnocellular octaval nucleus, and nucleus of the medial longitudinal fascicle grew their axon across and at least four millimeters beyond the lesion. The largest increases in swimming ability and number of regenerated cerebrospinal axons were observed between two and four weeks post-lesion. Regression analyses revealed a significant correlation between swimming ability and the number of regenerated axons. Our results indicate the involvement of cerebrospinal axons in swimming recovery after spinal cord injury in adult zebrafish.

Central ocular motor disorders, including gaze palsy and nystagmus.

An impairment of eye movements, or nystagmus, is seen in many diseases of the central nervous system, in particular those affecting the brainstem and cerebellum, as well as in those of the vestibular system. The key to diagnosis is a systematic clinical examination of the different types of eye movements, including: eye position, range of eye movements, smooth pursuit, saccades, gaze-holding function and optokinetic nystagmus, as well as testing for the different types of nystagmus (e.g., central fixation nystagmus or peripheral vestibular nystagmus). Depending on the time course of the signs and symptoms, eye movements often indicate a specific underlying cause (e.g., stroke or neurodegenerative or metabolic disorders). A detailed knowledge of the anatomy and physiology of eye movements enables the physician to localize the disturbance to a specific area in the brainstem (midbrain, pons or medulla) or cerebellum (in particular the flocculus). For example, isolated dysfunction of vertical eye movements is due to a midbrain lesion affecting the rostral interstitial nucleus of the medial longitudinal fascicle, with impaired vertical saccades only, the interstitial nucleus of Cajal or the posterior commissure; common causes with an acute onset are an infarction or bleeding in the upper midbrain or in patients with chronic progressive supranuclear palsy (PSP) and Niemann–Pick type C (NP-C). Isolated dysfunction of horizontal saccades is due to a pontine lesion affecting the paramedian pontine reticular formation due, for instance, to brainstem bleeding, glioma or Gaucher disease type 3; an impairment of horizontal and vertical saccades is found in later stages of PSP, NP-C and Gaucher disease type 3. Gaze-evoked nystagmus (GEN) in all directions indicates a cerebellar dysfunction and can have multiple causes such as drugs, in particular antiepileptics, chronic alcohol abuse, neurodegenerative cerebellar disorders or cerebellar ataxias; purely vertical GEN is due to a midbrain lesion, while purely horizontal GEN is due to a pontomedullary lesion. The pathognomonic clinical sign of internuclear ophthalmoplegia is an impaired adduction while testing horizontal saccades on the side of the lesion in the ipsilateral medial longitudinal fascicule. The most common pathological types of central nystagmus are downbeat nystagmus (DBN) and upbeat nystagmus (UBN). DBN is generally due to cerebellar dysfunction affecting the flocculus bilaterally (e.g., due to a neurodegenerative disease). Treatment options exist for a few disorders: miglustat for NP-C and aminopyridines for DBN and UBN. It is therefore particularly important to identify treatable cases with these conditions.

Distribution of axon diameters in cortical white matter: an electron-microscopic study on three human brains and a macaque.

The aim of this study was to obtain information on the axonal diameters of cortico-cortical fibres in the human brain, connecting distant regions of the same hemisphere via the white matter. Samples for electron microscopy were taken from the region of the superior longitudinal fascicle and from the transitional white matter between temporal and frontal lobe where the uncinate and inferior occipitofrontal fascicle merge. We measured the inner diameter of cross sections of myelinated axons. For comparison with data from the literature on the human corpus callosum, we also took samples from that region. For comparison with well-fixed material, we also included samples from corresponding regions of a monkey brain (Macaca mulatta). Fibre diameters in human brains ranged from 0.16 to 9 upmu hbox {m}. Distributions of diameters were similar in the three systems of cortico-cortical fibres investigated, both in humans and the monkey, with most of the average values below 1 upmu m diameter and a small population of much thicker fibres. Within individual human brains, the averages were larger in the superior longitudinal fascicle than in the transitional zone between temporal and frontal lobe. An asymmetry between left and right could be found in one of the human brains, as well as in the monkey brain. A correlation was also found between the thickness of the myelin sheath and the inner axon diameter for axons whose calibre was greater than about 0.6 upmu hbox {m}. The results are compared to white matter data in other mammals and are discussed with respect to conduction velocity, brain size, cognition, as well as diffusion weighted imaging studies.

Motion with Direction and Balance

In this issue of Neuron, three papers, Severi etal. (2014), Thiele etal. (2014), and Wang and McLean (2014), examine the descending circuitry involved in coordinating locomotor behavior in larval zebrafish. Visually evoked locomotor and steering movements in zebrafish are mediated by neurons in the nucleus of the medial longitudinal fascicle (nMLF) that project directly to spinal motoneurons. The final motor output induced by nMLF will involve integration in the hindbrain and premotor circuits in the spinal cord.

Anatomo-functional study of the temporo-parieto-occipital region: dissection, tractographic and brain mapping evidence from a neurosurgical perspective.

The temporo-parieto-occipital (TPO) junction is a complex brain territory heavily involved in several high-level neurological functions, such as language, visuo-spatial recognition, writing, reading, symbol processing, calculation, self-processing, working memory, musical memory, and face and object recognition. Recent studies indicate that this area is covered by a thick network of white matter (WM) connections, which provide efficient and multimodal integration of information between both local and distant cortical nodes. It is important for neurosurgeons to have good knowledge of the three-dimensional subcortical organisation of this highly connected region to minimise post-operative permanent deficits. The aim of this dissection study was to highlight the subcortical functional anatomy from a topographical surgical perspective. Eight human hemispheres (four left, four right) obtained from four human cadavers were dissected according to Klingler's technique. Proceeding latero-medially, the authors describe the anatomical courses of and the relationships between the main pathways crossing the TPO. The results obtained from dissection were first integrated with diffusion tensor imaging reconstructions and subsequently with functional data obtained from three surgical cases, all resection of infiltrating glial tumours using direct electrical mapping in awake patients. The subcortical limits for performing safe lesionectomies within the TPO region are as follows: within the parietal region, the anterior horizontal part of the superior longitudinal fasciculus and, more deeply, the arcuate fasciculus; dorsally, the vertical projective thalamo-cortical fibres. For lesions located within the temporal and occipital lobes, the resection should be tailored according to the orientation of the horizontal associative pathways (the inferior fronto-occipital fascicle, inferior longitudinal fascicle and optic radiation). The relationships between the WM tracts and the ventricle system were also examined. These results indicate that a detailed anatomo-functional awareness of the WM architecture within the TPO area is mandatory when approaching intrinsic brain lesions to optimise surgical results and to minimise post-operative morbidity.

Ptena, but not Ptenb, reduces regeneration after spinal cord injury in adult zebrafish

Based on the observation that the tumor suppressor gene PTEN (phosphatase and tensin homolog) reduces regeneration after spinal cord injury (SCI) as evidenced in the PTEN knockout mouse, we have investigated the function of Ptena and Ptenb, the two zebrafish homologs of mammalian PTEN, in adult zebrafish after spinal cord injury with the aim to assess the contribution of the two zebrafish genes to functional recovery in an animal species that spontaneously recovers from central nervous system injury. The inhibition of Ptena expression by antisense morpholino (MO) application improved spinal cord regeneration through 4 to 5weeks after injury. Retrograde tracing showed regrowth of axons from neurons of the regeneration-competent nucleus of the medial longitudinal fascicle in the brainstem in the Ptena MO-treated fish. Ptenb MO-treated fish recovered as well as control MO-treated fish at 4 and 5weeks after SCI, with their locomotion being similar to that of sham-injured and non-injured fish. The mRNA levels of Ptena were upregulated after SCI at the early stage after injury (12h and 6days) caudal to the lesion site, compared to the non-injured control, while the levels of Ptenb were upregulated only at 12h after injury. In situ hybridization experiments were in agreement with the qPCR measurements. At the protein level, Ptena was found to be expressed in spinal motoneurons and immature neurons. These results indicate that Ptena, but not Ptenb, inhibits regeneration in zebrafish, thus sharing this feature with PTEN in mammals. The fact that zebrafish regenerate better than mammals despite the inhibitory presence of Ptena is likely due to regeneration-conducive molecules that tip the balance from inhibition to enhancement. Interestingly, although Ptena and Ptenb have been shown to be functionally redundant in promoting the development of the fish larval central nervous system, they are not functionally redundant in the adult, suggesting that regeneration in fish is not predominantly due to the overall recapitulation of development.

Facilitation of ipsilateral actions of corticospinal tract neurons on feline motoneurons by transcranial direct current stimulation.

Ipsilateral actions of pyramidal tract (PT) neurons are weak but may, if strengthened, compensate for deficient crossed PT actions following brain damage. The purpose of the present study was to examine whether transcranial direct current stimulation (tDCS) can strengthen ipsilateral PT (iPT) actions; in particular, those relayed by reticulospinal neurons co-excited by axon collaterals of fibres descending in the iPT and contralateral PT (coPT) and of reticulospinal neurons descending in the medial longitudinal fascicle (MLF). The effects of tDCS were assessed in acute experiments on deeply anaesthetized cats by comparing postsynaptic potentials evoked in hindlimb motoneurons and discharges recorded from their axons in a ventral root, before, during and after tDCS. tDCS was consistently found to facilitate joint actions of the iPT and coPT, especially when they were stimulated together with the MLF. Both excitatory postsynaptic potentials and inhibitory postsynaptic potentials evoked in motoneurons and the ensuing ventral root discharges were facilitated, even though the facilitatory effects of tDCS were not sufficient for activation of motoneurons by iPT neurons alone. Facilitation outlasted single tDCS periods by at least a few minutes, and the effects evoked by repeated tDCS by up to 2h. The results of this study thus indicate that tDCS may increase the contribution of iPT actions to the recovery of motor functions after injuries to coPT neurons, and thereby assist rehabilitation, provided that corticoreticular and reticulospinal connections are preserved.

Neural progenitor cell implants in the lesioned medial longitudinal fascicle of adult cats regulate synaptic composition and firing properties of abducens internuclear neurons.

Transplants of neural progenitor cells (NPCs) into the injured CNS have been proposed as a powerful tool for brain repair, but, to date, few studies on the physiological response of host neurons have been reported. Therefore, we explored the effects of NPC implants on the discharge characteristics and synaptology of axotomized abducens internuclear neurons, which mediate gaze conjugacy for horizontal eye movements. NPCs were isolated from the subventricular zone of neonatal cats and implanted at the site of transection in the medial longitudinal fascicle of adult cats. Abducens internuclear neurons of host animals showed a complete restoration of axotomy-induced alterations in eye position sensitivity, but eye velocity sensitivity was only partially regained. Analysis of the inhibitory and excitatory components of the discharge revealed a normal re-establishment of inhibitory inputs, but only partial re-establishment of excitatory inputs. Moreover, their inhibitory terminal coverage was similar to that in controls, indicating that there was ultimately no loss of inhibitory synaptic inputs. Somatic coverage by synaptophysin-positive contacts, however, showed intermediate values between control animals and animals that had undergone axotomy, likely due to partial loss of excitatory inputs. We also demonstrated that severed axons synaptically contacted NPCs, most of which were VEGF immunopositive, and that abducens internuclear neurons expressed the VEGF receptor Flk1. Together, our results suggest that VEGF neurotrophic support might underlie the increased inhibitory-to-excitatory balance observed in the postimplant cells. The noteworthy improvement of firing properties of injured neurons following NPC implants indicates that these cells might provide a promising therapeutic strategy after neuronal lesions.

Poster #T182 CLINICAL PREDICTORS OF THE DIAGNOSTIC STABILITY OF BRIEF PSYCHOTIC DISORDER

There is a lack of convincing and replicative findings regarding white matter abnormalities in schizophrenia. Several multisite diffusion magnetic resonance imaging (dMRI) studies have been conducted to increase statistical power and reveal subtle white matter changes. Data pooling methods are crucial in joint analysis to compensate for the use of different scanners and image acquisition parameters. A harmonization method using raw dMRI data was developed to overcome the limited generalizability of previous data pooling methods. We obtained dMRI data of 242 healthy controls and 190 patients with schizophrenia from four different study sites. After applying the harmonization method to the raw dMRI data, a two-tensor whole-brain tractography was performed, and diffusion measures were compared between the two groups. The correlation of fractional anisotropy (FA) with the positive and negative symptoms was evaluated, and the interaction effect of diagnosis-by-age, age-squared, and sex was examined. The following white matter tracts showed significant group differences in the FA: the right superior longitudinal fascicle (SLF), the left-to-right lateral orbitofrontal commissural tract, pars orbitalis (pOr-pOr) commissural tract, and pars triangularis (pTr-pTr) commissural tract. The FA of the right SLF and pTr-pTr commissural tract were significantly associated with the Positive and Negative Syndrome Scale (PANSS) positive and negative scores. No significant interaction effect was observed. These findings add to the evidence on structural brain abnormalities in schizophrenia and can aid in obtaining a better understanding of the biological foundations of schizophrenia.

Ontogeny of genetic networks underlying central appetite‐controlling systems in the teleost Atlantic cod (LB830)

We examined the distribution of Neuropeptide Y (NPY), cocaine‐ and amphetamine‐regulated transcript (CART) and prepro‐orexin (pOX) in the brain of Atlantic cod by in situ hybridization from onset of exogenous feeding (4days post hatch, dph) to postlarval stage (76dph). All examined genes were expressed from 4dph and displayed temporal and spatial differences in expression during development. pOX mRNA was only expressed in hypothalamus. NPY and CART mRNA expressions had broad distributions in the brain, including telencephalon, diencephalon, and optic tectum. In addition, NPY transcripts were found in the preoptic region, while CART was found in medulla oblongata. New populations of CART positive neurons appeared in olfactory bulb, in the region of the nucleus of medial longitudinal fascicle, and later in midbrain tegmentum. We found several examples of co‐expression (NPY‐CART) and (CART‐pOX). Distributions of NPY and pOX transcripts suggest that telencephalon and hypothalamus are involved in stimulation of feeding in cod. Expression of CART indicates that “satiety centers” are located in hypothalamus, thalamus and medulla oblongata.Grant Funding Source: Supported by Research Council of Norway‐ CODE 199482

Awake mapping for low-grade gliomas involving the left sagittal stratum: anatomofunctional and surgical considerations

Preserving function while optimizing the extent of resection is the main goal in surgery for diffuse low-grade glioma (DLGG). This is particularly relevant for DLGG involving the sagittal stratum (SS), where damage can have severe consequences. Indeed, this structure is a major crossroad in which several important fascicles run. Thus, its complex functional anatomy is still poorly understood. Subcortical electrical stimulation during awake surgery provides a unique opportunity to investigate white matter pathways. This study reports the findings on anatomofunctional correlations evoked by stimulation during resection for gliomas involving the left SS. Surgical outcomes are also detailed. The authors performed a review of patients who underwent awake surgery for histopathologically confirmed WHO Grade II glioma involving the left SS in the neurosurgery department between August 2008 and August 2012. Information regarding clinicoradiological features, surgical procedures, and outcomes was collected and analyzed. Intraoperative electrostimulation was used to map the eloquent structures within the SS. Eight consecutive patients were included in this study. There were 6 men and 2 women, whose mean age was 41.7 years (range 32-61 years). Diagnosis was made because of seizures in 7 cases and slight language disorders in 1 case. After cortical mapping, subcortical stimulation detected functional fibers running in the SS in all patients: semantic paraphasia was generated by stimulating the inferior frontooccipital fascicle in 8 cases; alexia was elicited by stimulating the inferior longitudinal fascicle in 3 cases; visual disorders were induced by stimulating the optic radiations in 5 cases. Moreover, in front of the SS, phonemic paraphasia was evoked by stimulating the temporal part of the arcuate fascicle in 5 patients. The resection was stopped according to these functional limits in the 8 patients. After a transient postsurgical worsening, all patients recovered to normal results on examination, except for the persistence of a right superior quadrantanopia in 5 cases, with no consequences for quality of life. The 8 patients returned to a normal social and professional life. Total or subtotal resection was achieved in all cases but one. The authors suggest that the use of intrasurgical electrical mapping of the white matter pathways in awake patients opens the door to extensive resection of DLGG within the left SS while preserving the quality of life. Further anatomical, clinical, radiological, and electrophysiological studies are needed for a better understanding of the functional anatomy of this complex region.

Implanted neural progenitor cells regulate glial reaction to brain injury and establish gap junctions with host glial cells

Transplantation of neural stem/progenitor cells (NPCs) in the lesioned brain is able to restore morphological and physiological alterations induced by different injuries. The local microenvironment created at the site of grafting and the communication between grafted and host cells are crucial in the beneficial effects attributed to the NPC implants. We have previously described that NPC transplantation in an animal model of central axotomy restores firing properties and synaptic coverage of lesioned neurons and modulates their trophic factor content. In this study, we aim to explore anatomical relationships between implanted NPCs and host glia that might account for the implant-induced neuroprotective effects. Postnatal rat subventricular zone NPCs were isolated and grafted in adult rats after transection of the medial longitudinal fascicle. Brains were removed and analyzed eight weeks later. Immunohistochemistry for different glial markers revealed that NPC-grafted animals displayed significantly greater microglial activation than animals that received only vehicle injections. Implanted NPCs were located in close apposition to activated microglia and reactive astrocytes. The gap junction protein connexin43 was present in NPCs and glial cells at the lesion site and was often found interposed within adjacent implanted and glial cells. Gap junctions were identified between implanted NPCs and host astrocytes and less frequently between NPCs and microglia. Our results show that implanted NPCs modulate the glial reaction to lesion and establish the possibility of communication through gap junctions between grafted and host glial cells which might be involved in the restorative effects of NPC implants.

The persistent crucial role of the left hemisphere for language in left-handers with a left low grade glioma: a stimulation mapping study

Left-handers have a more bilateral language representation than right-handers. Therefore, in left-handers with a low-grade glioma (LGG) in the left hemisphere (LH), one could hypothesize that the right hemisphere (RH) might allow language compensation, at least partly, with no or only a minor persistent role of the LH in speech. However, although LGG induces language reorganization in right-handed patients, little is known in left-handers. Here, we report the first series of left-handers who underwent awake surgery for a left LGG using intraoperative mapping, in order to investigate whether there was still an involvement of LH in language. Ten consecutive left-handed patients were operated for a left LGG (three frontal, four paralimbic, one parietal, one temporal, one parieto-temporal tumor) using an awake procedure with intraoperative electrical language mapping. Intraoperative language disorders were elicited in all cases but one by electrostimulation in the LH. Cortical language sites were detected in nine cases. Subcortical stimulation also demonstrated the crucial role of left white matter pathways in language, including the inferior occipital-frontal fascicle, arcuate fascicle, lateral segment of the superior longitudinal fascicle and fibers from the ventral premotor cortex. Moreover, stimulation of deep gray nuclei generated language disturbances in four patients. These nine patients experienced transient postoperative language worsening, supporting the persistent critical role of LH in speech. In only one patient, no language deficit was evoked intraoperatively and postoperatively. The ten patients returned to a normal life. Total or subtotal resection was achieved in all cases but one. Our results suggest that, even though the RH may participate in language compensation, the LH in left-handers still plays a crucial role, despite a left slow-growing LGG. Thus, we propose to routinely consider awake surgery for left LGG removal in left-handers patients, to optimize the extent of resection while preserving language.

Identification of initially appearing glycine‐immunoreactive neurons in the embryonic zebrafish brain

Glycine is a major inhibitory neurotransmitter in the central nervous system of vertebrates. Here, we report the initial development of glycine-immunoreactive (Gly-ir) neurons and fibers in zebrafish. The earliest Gly-ir cells were found in the hindbrain and rostral spinal cord by 20 h post-fertilization (hpf). Gly-ir cells in rhombomeres 5 and 6 that also expressed glycine transporter 2 (glyt2) mRNA were highly stereotyped; they were bilaterally located and their axons ran across the midline and gradually turned caudally, joining the medial longitudinal fascicles in the spinal cord by 24 hpf. Gly-ir neurons in rhombomere 5 were uniquely identified, since there was one per hemisegment, whereas the number of Gly-ir neurons in rhombomere 6 were variable from one to three per hemisegment. Labeling of these neurons by single-cell electroporation and tracing them until the larval stage revealed that they became MiD2cm and MiD3cm, respectively. The retrograde labeling of reticulo-spinal neurons in Tg(glyt2:gfp) larva, which express GFP in Gly-ir cells, and a genetic mosaic analysis with glyt2:gfp DNA construct also supported this notion. Gly-ir cells were also distributed widely in the anterior brain by 27 hpf, whereas glyt2 was hardly expressed. Double staining with anti-glycine and anti-GABA antibodies demonstrated distinct distributions of Gly-ir and GABA-ir cells, as well as the presence of doubly immunoreactive cells in the brain and placodes. These results provide evidence of identifiable glycinergic (Gly-ir/glyt2-positive) neurons in vertebrate embryos, and they can be used in further studies of the neurons' development and function at the single-cell level.

Transverse Strains in Muscle Fascicles during Voluntary Contraction: A 2D Frequency Decomposition of B-Mode Ultrasound Images.

When skeletal muscle fibres shorten, they must increase in their transverse dimensions in order to maintain a constant volume. In pennate muscle, this transverse expansion results in the fibres rotating to greater pennation angle, with a consequent reduction in their contractile velocity in a process known as gearing. Understanding the nature and extent of this transverse expansion is necessary to understand the mechanisms driving the changes in internal geometry of whole muscles during contraction. Current methodologies allow the fascicle lengths, orientations, and curvatures to be quantified, but not the transverse expansion. The purpose of this study was to develop and validate techniques for quantifying transverse strain in skeletal muscle fascicles during contraction from B-mode ultrasound images. Images were acquired from the medial and lateral gastrocnemii during cyclic contractions, enhanced using multiscale vessel enhancement filtering and the spatial frequencies resolved using 2D discrete Fourier transforms. The frequency information was resolved into the fascicle orientations that were validated against manually digitized values. The transverse fascicle strains were calculated from their wavelengths within the images. These methods showed that the transverse strain increases while the longitudinal fascicle length decreases; however, the extent of these strains was smaller than expected.

EPA-1717 – Effects of exercise therapy on white matter integrity in patients with schizophrenia and healthy controls- a longitudinal DTI study

Introduction In the recent years, interest of researchers has been focused on exercise as a possible way to efficiently influence brain functions and plasticity. Several studies concluded that exercise can change brain morphology by affecting synapses, neurogenesis and angiogenesis and improve efficiency in working memory and executive performance. In schizophrenia, white matter integrity is compromised and to what extent exercise affects white matter integrity is unclear. Aims To investigate the effect of 6 months exercise therapy on white matter integrity in healthy controls and patients with schizophrenia. Methods A total of 33 patients with schizophrenia and 48 healthy controls, matched for demographic characteristics, were randomized into exercise or occupational therapy/life-as-usual. 3T-DTI data were acquired twice. After susceptibility-artifacts and ECC correction, TBSS was used for registration to standard space and computation of the FA-skeleton. The JHU-ICBM-tract atlas was used to define regions of interest (ROI) for the various fiber tracts. Mean FA values for the FA-skeleton within the separate tract ROIs were calculated. GLM-repeated measures design was done with time as within-subject factor, group and therapy as between-factors, and compliance as covariate. Results Significant increases in FA were found for time by randomization in the left corticospinal tract (LCST) (F=4,15, p=0,045), left superior longitudinal fascicle (LSLF)(F=5,092, p=0,027) and forceps major (F=5,687, p=0,02). Conclusions Exercise positively affects FA of tracts involved in primary motor functions (LCST), regulation of motor behavior, spatial attention, oculomotor functions and transfer of somatosensory information (LSLF) as well as interhemispheric connections (Forceps major) in both groups.

White Matter Correlates of Lexical Access in Aphasia

White Matter Correlates of Lexical Access in Aphasia

Fronto-parietal dorsal and ventral pathways in the context of different linguistic manipulations

This study investigates structural connectivity between left fronto-parietal brain regions that were identified in a previous fMRI study which used different linguistic manipulation tasks. Diffusion-weighted images were acquired from 20 volunteers. Structural connectivity between brain regions from the fMRI study was computed using probabilistic fiber tracking. For suprasegmental manipulation, left inferior parietal lobule (IPL) and left inferior frontal gyrus (IFG), pars opercularis, were connected by a dorsal pathway via the arcuate fascicle and superior longitudinal fascicle III. For segmental manipulation, left IPL and IFG, pars triangularis, were connected by a ventral pathway via the middle longitudinal fascicle and the extreme capsule. We conclude that the dorsal pathway provides a route for mapping from phonological memory in IPL to the inferior frontal articulatory network while the ventral pathway could facilitate the modulation of phonological units based on lexical-semantic aspects, mediate the complexity of auditory objects and the unification of actor-event schemata.

Directional diffusion of corticospinal tract supports therapy decisions in idiopathic normal-pressure hydrocephalus

Gait disturbance in patients with idiopathic normal pressure hydrocephalus (iNPH) may be caused by alterations of the corticospinal tract that we aimed to measure with diffusion tensor imaging (DTI). The directional diffusion parameters axial diffusivity and fractional anisotropy (FA) reflect axon integrity, whereas mean diffusivity, radial diffusivity and magnetization transfer ratio (MTR) reflect myelin content. Twenty-six patients with probable iNPH were grouped into drainage responders (n = 12) and drainage non-responders (n = 14) according to their improvement on gait assessment tests after a 3-day lumbar CSF drainage. We measured DTI and MTR of the corticospinal tract and, as reference, of the superior longitudinal fascicle before and after CSF withdrawal in iNPH and in ten age-matched controls. Drainage responders were re-examined after ventricoperitoneal shunting. Differences before any intervention and changes upon CSF withdrawal were evaluated. Axial diffusivity in corticospinal tract and superior longitudinal fascicle was higher in both patient groups compared to controls (p < 0.001). Only in the corticospinal tract of drainage responders was FA higher compared to controls, and both FA and axial diffusivity decreased after shunting. For axial diffusivity upon CSF drainage, a decrease of >0.7% discriminated drainage responders from drainage non-responders with 82% sensitivity, and a decrease of >1% predicted overall improvement after shunting with 87.5% sensitivity and 75% specificity. The specificity to discriminate responders/non-responders was low for all DTI values (max. 69% for FA values). High values of directional diffusion parameters in the corticospinal tract are found in iNPH patients indicating affection of its axons. Increased values and their decrease upon CSF drainage may facilitate treatment decisions in clinically uncertain cases.

Proper Development of the Outer Longitudinal Smooth Muscle of the Mouse Pylorus Requires Nkx2-5 and Gata3

Infantile hypertrophic pyloric stenosis is a common birth anomaly characterized by obstruction of the pyloric lumen. A genome-wide association study implicated NKX2-5, which encodes a transcription factor that is expressed in embryonic heart and pylorus, in the pathogenesis of infantile hypertrophic pyloric stenosis. However, the function of the NKX2-5 in pyloric smooth muscle development has not been examined directly. We investigated the pattern of Nkx2-5 during the course of murine pyloric sphincter development and examined coexpression of Nkx2-5 with Gata3 and Sox9-other transcription factors with pyloric-specific mesenchymal expression. We also assessed pyloric sphincter development in mice with disruption of Nkx2-5 or Gata3. We used immunofluorescence analysis to compare levels of NKX2-5, GATA3, and SOX9 in different regions of smooth muscle cells. Pyloric development was assessed in mice with conditional or germline deletion of Nkx2-5 or Gata3, respectively. Gata3, Nkx2-5, and Sox9 are coexpressed in differentiating smooth muscle cells of a distinct fascicle of the pyloric outer longitudinal muscle. Expansion of this fascicle coincides with development of the pyloric sphincter. Disruption of Nkx2-5 or Gata3 causes severe hypoplasia of this fascicle and alters pyloric muscle shape. Although expression of Sox9 requires Nkx2-5 and Gata3, there is no apparent hierarchical relationship between Nkx2-5 and Gata3 during pyloric outer longitudinal muscle development. Nkx2-5 and Gata3 are independently required for the development of a pyloric outer longitudinal muscle fascicle, which is required for pyloric sphincter morphogenesis in mice. These data indicate that regulatory changes that alter Nkx2-5 or Gata3 expression could contribute to pathogenesis of infantile hypertrophic pyloric stenosis.