Measurements and morphometric landmarks of the human spinal cord: A cadaveric study.

The topographical neuroanatomy of the human spinal cord (SC) is currently based on the adjacent vertebrae. This morphometric study sought to develop a dataset allowing for statistical analysis of human SC segment characteristics. Overall, 32 human SCs were dissected (18 female and 14 male donors), and individual SC segments were identified. Anterior and posterior lengths, thicknesses and widths were measured by two examiners. Statistical analyses included t-tests, as well as intraclass and Pearson's correlation coefficients. The SC length was significantly shorter in females than males. The cranial (C4) and caudal (T1/T2) limits of the cervical enlargement, along with its maximal width (C6-C7), were identified by combining widths and thicknesses of the segments. The thoracic region, T2 to T12, could be identified using segments widths and thicknesses values. The length of the lumbosacral region, from segments L2 to S5, was particularly stable, independently of SC length and sex. The lumbar enlargement was characterized by a thickness increase between the segments L2 and S1 which reached its maximum at the level of L3, L4, and L5, whereas the width was not significantly increased. From the S2 to S5 segments, width and thickness were equal, with both decreasing of 1 mm per segment. The morphometrical analysis of 32 human SCs provided a dataset allowing for statistical analysis of segmental measures with significant results. A combined approach mostly using widths and thicknesses provided landmarks of potential interest for the localization of SC segments in a clinical MRI setting.

Towards microstructure fingerprinting: Estimation of tissue properties from a dictionary of Monte Carlo diffusion MRI simulations.

Many closed-form analytical models have been proposed to relate the diffusion-weighted magnetic resonance imaging (DW-MRI) signal to microstructural features of white matter tissues. These models generally make assumptions about the tissue and the diffusion processes which often depart from the biophysical reality, limiting their reliability and interpretability in practice. Monte Carlo simulations of the random walk of water molecules are widely recognized to provide near groundtruth for DW-MRI signals. However, they have mostly been limited to the validation of simpler models rather than used for the estimation of microstructural properties. This work proposes a general framework which leverages Monte Carlo simulations for the estimation of physically interpretable microstructural parameters, both in single and in crossing fascicles of axons. Monte Carlo simulations of DW-MRI signals, or fingerprints, are pre-computed for a large collection of microstructural configurations. At every voxel, the microstructural parameters are estimated by optimizing a sparse combination of these fingerprints. Extensive synthetic experiments showed that our approach achieves accurate and robust estimates in the presence of noise and uncertainties over fixed or input parameters. In an in vivo rat model of spinal cord injury, our approach provided microstructural parameters that showed better correspondence with histology than five closed-form models of the diffusion signal: MMWMD, NODDI, DIAMOND, WMTI and MAPL. On whole-brain in vivo data from the human connectome project (HCP), our method exhibited spatial distributions of apparent axonal radius and axonal density indices in keeping with ex vivo studies. This work paves the way for microstructure fingerprinting with Monte Carlo simulations used directly at the modeling stage and not only as a validation tool.

Immediate post-operative MRI suggestive of the site and timing of glioblastoma recurrence after gross total resection: a retrospective longitudinal preliminary study.

OBJECTIVES: To retrospectively identify morphological and physiological post-operative magnetic resonance imaging (MRI) characteristics predictive of glioblastoma recurrences after gross total resection (gross-TR). METHODS: Resection margins of 24 glioblastoma were analysed immediately post-operatively (MRI ≤ 2 h) and early post-operatively (24 h ≤ MRI ≤ 48 h), and subdivided into areas with and without subtle contrast enhancement previously considered non-specific. On follow-up MRI, tumour regrowth areas were subdivided according to recurrence extent (focally/extended) and delay (≤6 and ≥12 months). Co-registration of pre-operative, immediately post-operative and early post-operative MRI with the first follow-up MRI demonstrating recurrence authorised their morphological (contrast enhancements) and physiological (rCBV) characterisation. RESULTS: Morphologically, on immediately post-operative MRI, micro-nodular and frayed enhancements correlate significantly with early recurrences (≤6 months). After gross-TR the absence of these enhancements is associated with a significant increase in progression-free survival (61 vs 15 weeks respectively) and overall survival (125 vs 51 weeks respectively). Physiologically, areas with a future focal recurrence have a trend toward higher rCBV than other areas. CONCLUSION: Immediately post-operative topography of micro-nodular and frayed enhancements is suggestive of recurrence location and delay. Absence of such enhancements is associated with a fourfold increase in progression-free survival and a 2.5-fold increase in overall survival. KEY POINTS: • Immediately post-operative MRI reveals contrast enhancement after glioblastoma gross total resection. • Immediately post-operative micro-nodular and frayed enhancement correlate with early recurrence. • Absence of micro-nodular/frayed enhancement is associated with 61 weeks' progression-free survival. • Absence of micro-nodular/frayed enhancement is associated with 125 weeks' overall survival.

Lesion Extension and Neuronal Loss after Spinal Cord Injury Using X-Ray Phase-Contrast Tomography in Mice.

Following spinal cord injury (SCI) the degree of functional (motor, autonomous, or sensory) loss correlates with the severity of nervous tissue damage. An imaging technique able to capture non-invasively and simultaneously the complex mechanisms of neuronal loss, vascular damage, and peri-lesional tissue reorganization is currently lacking in experimental SCI studies. Synchrotron X-ray phase-contrast tomography (SXPCT) has emerged as a non-destructive three-dimensional (3D) neuroimaging technique with high contrast and spatial resolution. In this framework, we developed a multi-modal approach combining SXPCT, histology and correlative methods to study neurovascular architecture in normal and spinal level C4-contused mouse spinal cords (C57BL/6J mice, age 2-3 months). The evolution of SCI lesion was imaged at the cell resolution level during the acute (30 min) and subacute (7 day) phases. Spared motor neurons (MNs) were segmented and quantified in different volumes localized at and away from the epicenter. SXPCT was able to capture neuronal loss and blood-brain barrier breakdown following SCI. Three-dimensional quantification based on SXPCT acquisitions showed no additional MN loss between 30 min and 7 days post-SCI. In addition, the analysis of hemorrhagic (at 30 min) and lesion (at 7 days) volumes revealed a high similarity in size, suggesting no extension of tissue degeneration between early and later time-points. Moreover, glial scar borders were unevenly distributed, with rostral edges being the most extended. In conclusion, SXPCT capability to image at high resolution cellular changes in 3D enables the understanding of the relationship between hemorrhagic events and nervous structure damage in SCI.

SV2A PET Imaging Is a Noninvasive Marker for the Detection of Spinal Damage in Experimental Models of Spinal Cord Injury.

Traumatic spinal cord injury (SCI) is a neurologic condition characterized by long-term motor and sensory neurologic deficits as a consequence of an external physical impact damaging the spinal cord. Anatomic MRI is considered the gold-standard diagnostic tool to obtain structural information for the prognosis of acute SCI; however, it lacks functional objective information to assess SCI progression and recovery. In this study, we explored the use of synaptic vesicle glycoprotein 2A (SV2A) PET imaging to detect spinal cord lesions noninvasively after SCI. Methods: Mice (n = 7) and rats (n = 8) subjected to unilateral moderate cervical (C5) contusion were euthanized 1 wk after SCI for histologic and autoradiographic (3H-labeled (4R)-1-[(3-methylpyridin-4-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one [UCB-J]) investigation of SV2A levels. Longitudinal 11C-UCB-J PET/CT imaging was performed in sham (n = 7) and SCI rats (n = 8) 1 wk and 6 wk after SCI. Animals also underwent an 18F-FDG PET scan during the latter time point. Postmortem tissue SV2A analysis to corroborate in vivo PET findings was performed 6 wk after SCI. Results: A significant SV2A loss (ranging from -70.3% to -87.3%; P < 0.0001) was measured at the epicenter of the impact in vitro in both mouse and rat contusion SCI models. Longitudinal 11C-UCB-J PET imaging detected SV2A loss in SCI rats (-49.0% ± 8.1% at 1 wk and -52.0% ± 12.9% at 6 wk after SCI), with no change observed in sham rats. In contrast, 18F-FDG PET imaging measured only subtle hypometabolism (-17.6% ± 14.7%). Finally, postmortem 3H-UCB-J autoradiography correlated with the in vivo SV2A PET findings (r = 0.92, P < 0.0001). Conclusion:11C-UCB-J PET/CT imaging is a noninvasive marker for SV2A loss after SCI. Collectively, these findings indicate that SV2A PET may provide an objective measure of SCI and thus represent a valuable tool to evaluate novel therapeutics. Clinical assessment of SCI with SV2A PET imaging is highly recommended.

Extra-axonal restricted diffusion as an in-vivo marker of reactive microglia.

Reactive microgliosis is an important pathological component of neuroinflammation and has been implicated in a wide range of brain diseases including brain tumors, multiple sclerosis, Parkinson's disease, Alzheimer's disease, and schizophrenia. Mapping reactive microglia in-vivo is often performed with PET scanning whose resolution, cost, and availability prevent its widespread use. The advent of diffusion compartment imaging (DCI) to probe tissue microstructure in vivo holds promise to map reactive microglia using MRI scanners. But this potential has never been demonstrated. In this paper, we performed longitudinal DCI in rats that underwent dorsal root axotomy triggering Wallerian degeneration of axons-a pathological process which reliably activates microglia. After the last DCI at 51 days, rats were sacrificed and histology with Iba-1 immunostaining for microglia was performed. The fraction of extra-axonal restricted diffusion from DCI was found to follow the expected temporal dynamics of reactive microgliosis. Furthermore, a strong and significant correlation between this parameter and histological measurement of microglial density was observed. These findings strongly suggest that extra-axonal restricted diffusion is an in-vivo marker of reactive microglia. They pave the way for MRI-based microglial mapping which may be important to characterize the pathogenesis of neurological and psychiatric diseases.

Anodal Transcutaneous Spinal Direct Current Stimulation (tsDCS) Selectively Inhibits the Synaptic Efficacy of Nociceptive Transmission at Spinal Cord Level.

Recently studies have aimed at developing transcutaneous spinal direct current stimulation (tsDCS) as a non-invasive technique to modulate spinal function in humans. Independent studies evaluating its after-effects on nociceptive or non-nociceptive somatosensory responses have reported comparable effects suggesting that tsDCS impairs axonal conduction of both the spino-thalamic and the medial lemniscus tracts. The present study aimed to better understand how tsDCS affects, in humans, the spinal transmission of nociceptive and non-nociceptive somatosensory inputs. We compared the after-effects of anodal low-thoracic, anodal cervical and sham tsDCS on the perception and brain responses elicited by laser stimuli selectively activating Aδ-thermonociceptors of the spinothalamic system and vibrotactile stimuli selectively activating low-threshold Aß-mechanoreceptors of the lemniscal system, delivered to the hands and feet. Low-thoracic tsDCS selectively and significantly affected the LEP-N2 wave elicited by nociceptive stimulation of the lower limbs, without affecting the LEP-N2 wave elicited by nociceptive stimulation of the upper limbs, and without affecting the SEP-N2 wave elicited by vibrotactile stimulation of either limb. This selective and segmental effect indicates that the neuromodulatory after-effects of tsDCS cannot be explained by anodal blockade of axonal conduction and, instead, are most probably due to a segmental effect on the synaptic efficacy of the local processing and/or transmission of nociceptive inputs in the dorsal horn.

Post-resection treatment of glioblastoma with an injectable nanomedicine-loaded photopolymerizable hydrogel induces long-term survival.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. Despite available therapeutic options, the prognosis for patients with GBM remains very poor. We hypothesized that the intra-operative injection of a photopolymerizable hydrogel into the tumor resection cavity could sustain the release of the anti-cancer drug paclitaxel (PTX) encapsulated in poly (lactic-co-glycolic acid) (PLGA) nanoparticles and prevent GBM recurrence. The tumor was resected 13 days after implantation and a pre-gel solution composed of polyethylene glycol dimethacrylate (PEG-DMA) polymer, a photoinitiator and PTX-loaded PLGA nanoparticles (PTX PLGA-NPs) was injected into the tumor resection cavity. A solid gel filling the whole cavity was formed immediately by photopolymerization using a 400 nm light. PTX in vitro release study showed a burst release (11%) in the first 8 h and a sustained release of 29% over a week. In vitro, U87 MG cells were sensitive to PTX PLGA-NPs with IC50 level of approximately 0.010 µg/mL. The hydrogel was well-tolerated when implanted in the brain of healthy mice for 2 and 4 months. Administration of PTX PLGA-NPs-loaded hydrogel into the resection cavity of GBM orthotopic model lead to more than 50% long-term survival mice (150 days) compared to the control groups (mean survival time 52 days). This significant delay of recurrence is very promising for the post-resection treatment of GBM.

Reliable EEG responses to the selective activation of C-fibre afferents using a temperature-controlled infrared laser stimulator in conjunction with an adaptive staircase algorithm.

Brain responses to the activation of C-fibres are obtained only if the co-activation of Aδ-fibres is avoided. Methods to activate C-fibres selectively have been proposed, but are unreliable or difficult to implement. Here, we propose an approach combining a new laser stimulator to generate constant-temperature heat pulses with an adaptive paradigm to maintain stimulus temperature above the threshold of C-fibres but below that of Aδ-fibres, and examine whether this approach can be used to record reliable C-fibre laser-evoked brain potentials. Brief CO2 laser stimuli were delivered to the hand and foot dorsum of 10 healthy subjects. The stimuli were generated using a closed-loop control of laser power by an online monitoring of target skin temperature. The adaptive algorithm, using reaction times to distinguish between late detections indicating selective activation of unmyelinated C-fibres and early detections indicating co-activation of myelinated Aδ-fibres, allowed increasing the likelihood of selectively activating C-fibres. Reliable individual-level electroencephalogram (EEG) responses were identified, both in the time domain (hand: N2: 704 ± 179 ms, P2: 984 ± 149 ms; foot: N2: 1314 ± 171 ms, P2: 1716 ± 171 ms) and the time-frequency (TF) domain. Using a control dataset in which no stimuli were delivered, a Receiver Operating Characteristics analysis showed that the magnitude of the phase-locked EEG response corresponding to the N2-P2, objectively quantified in the TF domain, discriminated between absence vs presence of C-fibre responses with a high sensitivity (hand: 85%, foot: 80%) and specificity (hand: 90%, foot: 75%). This approach could thus be particularly useful for the diagnostic workup of small-fibre neuropathies and neuropathic pain.

Injectable alginate hydrogel loaded with GDNF promotes functional recovery in a hemisection model of spinal cord injury.

We hypothesized that local delivery of GDNF in spinal cord lesion via an injectable alginate hydrogel gelifying in situ would support spinal cord plasticity and functional recovery. The GDNF release from the hydrogel was slowed by GDNF encapsulation in microspheres compared to non-formulated GDNF (free GDNF). When injected in a rat spinal cord hemisection model, more neurofilaments were observed in the lesion when the rats were treated with free GDNF-loaded hydrogels. More growing neurites were detected in the tissues surrounding the lesion when the animals were treated with GDNF microsphere-loaded hydrogels. Intense GFAP (astrocytes), low ßIII tubulin (neural cells) and RECA-1 (endothelial cells) stainings were observed for non-treated lesions while GDNF-treated spinal cords presented less GFAP staining and more endothelial and nerve fiber infiltration in the lesion site. The animals treated with free GDNF-loaded hydrogel presented superior functional recovery compared with the animals treated with the GDNF microsphere-loaded hydrogels and non-treated animals.

Intraoperative magnetic resonance imaging at 3-T using a dual independent operating room-magnetic resonance imaging suite: development, feasibility, safety, and preliminary experience.

OBJECTIVE: A twin neurosurgical magnetic resonance imaging (MRI) suite with 3-T intraoperative MRI (iMRI) was developed to be available to neurosurgeons for iMRI and for independent use by radiologists. METHODS: The suite was designed with one area dedicated to neurosurgery and the other to performing MRI under surgical conditions (sterility and anesthesia). The operating table is motorized, enabling transfer of the patient into the MRI system. These two areas can function independently, allowing the MRI area to be used for nonsurgical cases. We report the findings from the first 21 patients to undergo scheduled neurosurgery with iMRI in this suite (average age, 51 +/- 24 yr; intracranial tumor, 18 patients; epilepsy surgery, 3 patients). RESULTS: Twenty-six iMRI examinations were performed, 3 immediately before surgical incision, 9 during surgery (operative field partially closed), and 14 immediately postsurgery (operative field fully closed but patient still anesthetized and draped). Minor technical dysfunctions prolonged 10 iMRI procedures; however, no serious iMRI-related incidents occurred. Twenty-three iMRI examinations took an average of 78 +/- 20 minutes to perform. In three patients, iMRI led to further tumor resection because removable residual tumor was identified. Complete tumor resection was achieved in 15 of the 18 cases. CONCLUSION: The layout of the new complex allows open access to the 3-T iMRI system except when it is in use under surgical conditions. Three patients benefited from the iMRI examination to achieve total resection. No permanent complications were observed. Therefore, the 3-T iMRI is feasible and appears to be a safe tool for intraoperative surgical planning and assessment.