Corticospinal Research Articles

Clinical Outcome Assessments for Spasticity: Review, Critique, and Recommendations.

Spasticity is a common feature in patients with disruptions in corticospinal pathways. However, the term is used ambiguously. Here, spasticity is defined as enhanced velocity-dependent stretch reflexes and placed within the context of deforming spastic paresis encompassing other forms of muscle overactivity. This scoping review aims at evaluating the clinimetric quality of clinical outcome assessments (COAs) for spasticity across different pathologies and to make recommendations for their use. A literature search was conducted to identify COAs used to assess spasticity. An international expert panel evaluated the measurement properties in the included COAs. Recommendations were based on the MDS-COA program methodology based on three criteria: if the COA was (1) applied to patients with spastic paresis, (2) used by others beyond the developers, and (3) determined to be reliable, valid, and sensitive to change in patients with spasticity. We identified 72 COAs of which 17 clinician-reported outcomes (ClinROs) and 6 patient-reported outcomes (PROs) were reviewed. The Tardieu Scale was the only ClinRO recommended for assessing spasticity. One ClinRO-Composite Spasticity Index-and two PROs-Spasticity 0-10 Numeric Rating Scale and 88-Item Multiple Sclerosis Spasticity Scale-were recommended with caveats. The Ashworth-derived COAs were excluded after evaluation due to their focus on muscle tone rather than spasticity, as defined in this review. The Tardieu Scale is recommended for assessing spasticity, and two PROs are recommended with caveats. Consistent terminology about the various types of muscle overactivity is necessary to facilitate their assessment and treatment. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Recrystallization and spheroidization mechanisms in Ti6246 alloy under thermomechanical treatment

This paper provides a detailed analysis of the dynamic microstructure evolution of Ti-6Al-2Sn-4Zr-6Mo alloy (Ti6246) through a 4-pass hot rolling process. Additionally, it examines the effect of heat treatment on microstructure evolution during the post-annealing of the hot-rolled alloy. During the rolling process, dynamic recrystallization (DRX) predominantly takes place in the α-phase, leading to grain refinement and spheroidization as a consequence of DRX and lamellae spheroidization. Spheroidization of the lamellar structure is more pronounced in the 2-pass rolling process, while the level of DRX is greater in the 4-pass rolling process. The dislocations present within the α lamellae accumulate and entangle at the sub-grain boundary, leading to the formation of a high-angle grain boundary (HAGB). Meanwhile, the β phase infiltrates the grain boundaries of the α phase, leading to the formation of spheroidized equiaxed α grains. Schmid factors associated with the pyramidal slip systems are relatively high, facilitating the activation of slip systems during hot rolling processes. The evolution of the α-phase morphology during heat treatment processes in various rolling passes is primarily driven by static recrystallization (SRX) and grain boundary terminal migration mechanisms. The deformed microstructure volume fraction diminishes and transforms into substructures and recrystallized grains through post-annealing. Post-annealing facilitates the dissipation of stored deformation energy with increasing temperature, leading to a decrease in dislocation density and an enhancement in the extent of recrystallization. Accumulated deformation during rolling and the temperature of the heat treatment both play a role in affecting the static spheroidization process. Greater accumulated deformation and elevated post-annealing temperatures are advantageous for achieving grain spheroidization. The grain boundary splitting process is more pronounced, and the deformation energy is elevated during the 3,4-pass rolling.

Automated Fiber Quantification Analysis Identifies Tract-specific Microstructural Alterations in Brain in Intermittent exotropia

BackgroundGrowing evidence of neuroimaging has indicated brain microstructural abnormalities in comitant strabismus. Nonetheless, few studies have investigated neuropathological alterations in patients with intermittent exotropia (IXT). This study aimed at examining the characteristics of brain microstructure along major fiber tracts in IXT patients using an automated fiber quantification analysis. MethodsA total of 25 patients with IXT as well as 25 healthy participants matched for age and gender finished the diffusion tensor imaging scanning and the ophthalmic examination. Automated fiber quantification analysis of 20 major fiber tracts was carried out for IXT patients and healthy subjects, respectively. Diffusion metrics of 100 equidistant nodes resampled along each tract were measured for every subject and compared between two groups. Effect size analysis was performed to identify the most affected fiber tracts in IXT. ResultsWidely declined mean diffusivity was noted in IXT along major tracts containing bilateral thalamic radiations, bilateral corticospinal fasciculi, bilateral cingulum cingulate, left inferior fronto-occipital fasciculus, right arcuate fasciculus and superior longitudinal fasciculus. Local reduction in fractional anisotropy was observed in IXT along left cingulum hippocampus, right inferior longitudinal fasciculus and right uncinate fasciculus, in contrast to the regionally increased fractional anisotropy along bilateral thalamic radiation, left corticospinal tract and left arcuate fasciculus. Among the tracts with significantly changed diffusion metrics in IXT, right inferior longitudinal fasciculus was the most affected one in fractional anisotropy while left thalamic radiation was the most influenced one in mean diffusivity. ConclusionsAbnormalities in microstructural properties along visual-related fiber tracts are likely to contribute to difficulties in visual information processing in IXT patients, which could serve as the neural basis of underlying pathological mechanism of IXT.

Assessment of corticospinal tract damage and cytokines response in early and late stages of acute unilateral brainstem infarction patients

Assessment of corticospinal tract damage and cytokines response in early and late stages of acute unilateral brainstem infarction patients

Neonatal inflammation and near-term white matter microstructure in infants born very preterm

BackgroundSevere neonatal inflammatory conditions in very preterm infants (VPT: <32 weeks gestational age, GA) are linked to adverse neurodevelopmental outcomes. Differences in white matter (WM) microstructure of the corpus callosum (CC) have been observed at age 6 in VPT children with a history of severe neonatal inflammation. The goal of this study was to determine whether these CC differences can be detected at term-equivalent age using diffusion MRI (dMRI), and whether neonatal inflammation is associated with altered WM in additional tracts implicated in the encephalopathy of prematurity. MethodsWe conducted a retrospective study of VPT infants (n = 152) born at 22–32 weeks GA, classified based on the presence (I+, n = 80) or absence (I-, n = 72) of severe neonatal inflammatory conditions (bronchopulmonary dysplasia, necrotizing enterocolitis, or culture-positive sepsis). Analysis of covariance (ANCOVA) assessed group differences in near-term dMRI mean fractional anisotropy (FA) and mean diffusivity (MD) across seven segments of the CC and the anterior thalamic radiation, arcuate fasciculus, cingulum, corticospinal tract, inferior longitudinal fasciculus, superior cerebellar peduncle, and uncinate fasciculus. Due to imbalance of GA in the full sample, secondary ANCOVA analyses were performed in a GA-matched subset (n = 42) to further isolate the effect of inflammation. ResultsFA was significantly lower in the I+ group compared to the I- group in the anterior frontal, posterior parietal, temporal, and occipital segments of the CC, and in the cingulum, inferior longitudinal fasciculus, and superior cerebellar peduncle. This general pattern persisted in the GA-matched subset, with significant differences in the anterior frontal and temporal CC segments. ConclusionsVPT infants with severe neonatal inflammation had lower FA in multiple white matter tracts, suggesting that inflammation-related alterations in WM development begin in the neonatal period. The observed differences detected using dMRI at term-equivalent age corroborate prior findings and may provide a window of opportunity for early identification of VPT infants at increased risk of poor neurodevelopmental outcomes.

Structural connectivity changes in focal epilepsy: Beyond the epileptogenic zone.

Epilepsy is recognized increasingly as a network disease, with changes extending beyond the epileptogenic zone (EZ). However, more studies of structural connectivity are needed to better understand the behavior and nature of this condition. In this study, we applied differential tractography, a novel technique that measures changes in anisotropic diffusion, to assess widespread structural connectivity alterations in a total of 42 patients diagnosed with medically refractory epilepsy (MRE), including 27 patients with focal epilepsy and 15 patients with multifocal epilepsy that were included to validate our hypothesis. All patients were compared individually to an averaged database constructed from 19 normal controls regressed by age and sex. Statistical analyses revealed specific distribution patterns of tracts with increased connectivity that were located in multiple subcortical structures across all patients including the arcuate fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, uncinate fasciculus, fornix, and short U fibers. Conversely, pathways with a significant decrease in connectivity (p < .05) exhibited a more central distribution near mesial structures across all patients (corpus callosum, cingulum, corticospinal tract, and sensory fibers). Our findings add to the growing evidence that focal epilepsy is not solely anatomically confined, but is rather a network disorder that extends beyond the EZ, and differential tractography shows strong potential as a clinical biomarker for assessing structural connectivity alterations in patients with epilepsy.

Theta Burst Stimulation Modulates Exercise Performance by Influencing Central Fatigue and Corticospinal Excitability.

Theta-burst stimulation (TBS) over the primary motor cortex modulates activity of the underlying neural tissue, but little is known about its consequence on neuromuscular fatigue (NMF) and its neural correlates. This study aimed to compare the effects of facilitatory versus inhibitory TBS on the NMF and excitability/inhibition of the corticospinal pathway in an unfatigued/fatigued muscle. The effects of three TBS protocols (facilitatory/intermittent: iTBS; inhibitory/continuous: cTBS, and sham: sTBS) were tested on exercise performance, neuromuscular function, corticospinal excitability and inhibition in twenty young healthy participants. Transcranial magnetic and peripheral electrical stimulations were used at baseline, following TBS (unfatigued state), and after a fatiguing sustained contraction (fatigued state) at 35% of the maximal voluntary isometric contraction (MVIC) of the elbow flexors. Time-to-task failure was shorter for cTBS (142±51 s) and longer for iTBS (214±68 s) compared with sTBS (173±65 s) (P < .05). In an unfatigued state, cTBS reduced MVIC and voluntary activation (VA), increased motor-evoked potential (MEP), and silent period (SP) (P < 0.05), while iTBS did not cause any change. In a fatigued state, MVIC and VA decreased in all TBS sessions (P < 0.05). However, the reduction in VA was larger after cTBS (Δ-18±18%) compared with iTBS (Δ-3±5%), and sTBS (Δ-9±9%) (P < 0.001). Furthermore, the increase in MEP and SP were greater for cTBS (P < .05), compared to iTBS and sTBS (P < .05). Facilitatory TBS augments exercise performance that is independent of central parameters and corticospinal mechanisms whilst inhibitory TBS attenuates exercise performance through an exacerbation in the development of central fatigue and possibly intracortical inhibition.

Efficacy of High-Definition Transcranial Alternating Current Stimulation (HD-tACS) at the M1 Hotspot Versus C3 Site in Modulating Corticospinal Tract Excitability.

Previous studies have shown that beta-band transcranial alternating current stimulation (tACS) applied at the M1 hotspot can modulate corticospinal excitability. However, it remains controversial whether tACS can influence motor unit activities at the spinal cord level. This study aims to compare the efficacy of applying tACS over the hotspot versus the conventional C3 site on motor unit activities and subsequent behavioral changes. This study used a randomized crossover trial design, where fifteen healthy participants performed a paced ball-squeezing exercise while receiving high-definition tACS (HD-tACS) at 21 Hz and 2 mA for 20 min. HD-tACS targeted either the flexor digitorum superficialis (FDS) hotspot or the C3 site, with the order of stimulation randomized for each participant and a 1-week washout period between sessions. Motor unit activities were recorded from the FDS. HD-tACS intervention significantly reduced the variability of motor unit firing rates and increased force variability during isometric force production. The significant modulation effects were seen only when the intervention was applied at the hotspot, but not at the C3 site. Our findings demonstrate that HD-tACS significantly modulates motor unit activities and force variability. The results indicate that cortical-level entrainment by tACS can lead to the modulation of spinal motor neuron activities. Additionally, this study provides further evidence that the C3 site may not be the optimal target for tACS intervention for hand muscles, highlighting the need for personalized neuromodulation strategies.

Development and validation a novel FEZF2 based fluorescent reporter for corticospinal motor neurons.

Corticospinal motor neurons (CSMNs), also named upper motor neurons, are the giant pyramidal neurons called Betz cells. In mammals, the majority of CSMNs reside within layer V of the primary motor cortex, where they extend long axon bundles named the pyramidal tract into the brainstem and the spinal cord to control voluntary movement. CSMN lesions are implicated in a variety of neurodegenerative disorders, such Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis and Hereditary Spastic paraplegia. Although FEZF2-CTIP2 genetic axis have been indicated as the cardinal molecular pathway underlying the development of CSMNs, these proteins are transcription factors that are mostly used to label the nuclei of CSMNs in the fixed cells and tissues. Therefore, a fluorescent reporter to mark CSMNs will be invaluable in identifying living CSMNs, including their extended processes, for time-lapse imaging and high-throughput molecular analyses with much more improved specificity. Based on the in-silico analysis, we identified a putative region within the promoter sequence of FEZF2 and assembled it with an indispensable enhancer motif at its downstream of the gene to form a complex promoter that drives the expression of reporter GFP. The plasmid and virus of FEZF2:eGFP reporter constructs were further validated for its use in specifically labeling CSMNs in primary neuronal cultures from the embryonic rat motor cortex, postnatal mouse cortex. This innovative molecular labeling tool has the potential to offer indispensable support in diverse experimental setups, enabling a comprehensive understanding of the susceptibility and specificity of CSMNs in a wide array of neurological disorders.

Tunnel sign in patients with melioidosis: a case series from South India

Abstract Introduction The tunnel sign (linear contrast enhancement along the corticospinal tract) can aid in the early diagnosis of neuromelioidosis, a potentially fatal condition requiring urgent diagnosis. Methodology We retrospectively analyzed the hospital data of all patients with culture-confirmed melioidosis between 2018 and 2023 in a tertiary care hospital in South India. MRI scans of patients with neuromelioidosis were reviewed for the presence of the tunnel sign. Results Of the 177 patients with melioidosis, 21 had possible neurological involvement. Seven had confirmed neuromelioidosis. Of the six patients with neuromelioidosis, where an MRI scan was available, a tunnel sign was noted in four. Conclusion We report this study to create awareness amongst physicians to look for this sign in patients with suspected neuromelioidosis.

Changing the view on spastic movement disorder management to improve active movement competence in the upper motor neuron syndrome: a clinical perspective.

It is common in clinical practice to evaluate active movement in spastic movement disorders (SMDs) associated with the upper motor neuron syndrome in terms of resistance to passive movement in the rest position, with the assumption that this may reflect motor control when the patient is in active motion. In addition, the definition of spasticity as a velocity-dependent resistance to passive movement does not account for the impact of abnormal muscle synergies (synkinesia), on active motion of upper and lower limbs in SMDs. In this article, we put forward our theory that synkinetic movement patterns are controlled by activation from spinal afferents and inhibition from the cortex, and become disturbed following a loss of inhibition and change to spinal afferents following damage to the corticospinal tract. In this regard, we propose a change in the focus from passive to active function at the evaluation stage of the SMD management plan, and a new treatment approach to modulate muscle synergies with botulinum neurotoxin type A therapy.

Identifying amyotrophic lateral sclerosis using diffusion tensor imaging, and correlation with neurofilament markers

To determine diagnostic value of diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients and investigate the association between DTI and neurofilaments (NFs), including serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). Forty-three clinically diagnosed ALS patients and 32 control subjects without neurological disorders underwent routine MRI (magnetic resonance imaging) and DTI scans. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) at axial levels of internal capsules and cerebral peduncles along the corticospinal tract (CST) were measured. The study compared the differences of DTI parameters between ALS patients and controls using the Mann-Whitney U test. Diagnostic efficacy of each DTI metric was evaluated using the receiver operating characteristic (ROC) curve. NFs (NFL and pNFH levels in serum and CSF) were measured by enzyme-linked immunosorbent assay. Correlation analyses were conducted between DTI parameters and NFs. Capsule-MD and Peduncle-MD in ALS patients were higher than those in controls; whereas Capsule-FA and Peduncle-FA in ALS patients were lower than those in controls (all, p < 0.05). The area under curve (AUC) was 0.730 for Capsule-FA, 0.828 for Capsule-MD, 0.890 for Peduncle-FA, and 0.896 for Peduncle-MD. Capsule-FA was negatively correlated with CSF-NFL (r = − 0.813, p < 0.001), Serum-NFL (r = − 0.493, p = 0.001), CSF-pNFH (r = − 0.637, p < 0.001), and Serum-pNFH (r = − 0.672, p < 0.001); Peduncle-FA negatively with CSF-NFL (r = − 0.562, p < 0.001), CSF-pNFH (r = − 0.506, p = 0.001), and Serum-pNFH (r = − 0.488, p = 0.001); Peduncle-MD positively with CSF-NFL (r = 0.516, p < 0.001), CSF-pNFH (r = 0.494, p = 0.001). DTI had superior performance in identifying ALS patients and could serve as a reliable predictor. DTI parameters related to neurofilament markers, and Capsule-FA may become a robust surrogate biomarker indicating disease severity and progression rate for ALS patients.

Distinct Constructs Underlie Patient-Reported and Performance-Rated Outcomes after Stroke.

Patient-reported outcome measures (PROMs), which capture patients' perspectives on the consequences of health and disease, are widely used in neurological care and research. However, it is unclear how PROMs relate to performance-rated impairments. Sociodemographic factors are known to affect PROMs. Direct damage to brain regions critical for self-awareness (i.e., parietal regions and the salience/ventral-attention network) may also impair self-report outcomes. This study examined the relationship between PROMs and performance-based measures in stroke survivors with arm motor impairments. We hypothesized that PROMs would be distinct from performance-based outcomes, influenced by sociodemographic factors, and linked to damage in brain circuits involved in self-perception. We longitudinally assessed 54 stroke survivors using patient-reported and performance-rated measures at 4 timepoints. We used factor analysis to reveal the outcome battery's factorial structure. Linear regression examined the association between classes of measures and sociodemographics. Voxel-lesion-symptom-mapping, region-of-interest-based analysis, and voxel-lesion-network-mapping investigated the relationship between classes of outcomes and stroke-related injury. Performance-based and patient-reported measures formed distinct factors, consistent across recovery phases. Higher education (β1 = 0.36, p = 0.02) and income adequacy (β2 = 0.48, p = 0.05) were associated with patient-reported, but not performance-rated outcomes. Greater parietal lobe injury, irrespective of hemisphere, was associated with worse patient-reported outcomes; greater corticospinal tract injury related to worse performance-rated outcomes. Lesions with greater functional connectivity to the salience/ventral-attention network were associated with worse patient-reported outcomes (r = -0.35, p = 0.009). Our findings reveal important differences between performance-rated and patient-reported outcomes, each with specific associated factors and anatomy post-stroke. Incorporating sociodemographic and neuroanatomic characteristics into neurorehabilitation strategies may inform and optimize patient outcomes. ANN NEUROL 2024.

SURGICAL APPROACH TO THALAMIC CAVERNOUS MALFORMATIONS

Introduction Thalamus is a high eloquent brain region, because it contains important relay nucleus and is surrounded by vital neural and vascular structures. Cavernous malformations involving deep structures such as the basal ganglia and thalamus account for 5–10% of all cerebral cavernomas and can cause devastating neurological deficits. Surgical approach to thalamic cavernomas is associated with risks of new or worsening neurologic deficits. The benefit of surgery must be carefully weighed on an individualized basis. There are several surgical routes that can be used to approach thalamic lesions, mainly transcortical and interhemispheric approaches. A particular approach should be selected based on the location of the cavernoma in the thalamus to minimize lesion of the unaffected brain. Methods We present the case of a 43-year-old right-handed lady with right bleeding posterolateral thalamic cavernoma, admitted to the neurosurgery department of Sibiu MedLife Polisano Hospital in February 2024. The patient underwent surgery, through a transcortical trans-sulcal para-fascicular, navigation guided approach. Preoperative tractography imaging, tubular cerebral corridor retractor system and intraoperative monitoring of the cortico-spinal tract, through motor evoked potentials (transcortical, cortical and subcortical mapping) and of the spinotahamic tract through somatosensory evoked potentials were used. The postoperative course was uneventful and the patient was discharged on the 7th postoperative day. Conclusions Thalamus is a complex structure located in a deep brain area and surgery for these region carries high risks, so the surgeon must carefully tailor these patients. The transcortical transsulcal para-fascicular approach is feasible and safe using the cerebral tubular corridor, neuronavigation and neuromonitoring. Advanced surgical technology offers the advantages of minimizing the risks of new neurological deficits.

Molecular signaling predicts corticospinal axon growth state and muscle response plasticity induced by neuromodulation

Electrical motor cortex stimulation can produce corticospinal system plasticity and enhance motor function after injury. We investigate molecular mechanisms of structural and physiological plasticity following electrical neuromodulation, focusing on identifying molecular predictors, or biomarkers, for durable plasticity. We used two neuromodulation protocols, repetitive multipulse stimulation (rMPS) and patterned intermittent theta burst stimulation (iTBS), incorporating different stimulation durations and follow-up periods. We compared neuromodulation efficacy in promoting corticospinal tract (CST) sprouting, motor cortex muscle evoked potential (MEP) LTP-like plasticity, and their associated molecular underpinnings. Only iTBS produced CST sprouting after short-term neuromodulation (1 d of stimulation; 9-d survival for sprouting expression); both iTBS and rMPS produced sprouting with long-term (10-d) neuromodulation. Significant mTOR signaling activation and phosphatase and tensin homolog (PTEN) protein deactivation predicted axon growth across all neuromodulation conditions that produced significant sprouting. Both neuromodulation protocols, regardless of duration, were effective in producing MEP enhancement. However, persistent LTP-like enhancement of MEPs at 30 d was only produced by long-term iTBS. Statistical modeling suggests that Stat3 signaling is the key mediator of MEP enhancement. Cervical spinal cord injury (SCI) alone did not affect baseline molecular signaling. Whereas iTBS and rMPS after SCI produced strong mTOR activation and PTEN deactivation, only iTBS produced Stat3 activation. Our findings support differential molecular biomarkers for neuromodulation-dependent structural and physiological plasticity and show that motor cortex epidural neuromodulation produces molecular changes in neurons that support axonal growth after SCI. iTBS may be more suitable for repair after SCI because it promotes molecular signaling for both CST growth and MEP plasticity.

NIMG-72. VOXEL-WISE, MULTIVARIABLE, COX PROPORTIONAL HAZARD STATISTICAL PARAMETER MAPPING TO INVESTIGATE THE INTERPLAY BETWEEN TUMOR LOCATION, PROGNOSTIC VARIABLES, AND EXPERIMENTAL TREATMENT IN A PHASE 3 TRIAL OF NEWLY-DIAGNOSED GLIOBLASTOMA TREATED WITH CHEMORADIATION WITH OR WITHOUT BEVACIZUMAB

Abstract BACKGROUND Tumor location is known to impact overall survival (OS) in glioblastoma. However, there is a lack of quantitative tools for studying the interplay between tumor location, prognostic variables, and treatments. In the current study we develop a voxel-wise statistical parameter mapping technique using a multivariable Cox regression model to describe the influence of tumor location on treatment effects in newly diagnosed glioblastoma. METHODS 598 newly diagnosed glioblastoma patients from the phase 3 AVAglio trial were studied. Areas of T2/FLAIR hyperintensity and resection cavities on post-surgical MRI scans were segmented and aligned to MNI atlas space. Voxel-wise Cox proportional hazards models for OS were run for each image voxel and included tumor presence in a specific voxel, age, MGMT promoter methylation, baseline tumor volume, and treatment (chemoradiation with or without bevacizumab). Results. After adjusting for other variables, tumor location was an independent predictor of favorable OS for tumors with involvement in the right prefrontal cortex (p&amp;lt;0.05, HR ranging ~0.48–0.65) and a predictor of shorter OS for tumors in the left mesial/basal temporo-occipital areas (p&amp;lt;0.05, HR ~3–6.2) and in the left hemisplenium of the corpus callosum (p&amp;lt;0.05, HR ~2.5–3). Baseline tumor volume (HR ~4–6 x10-6), MGMT status (HR ~0.38–0.41), and age (HR ~1.020–1.025) were significative predictors regardless of location (p&amp;lt;0.05 in all locations). Interestingly, chemoradiation plus bevacizumab treatment showed a favorable OS compared with chemoradiation alone for tumors with involvement in the right corticospinal tract, right motor and sensory cortices, and left hemisplenium of the corpus callosum (p&amp;lt;0.05, HR ~0.82). CONCLUSIONS Tumor involvement in the prefrontal cortex is associated with favorable prognosis, while tumors in mesial/basal temporo-occipital areas or splenium of the corpus callosum are associated with shorter OS. Chemoradiation plus bevacizumab may improve OS for tumors involving eloquent motor areas and the corticospinal tract.

RADT-24. WALLERIAN DEGENERATION OF THE CORTICOSPINAL TRACT IN GLIOMAS: A RETROSPECTIVE ANALYSIS AND A SYSTEMATIC REVIEW OF MOTOR FUNCTION IN ELOQUENT AREAS POST-RADIATION THERAPY. HOW IMPORTANT IS MOTOR FUNCTION FOR PATIENTS WITH GLIOMAS IN RADIATION THERAPY?

Abstract BACKGROUND The quality of life for patients with gliomas is significantly impacted by tumor characteristics, treatment modalities, and radiation dosages. Variability in radiotherapy protocols and differences in tissue tolerance necessitate a detailed risk-benefit assessment, especially in eloquent brain areas responsible for motor functions. METHODS A retrospective analysis of electronic medical records from a Brazilian Radiation Therapy Department (2018-2023) was conducted. Patients with gliomas who underwent surgical resection and adjuvant radiochemotherapy, subsequently developing Wallerian Degeneration of the Corticospinal Tract (WDCT), were included. Additionally, a systematic search was performed in PubMed, Embase, and Cochrane databases, focusing on radiotherapy in eloquent areas and evaluating motor function. Of the 1,064 studies identified, 11 underwent full-text review by two independent examiners. RESULTS Among 192 glioma patients, 13 (6.77%) developed WDCT, all with high-grade gliomas, including 3 post-reirradiation cases. Retrospective dosimetric analysis of the corticospinal tract was performed for two patients who had tractography. Patient 1, with right frontoparietal tumor, had an ipsilateral corticospinal tract volume of 10.6 cm³, a max dose of 62.81 Gy, and 0.5 cc receiving 62.2 Gy; the contralateral tract volume was 18.5 cm³, with 0.5 cc receiving 51 Gy. Patient 2, with right frontal tumor, had an ipsilateral corticospinal tract volume of 31.1 cm³, a max dose of 42.76 Gy, and 0.5 cc receiving 42.37 Gy; the contralateral tract volume was 30.3 cm³, with 0.5 cc receiving 24.19 Gy. The systematic review identified 5 studies reporting pre- and post-radiotherapy motor outcomes in eloquent areas, with 4 focusing exclusively on gliomas. However, heterogeneity in radiotherapy techniques and outcome assessments precluded a meta-analysis. CONCLUSION Motor function in glioma patients undergoing radiation therapy remains an underexplored area. Future studies should focus on standardized assessments of functional outcomes to establish dose constraints and optimize treatment protocols, thus improving the quality of life for glioma patients.

Cell type–specific gene therapy confers protection against motor neuron disease caused by a TFG variant

Inherited forms of motor neuron disease (MND), including hereditary spastic paraplegias (HSP), are associated with the death or dysfunction of nerve cells that control skeletal muscle activity. However, in some cases, the impacts of genetic variants underlying MND act in a non-cell autonomous manner, instead affecting the function of other cell types necessary for neuronal maintenance. Pathological mutations in TFG, which have been implicated in HSP, lead to axonopathy within the corticospinal tract, but it remains unclear whether this problem arises due to perturbations within neurons or supporting neuroglia. To address this question, we leveraged a rat model harboring the recessive TFG p.R106C mutation (mRATBN7.2, g.11:43897639C>T, c.316C>T), which recapitulates multiple phenotypes associated with HSP in humans, including progressive motor deficits, leg spasticity, and indications of an inflammatory response within the motor cortex. In particular, we took advantage of cell type-specific gene therapies to demonstrate that the reintroduction of wild-type TFG into synapsin 1-positive neurons provides robust protection against MND, whereas its expression in GFAP-positive glial cells provides no significant improvement in quantitative measures of gait, despite a dramatic reduction in the presence of reactive astrocytes throughout the brain. These data strongly suggest that therapeutic approaches targeting neurons should be pursued in cases of TFG-HSP, with our animal model offering a unique platform for preclinical assessment.

CTIM-01. OUTCOMES AND IMMUNE RESPONSES AFTER PEPTIDE VACCINATION TARGETING HUMAN CYTOMEGALOVIRUS ANTIGEN PP65 IN CHILDREN AND YOUNG ADULTS WITH RECURRENT HIGH-GRADE GLIOMA AND MEDULLOBLASTOMA: RESULTS OF A PHASE 1 TRIAL

Abstract INTRODUCTION The human cytomegalovirus (CMV) antigen pp65 is ubiquitously expressed in high-grade glioma (HGG) and medulloblastoma but not in adjacent brain. The primary objective of this phase I trial (NCT03299309) was to assess the safety and feasibility of a novel peptide vaccine targeting pp65 (PEP-CMV) in children/young adults with recurrent medulloblastoma and HGG. METHODS PEP-CMV is comprised of a synthetic long peptide of 26 amino acids and is administered as an emulsion in Montanide ISA 51. Patients receive a 5-day course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning to promote dendritic cell migration, then PEP-CMV intradermally in the groin every two weeks for 3 doses, then monthly. RESULTS 42 patients were enrolled. The mean age was 23.2 ± 9.3 years. 55% of patients were male. The median KPS was 80. The median number of prior chemotherapy regimens was 4 (range 1-15). Of the 38 patients who received PEP-CMV, the maximum grade adverse events (AE) possibly, probably, or definitely related to PEP-CMV were: 17 (45%) Grade 1 AEs, 16 (42%) Grade 2 AEs, 2 (5%) Grade 3 AEs (encephalopathy and pyramidal tract syndrome), and one (3%) Grade 4 AE (cerebral edema). One patient developed cytokine release syndrome (Grade 2). The median PFS was 2.5 months (95% CI:2.2, 3.2) and median OS was 6.4 months (95% CI:3.4, 7.9). The 12-month OS was 26.6% (95% CI:14, 41.1%). Of the 21 patients with evaluable immune monitoring data (received ≥3 vaccines/known CMV status), T cell reactivity on IFNγ pp65 ELISpot was increased after PEP-CMV delivery (median 2 vs 22, P=0.01). PFS and OS were significantly better in patients with low levels of CD56brightCD16dim phenotype NK cells: P=0.029 and P=0.047, respectively. Patients with naïve CD8+ counts over the median had significantly better PFS (P=0.006). CONCLUSIONS PEP-CMV is well-tolerated and elicits an antigen-specific immune response in heavily pretreated, multiply recurrent patients with a 12-month OS of 26.6%.

Comparison of strategies based on DTI visualisation for stereotactic minimally invasive surgery in the treatment of moderate-volume thalamo-basal ganglia cerebral haemorrhage: a protocol for a multicenter prospective study

IntroductionHypertensive intracerebral hemorrhage (HICH) is a condition associated with significant morbidity, mortality, and disability, particularly among the elderly population. The management of moderate thalamic-basal ganglia cerebral hemorrhage primarily relies on conservative approaches. Nevertheless, the rate of long-term disability remains high. In recent years, there has been significant advancement in minimally invasive surgery and diffusion tensor imaging techniques. Consequently, the utilization of Diffusion Tensor Imaging (DTI) technology in patients with cerebral haemorrhage allows for the identification of the haematoma’s location in relation to the Corticospinal Tract (CST). This enables the development of precise puncture pathways that can be visualized, thereby avoiding any potential damage to the CST.Methods and analysisDiffusion Tensor Imaging (DTI) is a method used to assess the structural and physiological characteristics of biological tissue by examining the diffusion behavior of water molecules.In the central nervous system, limb paralysis will be inevitable if the corticospinal tract is damaged. By employing DTI imaging techniques on individuals, it becomes possible to visualize the spatial relationship between the hematoma and the CST. This approach allows avoidance of the CST during preoperative planning of the puncture path, thus reducing secondary injuries caused by the procedure. The primary objective of this study was to assess the ability of patients in the minimally invasive surgery group and the conservative group to perform activities of daily living after 6 months of treatment. In addition, secondary outcomes included assessment of hematoma resorption/clearance ratios, cytokine levels, complication rates, and therapeutic indexes at different treatment durations, as well as long-term safety and efficacy at 2–3 years of follow-up. Furthermore, subgroup analysis, and sensitivity analysis were conducted to further analyze the data. Logistic single-variate and multivariate regression analyses were applied to understand the adverse factors affecting prognosis.Ethics and disseminationThe clinical study was reviewed and approved by the Ethics Committee of the First People’s Hospital of Yibin. The ethical number is: 2023 Review (64).Registration numberThis protocol is registered in the Prospective Registry of Chinese Clinical Trial Registries (PROCCTR). The full date of first registration is 28/12/2023. The registration number for PROCCTR is ChiCTR2300079252.