Gradient of microstructural damage along the dentato-thalamo-cortical tract in Friedreich ataxia.

OBJECTIVE: The dentato-thalamo-cortical tract (DTT) is the main cerebellar efferent pathway. Degeneration of the DTT is a core feature of Friedreich ataxia (FRDA). However, it remains unclear whether DTT disruption is spatially specific, with some segments being more impacted than others. This study aimed to investigate microstructural integrity along the DTT in FRDA using a profilometry diffusion MRI (dMRI) approach. METHODS: MRI data from 45 individuals with FRDA (mean age: 33.2 ± 13.2, Male/Female: 26/19) and 37 healthy controls (mean age: 36.5 ± 12.7, Male/Female:18/19) were included in this cross-sectional multicenter study. A profilometry analysis was performed on dMRI data by first using tractography to define the DTT as the white matter pathway connecting the dentate nucleus to the contralateral motor cortex. The tract was then divided into 100 segments, and dMRI metrics of microstructural integrity (fractional anisotropy, mean diffusivity and radial diffusivity) at each segment were compared between groups. The process was replicated on the arcuate fasciculus for comparison. RESULTS: Across all diffusion metrics, the region of the DTT connecting the dentate nucleus and thalamus was more impacted in FRDA than downstream cerebral sections from the thalamus to the cortex. The arcuate fasciculus was minimally impacted. INTERPRETATION: Our study further expands the current knowledge about brain involvement in FRDA, showing that microstructural abnormalities within the DTT are weighted to early segments of the tract (i.e., the superior cerebellar peduncle). These findings are consistent with the hypothesis of DTT undergoing anterograde degeneration arising from the dentate nuclei and progressing to the primary motor cortex.

Modeling the impact of neuromorphological alterations in Down syndrome on fast neural oscillations.

Cognitive disorders, including Down syndrome (DS), present significant morphological alterations in neuron architectural complexity. However, the relationship between neuromorphological alterations and impaired brain function is not fully understood. To address this gap, we propose a novel computational model that accounts for the observed cell deformations in DS. The model consists of a cross-sectional layer of the mouse motor cortex, composed of 3000 neurons. The network connectivity is obtained by accounting explicitly for two single-neuron morphological parameters: the mean dendritic tree radius and the spine density in excitatory pyramidal cells. We obtained these values by fitting reconstructed neuron data corresponding to three mouse models: wild-type (WT), transgenic (TgDyrk1A), and trisomic (Ts65Dn). Our findings reveal a dynamic interplay between pyramidal and fast-spiking interneurons leading to the emergence of gamma activity (∼40 Hz). In the DS models this gamma activity is diminished, corroborating experimental observations and validating our computational methodology. We further explore the impact of disrupted excitation-inhibition balance by mimicking the reduction recurrent inhibition present in DS. In this case, gamma power exhibits variable responses as a function of the external input to the network. Finally, we perform a numerical exploration of the morphological parameter space, unveiling the direct influence of each structural parameter on gamma frequency and power. Our research demonstrates a clear link between changes in morphology and the disruption of gamma oscillations in DS. This work underscores the potential of computational modeling to elucidate the relationship between neuron architecture and brain function, and ultimately improve our understanding of cognitive disorders.

Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report the development of a real-time quaking-induced conversion (RT-QuIC) seed amplification assay using a recombinant human SOD1 substrate to measure SOD1 seeding activity in postmortem spinal cord and motor cortex tissue from persons with different ALS etiologies. Our SOD1 RT-QuIC assay detected SOD1 seeds in motor cortex and spinal cord dilutions down to 10-5. Importantly, we detected SOD1 seeding activity in specimens from both sporadic and familial ALS cases, with the latter having mutations in either their SOD1 or C9ORF72 genes. Analyses of RT-QuIC parameters indicated similar lag phases in spinal cords of sporadic and familial ALS patients, but higher ThT fluorescence maxima by SOD1 familial ALS specimens and sporadic ALS thoracic cord specimens. For a subset of sporadic ALS patients, motor cortex and spinal cords were examined, with seeding activity in both anatomical regions. Our results suggest SOD1 seeds are in ALS patient neural tissues not linked to SOD1 mutation, suggesting that SOD1 seeding activity may be a promising biomarker, particularly in sporadic ALS cases for whom genetic testing is uninformative.

Structural changes in eloquent cortex secondary to glioma in sensorimotor area.

This study aims to investigate the structural reorganization in the sensorimotor area of the brain in patients with gliomas, distinguishing between those with impaired and unimpaired strength. Using voxel-based morphometry (VBM) and region of interest (ROI) analysis, gray matter volumes (GMV) were compared in the contralesional primary motor gyrus, primary sensory gyrus, premotor area, bilateral supplementary motor area, and medial Brodmann area 8 (BA8). The results revealed that in patients with right hemisphere gliomas, the right medial BA8 volume was significantly larger in the impaired group than in the unimpaired group, with both groups exceeding the volume in 16 healthy controls (HCs). In patients with left hemisphere gliomas, the right supplementary motor area (SMA) was more pronounced in the impaired group compared to the unimpaired group, and both groups were greater than HCs. Additionally, the volumes of the right medial BA8 in both the impaired group were greater than HCs. Contralateral expansions in the gray matter of hand- and trunk-related cortices of the premotor area, precentral gyrus, and postcentral gyrus were observed compared to HCs. Furthermore, a negative correlation was found between hand Medical Research Council (MRC) score and volumes of the contralateral SMA and bilateral medial BA8. Notably, our findings reveal consistent results across both analytical approaches in identifying significant structural reorganizations within the sensorimotor cortex. These consistent findings underscore the adaptive neuroplastic responses to glioma presence, highlighting potential areas of interest for further neurosurgical planning and rehabilitation strategies.

Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis.

The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.

TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression.

TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.

Anatomical analysis of white fiber tracts in SMA and its implications related to en-masse tumor resection technique.

OBJECTIVE: Anatomy and connections of the supplementary motor area (SMA) are studied essentially to analyze the SMA syndrome. Experience with surgical treatment of 19 tumors located in SMA is analyzed. MATERIAL AND METHODS: The cortical anatomy and subcortical connectivity of the SMA was studied on ten previously frozen and formalin fixed human cadaveric brain specimens. The white fiber dissection was performed using Klingler's method. Nineteen patients with low grade gliomas in the region of the SMA treated surgically were clinically analyzed. RESULTS: The white fiber connections of the SMA include short arcuate connections with the pre-central, middle and inferior frontal gyri, the medial part of the SLF, the cingulum, the frontal aslant tract (FAT), the claustro-cortical fibers, the fronto-striatal tract and the crossed frontal aslant tract. All tumors were operated using en-masse surgical technique described by us and its subsequent modifications that focused on attempts towards preservation of related critical fiber tracts namely FAT, cingulum and corpus callosum presumed to be responsible for postoperative SMA syndrome. Eight patients developed an SMA syndrome in the immediate post-operative period. Eleven patients did not develop any post-operative neurological deficits. In all these 11 patients it was apparent that the cingulum, FAT and the corpus callosal fibers were preserved during surgery by modifying the tumor resection technique. CONCLUSIONS: SMA syndrome is a frequent occurrence following surgery in patients with tumors in the region of the SMA complex. Surgical strategy that preserves the cingulum and the FAT can prevent the occurrence of the SMA syndrome.

LINC complex alterations are a key feature of sporadic and familial ALS/FTD.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in the C9ORF72 gene (C9). Importantly, we show that such alterations are present in vivo in a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex specimens. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.

Parkinsonism originates in a discrete secondary and dystonia in a primary motor cortical-basal ganglia subcircuit.

Although manifesting contrasting phenotypes, Parkinson's disease and dystonia, the two most common movement disorders, can originate from similar pathophysiology. Previously, we demonstrated that lesioning (silencing) of a discrete dorsal region in the globus pallidus (rodent equivalent to globus pallidus externa) in rats and produced parkinsonism, while lesioning a nearby ventral hotspot-induced dystonia. Presently, we injected fluorescent-tagged multi-synaptic tracers into these pallidal hotspots (n = 36 Long Evans rats) and permitted 4 days for the viruses to travel along restricted connecting pathways and reach the motor cortex before sacrificing the animals. Viral injections in the Parkinson's hotspot fluorescent labeled a circumscribed region in the secondary motor cortex, while injections in the dystonia hotspot labeled within the primary motor cortex. Custom probability mapping and N200 staining affirmed the segregation of the cortical territories for Parkinsonism and dystonia to the secondary and primary motor cortices. Intracortical microstimulation localized territories specifically to their respective rostral and caudal microexcitable zones. Parkinsonian features are thus explained by pathological signaling within a secondary motor subcircuit normally responsible for initiation and scaling of movement, while dystonia is explained by abnormal (and excessive) basal ganglia signaling directed at primary motor corticospinal transmission.

Transcranial Magnetic Stimulation-Based Machine Learning Prediction of Tumor Grading in Motor-Eloquent Gliomas.

BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is a well-established preoperative mapping tool for motor-eloquent glioma surgery. Machine learning (ML) and nTMS may improve clinical outcome prediction and histological correlation. METHODS: This was a retrospective cohort study of patients who underwent surgery for motor-eloquent gliomas between 2018 and 2022. Ten healthy subjects were included. Preoperative nTMS-derived variables were collected: resting motor threshold (RMT), interhemispheric RMT ratio (iRMTr)-abnormal if above 10%-and cortical excitability score-number of abnormal iRMTrs. World Health Organization (WHO) grade and molecular profile were collected to characterize each tumor. ML models were fitted to the data after statistical feature selection to predict tumor grade. RESULTS: A total of 177 patients were recruited: WHO grade 2-32 patients, WHO grade 3-65 patients, and WHO grade 4-80 patients. For the upper limb, abnormal iRMTr were identified in 22.7% of WHO grade 2, 62.5% of WHO grade 3, and 75.4% of WHO grade 4 patients. For the lower limb, iRMTr was abnormal in 23.1% of WHO grade 2, 67.6% of WHO grade 3%, and 63.6% of WHO grade 4 patients. Cortical excitability score ( P = .04) was statistically significantly related with WHO grading. Using these variables as predictors, the ML model had an accuracy of 0.57 to predict WHO grade 4 lesions. In subgroup analysis of high-grade gliomas vs low-grade gliomas, the accuracy for high-grade gliomas prediction increased to 0.83. The inclusion of molecular data into the model-IDH mutation and 1p19q codeletion status-increases the accuracy of the model in predicting tumor grading (0.95 and 0.74, respectively). CONCLUSION: ML algorithms based on nTMS-derived interhemispheric excitability assessment provide accurate predictions of HGGs affecting the motor pathway. Their accuracy is further increased when molecular data are fitted onto the model paving the way for a joint preoperative approach with radiogenomics.

Multi-institutional study of 'Sandwich treatment' for motor area large brain metastases (LBM) with diameter over 3 cm.

BACKGROUND: The objective of the present study was to explore the effectiveness and safety of 'Sandwich treatment' strategy for large brain metastases (LBM) with diameter over 3 cm (minimum volume >= 15 cm3) located in motor area. PATIENTS AND METHODS: Patients from four gamma knife center that received 'Sandwich treatment' were retrospectively studied from January 2016 to March 2023. The strategy was one-week treatment course including 2 stages of stereotactic radiosurgery (SRS) and using bevacizumab once during SRS gap. The tumor volume and peri-tumor edema changes were analyzed before and after 'Sandwich treatment'. Manual muscle testing (MMT) score and Barthel Index (BI) score were used to evaluate the changes of patients' movement and physical strength rehabilitation. The patients' overall survival (OS) and tumor local control (TLC) rate was calculated. Cox regression model was used to analyze the risk factors that related to TLC. RESULTS: 61 patients with 72 lesions received the 'Sandwich treatment'. The median prescription dose was 13.0 Gy and 12.5 Gy at the first- and second-stage SRS. The mean tumor volume at the time of 'Sandwich treatment' and 3 months later was 20.1 cm3 and 12.3, respectively (P < 0.01). The mean peri-tumor edema volume at the first- and second-stage SRS was 12.6 cm3 and 5.2 cm3, respectively (P < 0.01). Patients' median MMT score improved from 6 at the beginning to 8 at the end of 'Sandwich treatment' (P < 0.01), BI score was also greatly improved from 45 at the time of 'Sandwich treatment' to 95 after 3 months (P < 0.01). Patients' median OS was 14.0 months, and the 3, 6, 12 months OS rate was 92.0%, 86.0% and 66.0%, respectively. The TLC rate at 3, 6, 12 months was 98.4%, 93.4%, and 85.3%, respectively. Patients with lung cancer had lower risk of tumor relapse. The cumulative incidence of patient's hemorrhage and radiation necrosis was 4.92% (3/61) and 13.11% (8/61) after 'Sandwich treatment'. CONCLUSIONS: 'Sandwich treatment' strategy is safe and effective for LBM located in motor area. The strategy could rapidly improve the patients' movement and enhance their physical strength rehabilitation.

TAF15 amyloid filaments in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.

Outcomes of Gamma Knife Radiosurgery for Brain Metastases in the Motor Cortex.

BACKGROUND AND OBJECTIVES: To study the clinical, imaging, and survival outcomes in patients with motor cortex brain metastases treated with stereotactic radiosurgery (SRS). METHODS: Imaging and clinical data were obtained from our prospective patient registry. Tumor volumes were obtained from serial imaging data. RESULTS: The outcomes of 208 patients with metastases involving the motor cortex who underwent SRS between 2012 and 2021 were analyzed. A total of 279 metastases (0.01 cm 3 -12.18 cm 3 , mean 0.74 cm 3 ) were irradiated. The SRS margin dose varied from 10 to 20 Gy (mean 16.9 Gy). The overall tumor control rate was 97.8%. Perilesional edema was noted in 69 (25%) tumors at presentation. Adverse radiation effects (ARE) were noted in 6% of all tumors but were symptomatic in only 1.4%. Median time to appearance of symptomatic ARE was 8 months. Edema without ARE was observed in 13%. New focal seizures were noted in 5 patients (2%) and new generalized seizures in 1 patient (0.3%). Thirty-six patients (17%) presented with motor deficits. At final follow-up, 32 (85%) were improved or unchanged, 13 (41%) had a normal examination, 10 (31%) had mild deficits, and 9 (28%) still had moderate deficits. New remote brain metastases were found in 31% of patients at a median of 8 months. After treatment, the Karnofsky performance score distribution of the population showed an overall right shift and a median survival of 10 months. Patients with incidentally found brain metastases had significantly better survival than those presenting with deficits (median 13 vs 9 months) ( P = .048). Absence of a neurological deficit, recursive partitioning analysis Class I and II, and dose >18 Gy were each associated with a significant survival advantage. CONCLUSION: SRS for motor cortex metastases is safe in most patients and effective in providing tumor control. Patients treated before neurological deficits develop show better outcomes.

Differential cortical gray matter changes in early- and late-onset patients with amyotrophic lateral sclerosis.

Age at onset may be an important feature associated with distinct subtypes of amyotrophic lateral sclerosis (ALS). Little is known about the neuropathological mechanism of early-onset ALS (EO-ALS) and late-onset ALS (LO-ALS). Ninety ALS patients were divided into EO-ALS and LO-ALS group, and 128 healthy controls were matched into young controls(YCs) and old controls (OCs). A voxel-based morphometry approach was employed to investigate differences in gray matter volume (GMV). Significant age at onset-by-diagnosis interactions were found in the left parietal operculum, left precentral gyrus, bilateral postcentral gyrus, right occipital gyrus, and right orbitofrontal cortex. Post hoc analysis revealed a significant decrease in GMV in all affected regions of EO-ALS patients compared with YCs, with increased GMV in 5 of the 6 brain regions, except for the right orbitofrontal cortex, in LO-ALS patients compared with OCs. LO-ALS patients had a significantly increased GMV than EO-ALS patients after removing the aging effect. Correspondingly, GMV of the left postcentral gyrus correlated with disease severity in the 2 ALS groups. Our findings suggested that the pathological mechanisms in ALS patients with different ages at onset might differ. These findings provide unique insight into the clinical and biological heterogeneity of the 2 ALS subtypes.

Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease.

There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). Mucuna pruriens has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of Mucuna pruriens, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase (TH) protein expression in the nigrostriatal pathway, or glutamate biomarkers in both the striatum and motor cortex. Following MPTP administration, resulting in an 80 % loss of striatal TH, treatment with Mucuna pruriens failed to rescue either striatal TH or the dopamine transporter back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with Mucuna pruriens. This Mucuna pruriens-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins, GLAST (EAAT1) and EAAC1 (EAAT3), and the vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with Mucuna pruriens, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.

Proteomic investigation of ALS motor cortex identifies known and novel pathogenetic mechanisms.

The key pathological feature in ALS is death of motor neurones from the brain and spinal cord, but the molecular mechanisms underlying this degeneration remain unknown. Quantifying the motor cortex proteome in autopsy brain and comparing tissues from ALS cases and non-ALS controls is critical to understanding these mechanisms. We used Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) to characterize the proteomes of the motor cortex from ALS cases (n = 8) and control subjects (n = 8). A total of 1427 proteins were identified at a critical local false discovery rate < 5%; 187 of these exhibited significant expression differences between ALS cases and controls. Of these, 91 proteins were significantly upregulated and 96 proteins were significantly downregulated. Bioinformatics analysis revealed that these proteins are involved in molecular transport, protein trafficking, free radical scavenging, lipid metabolism, cell death and survival, nucleic acid metabolism, inflammatory response or amino acid metabolism and carbohydrate metabolism. Differentially expressed proteins were subjected to pathway analysis. This revealed abnormalities in pathways involving mitochondrial function, sirtuin signaling, oxidative phosphorylation, glycolysis, phagosome maturation, SNARE signaling, redox regulation and several others. Core analysis revealed mitochondrial dysfunction to be the top canonical pathway. The top-enriched networks involved JNK activation and inhibition of AKT signaling, suggesting that disruption of these signaling pathways could lead to demise of motor neurons in the ALS motor cortex.

Radiological correlates of pseudobulbar affect: Corticobulbar and cerebellar components in primary lateral sclerosis.

INTRODUCTION: Pseudobulbar affect (PBA) is a distressing symptom of a multitude of neurological conditions affecting patients with a rage of neuroinflammatory, neurovascular and neurodegenerative conditions. It manifests in disproportionate emotional responses to minimal or no contextual stimulus. It has considerable quality of life implications and treatment can be challenging. METHODS: A prospective multimodal neuroimaging study was conducted to explore the neuroanatomical underpinnings of PBA in patients with primary lateral sclerosis (PLS). All participants underwent whole genome sequencing and screening for C9orf72 hexanucleotide repeat expansions, a comprehensive neurological assessment, neuropsychological screening (ECAS, HADS, FrSBe) and PBA was evaluated by the emotional lability questionnaire. Structural, diffusivity and functional MRI data were systematically evaluated in whole-brain (WB) data-driven and region of interest (ROI) hypothesis-driven analyses. In ROI analyses, functional and structural corticobulbar connectivity and cerebello-medullary connectivity alterations were evaluated separately. RESULTS: Our data-driven whole-brain analyses revealed associations between PBA and white matter degeneration in descending corticobulbar as well as in commissural tracts. In our hypothesis-driven analyses, PBA was associated with increased right corticobulbar tract RD (p = 0.006) and decreased FA (p = 0.026). The left-hemispheric corticobulbar tract, as well as functional connectivity, showed similar tendencies. While uncorrected p-maps revealed both voxelwise and ROI trends for associations between PBA and cerebellar measures, these did not reach significance to unequivocally support the "cerebellar hypothesis". CONCLUSIONS: Our data confirm associations between cortex-brainstem disconnection and the clinical severity of PBA. While our findings may be disease-specific, they are consistent with the classical cortico-medullary model of pseudobulbar affect.

Focal tonic seizures with asymmetrical posturing could allow voluntary movements: A lesson to not be misled for a non-epileptic event.

This report documents the clinical features of supplementary motor area seizures with voluntary movements in two patients. The first case describes a 13-year-old boy with a 2-year history of nocturnal seizures, characterized by an asymmetrical brief tonic posture followed by bilateral rapid hand shaking, but without impaired awareness. Magnetic resonance imaging revealed no abnormalities. Video electroencephalogram indicated interictal focal spikes and ictal activity 2 s before clinical onset in the frontal midline area. The patient stated that he purposely shook his hands to lessen the seizure-induced upper limb stiffness. The second case describes a 43-year-old man with a 33-year history of nocturnal seizures, characterized by an asymmetric brief tonic posture, with the right hand grabbing to hold this posture, but without impaired awareness. Video electroencephalogram indicated that he voluntarily moved his right hand during the latter part of the seizures; however, no clear ictal electroencephalogram change was noted. Magnetic resonance imaging revealed a mass lesion in the right medial superior frontal gyrus. Fluorodeoxyglucose-positron emission tomography and ictal single-photon emission computed tomography indicated ictal focus in the mesial frontal area, as confirmed by invasive electroencephalogram and seizure freedom after surgery. Both patients had typical supplementary motor area seizures, except they could perform voluntary movements in the body parts. The co-occurrence of supplementary motor area seizures and voluntary movements is clinically useful, as it may help avoid the inaccurate and misleading diagnosis of non-epileptic events such as psychogenic non-epileptic seizures.