Gamma-aminobutyric acid and glutamate/glutamine levels in the dentate nucleus and periaqueductal gray in new daily persistent headache: a magnetic resonance spectroscopy study.

BACKGROUND: Magnetic resonance spectroscopy (MRS) studies have indicated that the imbalance between gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels was the potential cause of migraine development. However, the changes in the GABA and Glx levels in patients with New daily persistent headache (NDPH) remain unclear. This study aimed to investigate the changes in GABA and Glx levels in the periaqueductal gray (PAG) and dentate nucleus (DN) in patients with NDPH using the MEGA-PRESS sequence. METHODS: Twenty-one NDPH patients and 22 age- and sex-matched healthy controls (HCs) were included and underwent a 3.0T MRI examination, using the MEGA-PRESS sequence to analyze GABA and Glx levels of PAG and DN. The correlations between these neurotransmitter levels and clinical characteristics were also analyzed. RESULTS: There were no significant differences in the GABA+/Water, GABA+/Cr, Glx/Water, and Glx/Cr levels in both PAG and DN between the two groups (all p > 0.05). Moderate-severe NDPH patients had lower levels of Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) in DN than minimal-mild NDPH patients. In patients with NDPH, higher Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and higher Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were found to be correlated with lower Visual Analogue Scale scores. Additionally, a positive correlation was observed between the GABA+/Cr levels in the DN and the Generalized Anxiety Disorder-7 scores (r = 0.519, p = 0.039, n = 16). CONCLUSIONS: The results of this study indicated that the GABA and Glx levels in the PAG and DN may not be the primary contributor to the development of NDPH. The correlations between certain clinical scales and the neurotransmitter levels may be derived from the NDPH related symptoms.

Structured connectivity in the output of the cerebellar cortex.

The spatial organization of a neuronal circuit is critically important for its function since the location of neurons is often associated with function. In the cerebellum, the major output of the cerebellar cortex are synapses made from Purkinje cells onto neurons in the cerebellar nuclei, yet little has been known about the spatial organization of these synapses. We explored this question using whole-cell electrophysiology and optogenetics in acute sagittal cerebellar slices to produce spatial connectivity maps of cerebellar cortical output in mice. We observed non-random connectivity where Purkinje cell inputs clustered in cerebellar transverse zones: while many nuclear neurons received inputs from a single zone, several multi-zonal connectivity motifs were also observed. Single neurons receiving input from all four zones were overrepresented in our data. These findings reveal that the output of the cerebellar cortex is spatially structured and represents a locus for multimodal integration in the cerebellum.

Linking abnormal neural activity patterns to motor deficits.

Abnormal activity in the cerebellar nuclei can be used to predict motor symptoms and induce them experimentally, pointing to potential therapeutic strategies.

Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor.

The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared across etiologically distinct but phenotypically similar disease models. Mimicking these pathophysiological spike signatures with optogenetics induced the predicted motor impairments in otherwise healthy mice. These data show that distinct spike signatures promote the behavioral presentation of cerebellar diseases.

Intentional movement is fundamental to achieving many goals, whether they are as complicated as driving a car or as routine as feeding ourselves with a spoon. The cerebellum is a key brain area for coordinating such movement. Damage to this region can cause various movement disorders: ataxia (uncoordinated movement); dystonia (uncontrolled muscle contractions); and tremor (involuntary and rhythmic shaking). While abnormal electrical activity in the brain associated with movement disorders has been recorded for decades, previous studies often explored one movement disorder at a time. Therefore, it remained unclear whether the underlying brain activity is similar across movement disorders. Van der Heijden and Brown et al. analyzed recordings of neuron activity in the cerebellum of mice with movement disorders to create an activity profile for each disorder. The researchers then used machine learning to generate a classifier that could separate profiles associated with manifestations of ataxia, dystonia, and tremor based on unique features of their neural activity. The ability of the model to separate the three types of movement disorders indicates that abnormal movements can be distinguished based on neural activity patterns. When additional manifestations of these abnormal movements were considered, multiple mouse models of dystonia and tremor tended to show similar profiles. Ataxia models had several different types of neural activity that were all distinct from the dystonia and tremor profiles. After identifying the activity associated with each movement disorder, Van der Heijden and Brown et al. induced the same activity in the cerebella of healthy mice, which then caused the corresponding abnormal movements. These findings lay an important groundwork for the development of treatments for neurological disorders involving ataxia, dystonia, and tremor. They identify the cerebellum, and specific patterns of activity within it, as potential therapeutic targets. While the different activity profiles of ataxia may require more consideration, the neural activity associated with dystonia and tremor appears to be generalizable across multiple manifestations, suggesting potential treatments could be broadly applicable for these disorders.

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.

A spatial-temporal map of glutamatergic neurogenesis in the murine embryonic cerebellar nuclei uncovers a high degree of cellular heterogeneity.

The nuclei are the main output structures of the cerebellum. Each and every cerebellar cortical computation reaches several areas of the brain by means of cerebellar nuclei processing and integration. Nevertheless, our knowledge of these structures is still limited compared to the cerebellar cortex. Here, we present a mouse genetic inducible fate-mapping study characterizing rhombic lip-derived glutamatergic neurons of the nuclei, the most conspicuous family of long-range cerebellar efferent neurons. Glutamatergic neurons mainly occupy dorsal and lateral territories of the lateral and interposed nuclei, as well as the entire medial nucleus. In mice, they are born starting from about embryonic day 9.5, with a peak between 10.5 and 12.5, and invade the nuclei with a lateral-to-medial progression. While some markers label a heterogeneous population of neurons sharing a common location (BRN2), others appear to be lineage specific (TBR1, LMX1a, and MEIS2). A comparative analysis of TBR1 and LMX1a distributions reveals an incomplete overlap in their expression domains, in keeping with the existence of separate efferent subpopulations. Finally, some tagged glutamatergic progenitors are not labeled by any of the markers used in this study, disclosing further complexity. Taken together, our results obtained in late embryonic nuclei shed light on the heterogeneity of the excitatory neuron pool, underlying the diversity in connectivity and functions of this largely unexplored cerebellar territory. Our findings contribute to laying the groundwork for a comprehensive functional analysis of nuclear neuron subpopulations.

Neurosurgical treatment of spasticity: a potential return to the cerebellum.

OBJECTIVE: Neurosurgical targeting of the cerebellar dentate nucleus via ablative dentatotomy and stimulation of the dentate nucleus was historically used for effective treatment of spasticity. Yet for decades, neurosurgical treatment of spasticity targeting the cerebellum was bypassed in favor of alternative treatments such as intrathecal baclofen pumps and selective dorsal rhizotomies. Cerebellar neuromodulation has recently reemerged as a promising and effective therapy for spasticity and related movement disorders. METHODS: In this narrative review, the authors contextualize the historical literature of cerebellar neuromodulation, comparing it with modern approaches and exploring future directions with regard to cerebellar neuromodulation for spasticity. RESULTS: Neurosurgical intervention on the cerebellum dates to the use of dentatotomy in the 1960s, which had progressed to electrical stimulation of the cerebellar cortex and dentate nucleus by the 1980s. By 2024, modern neurosurgical approaches such as tractography-based targeting of the dentate nucleus and transcranial magnetic stimulation of cerebellar cortex have demonstrated promise for treating spasticity. CONCLUSIONS: Cerebellar neuromodulation of the dentate nucleus and cerebellar cortex are promising therapies for severe cases of spasticity. Open areas for exploration in the field include the following: tractography-based targeting, adaptive cerebellar stimulation, and investigations into the network dynamics between the cerebellar cortex, deep cerebellar nuclei, and the subcortical and cortical structures of the cerebrum.

Engrailed transcription factors direct excitatory cerebellar neuron diversity and survival.

The neurons of the three cerebellar nuclei (CN) are the primary output neurons of the cerebellum. The excitatory neurons (e) of the medial (m) CN (eCNm) were recently divided into molecularly defined subdomains in the adult; however, how they are established during development is not known. We define molecular subdomains of the mouse embryonic eCNm using single-cell RNA-sequencing and spatial expression analysis, showing that they evolve during embryogenesis to prefigure the adult. Furthermore, eCNm are transcriptionally divergent from cells in the other nuclei by embryonic day 14.5. We previously showed that loss of the homeobox genes En1 and En2 leads to loss of approximately half of the embryonic eCNm. We demonstrate that mutation of En1/2 in the embryonic eCNm results in death of specific posterior eCNm molecular subdomains and downregulation of TBR2 (EOMES) in an anterior embryonic subdomain, as well as reduced synaptic gene expression. We further reveal a similar function for EN1/2 in mediating TBR2 expression, neuron differentiation and survival in the other excitatory neurons (granule and unipolar brush cells). Thus, our work defines embryonic eCNm molecular diversity and reveals conserved roles for EN1/2 in the cerebellar excitatory neuron lineage.

Dentate nucleus: a review and implications for dentatotomy.

PURPOSE: The dentate nucleus (DN) is the largest, most lateral, and phylogenetically most recent of the deep cerebellar nuclei. Its pivotal role encompasses the planning, initiation, and modification of voluntary movement but also spans non-motor functions like executive functioning, visuospatial processing, and linguistic abilities. This review aims to offer a comprehensive description of the DN, detailing its embryology, anatomy, physiology, and clinical relevance, alongside an analysis of dentatotomy. METHODS AND RESULTS: We delve into the history, embryology, anatomy, vascular supply, imaging characteristics, and clinical significance of the DN. Furthermore, we thoroughly review the dentatotomy, emphasizing its role in treating spasticity. CONCLUSIONS: Understanding the intricacies of the anatomy, physiology, vasculature, and projections of the DN has taken on increased importance in current neurosurgical practice. Advances in technology have unveiled previously unknown functions of the deep cerebellar nuclei, predominantly related to non-motor domains. Such discoveries are revitalizing older techniques, like dentatotomy, and applying them to newer, more localized targets.

Electrophysiological Correlates of Dentate Nucleus Deep Brain Stimulation for Poststroke Motor Recovery.

While ipsilesional cortical electroencephalography has been associated with poststroke recovery mechanisms and outcomes, the role of the cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that poststroke motor control relies on increased corticocerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting poststroke motor rehabilitation. We investigated the excitability of the ipsilesional cortex, the dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, 10 human participants (two women) at the end of 4-8 months of DN deep brain stimulation (DBS) showed (1) significantly improved motor control indexed by computerized motor tasks; (2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and (3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the poststroke state and its connectivity with the ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of corticocerebellar-cortical network after stroke and its modulation by DN-DBS.

Dynamic effective connectivity in the cerebellar dorsal dentate nucleus and the cerebrum, cognitive impairment, and clinical correlates in patients with schizophrenia.

BACKGROUND: Schizophrenia (SZ) is characterized by disconnected cerebral networks. Recent studies have shown that functional connectivity between the cerebellar dorsal dentate nucleus (dDN) and cerebrum is correlated with psychotic symptoms, and processing speed in SZ patients. Dynamic effective connectivity (dEC) is a reliable indicator of brain functional status. However, the dEC between the dDN and cerebrum in patients with SZ remains largely unknown. METHODS: Resting-state functional MRI data, symptom severity, and cognitive performance were collected from 74 SZ patients and 53 healthy controls (HC). Granger causality analysis and sliding time window methods were used to calculate dDN-based dEC maps for all subjects, and k-means clustering was performed to obtain several dEC states. Finally, between-group differences in dynamic effective connectivity variability (dECV) and clinical correlations were obtained using two-sample t-tests and correlation analysis. RESULTS: We detected four dEC states from the cerebrum to the right dDN (IN states) and three dEC states from the right dDN to the cerebrum (OUT states), with SZ group having fewer transitions in the OUT states. SZ group had increased dECV from the right dDN to the right middle frontal gyrus (MFG) and left lingual gyrus (LG). Correlations were found between the dECV from the right dDN to the right MFG and symptom severity and between the dECV from the right dDN to the left LG and working memory performance. CONCLUSIONS: This study reveals a dynamic causal relationship between cerebellar dDN and the cerebrum in SZ and provides new evidence for the involvement of cerebellar neural circuits in neurocognitive functions in SZ.

Evaluation of signal intensity changes in dentate nucleus and globus pallidus on magnetic resonance imaging after intrathecal gadolinium-based contrast agent administration.

PURPOSE: Gadolinium deposition has been reported in several normal anatomical structures in the brain after repeated administration of intravenous gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI). This study presents preliminary results to see if there is any gadolinium deposition in the dentate nucleus and globus pallidus after using intrathecal GBCAs. METHODS: Between November 2018 and November 2020, 29 patients who underwent intrathecal contrast-enhanced MR cisternography with the suspicion of rhinorrhea were included in this prospective study. In contrast-enhanced MR cisternography, gadoterate meglumine was administered by intrathecal injection at a dose of 1 ml. One month later, patients had a control MRI with 3D T1 SPACE fat-saturated (FS) and susceptibility weighted images (SWI) sequences. The ratio of dentate nucleus signal intensity to middle cerebellar peduncle signal intensity (DN/MCP ratio) and the ratio of globus pallidus signal intensity to thalamus signal intensity (GP/T ratio) were calculated using region of interest (ROI) on pre-contrast and control MRI sequences. RESULTS: There was no significant difference for DN/MCP ratio and GP/T ratio on 3D T1 SPACE FS and SWI sequences after intrathecal GBCAs administration compared to baseline MRI. CONCLUSION: Administration of intrathecal GBCAs did not cause a measurable change in the signal intensity of the dentate nucleus and globus pallidus after a single injection.

Developmentally Unique Cerebellar Processing Prioritizes Self- over Other-Generated Movements.

Animals must distinguish the sensory consequences of self-generated movements (reafference) from those of other-generated movements (exafference). Only self-generated movements entail the production of motor copies (i.e., corollary discharges), which are compared with reafference in the cerebellum to compute predictive or internal models of movement. Internal models emerge gradually over the first three postnatal weeks in rats through a process that is not yet fully understood. Previously, we demonstrated in postnatal day (P) 8 and P12 rats that precerebellar nuclei convey corollary discharge and reafference to the cerebellum during active (REM) sleep when pups produce limb twitches. Here, recording from a deep cerebellar nucleus (interpositus, IP) in P12 rats of both sexes, we compared reafferent and exafferent responses with twitches and limb stimulations, respectively. As expected, most IP units showed robust responses to twitches. However, in contrast with other sensory structures throughout the brain, relatively few IP units showed exafferent responses. Upon finding that exafferent responses occurred in pups under urethane anesthesia, we hypothesized that urethane inhibits cerebellar cortical cells, thereby disinhibiting exafferent responses in IP. In support of this hypothesis, ablating cortical tissue dorsal to IP mimicked the effects of urethane on exafference. Finally, the results suggest that twitch-related corollary discharge and reafference are conveyed simultaneously and in parallel to cerebellar cortex and IP. Based on these results, we propose that twitches provide opportunities for the nascent cerebellum to integrate somatotopically organized corollary discharge and reafference, thereby enabling the development of closed-loop circuits and, subsequently, internal models.

Localized Changes in Dentate Nucleus Shape and Magnetic Susceptibility in Friedreich Ataxia.

BACKGROUND: The dentate nuclei of the cerebellum are key sites of neuropathology in Friedreich ataxia (FRDA). Reduced dentate nucleus volume and increased mean magnetic susceptibility, a proxy of iron concentration, have been reported by magnetic resonance imaging studies in people with FRDA. Here, we investigate whether these changes are regionally heterogeneous. METHODS: Quantitative susceptibility mapping data were acquired from 49 people with FRDA and 46 healthy controls. The dentate nuclei were manually segmented and analyzed using three dimensional vertex-based shape modeling and voxel-based assessments to identify regional changes in morphometry and susceptibility, respectively. RESULTS: Individuals with FRDA, relative to healthy controls, showed significant bilateral surface contraction most strongly at the rostral and caudal boundaries of the dentate nuclei. The magnitude of this surface contraction correlated with disease duration, and to a lesser extent, ataxia severity. Significantly greater susceptibility was also evident in the FRDA cohort relative to controls, but was instead localized to bilateral dorsomedial areas, and also correlated with disease duration and ataxia severity. CONCLUSIONS: Changes in the structure of the dentate nuclei in FRDA are not spatially uniform. Atrophy is greatest in areas with high gray matter density, whereas increases in susceptibility-reflecting iron concentration, demyelination, and/or gliosis-predominate in the medial white matter. These findings converge with established histological reports and indicate that regional measures of dentate nucleus substructure are more sensitive measures of disease expression than full-structure averages. Biomarker development and therapeutic strategies that directly target the dentate nuclei, such as gene therapies, may be optimized by targeting these areas of maximal pathology. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Real-time field-programmable gate array-based closed-loop deep brain stimulation platform targeting cerebellar circuitry rescues motor deficits in a mouse model of cerebellar ataxia.

AIMS: The open-loop nature of conventional deep brain stimulation (DBS) produces continuous and excessive stimulation to patients which contributes largely to increased prevalence of adverse side effects. Cerebellar ataxia is characterized by abnormal Purkinje cells (PCs) dendritic arborization, loss of PCs and motor coordination, and muscle weakness with no effective treatment. We aim to develop a real-time field-programmable gate array (FPGA) prototype targeting the deep cerebellar nuclei (DCN) to close the loop for ataxia using conditional double knockout mice with deletion of PC-specific LIM homeobox (Lhx)1 and Lhx5, resulting in abnormal dendritic arborization and motor deficits. METHODS: We implanted multielectrode array in the DCN and muscles of ataxia mice. The beneficial effect of open-loop DCN-DBS or closed-loop DCN-DBS was compared by motor behavioral assessments, electromyography (EMG), and neural activities (neurospike and electroencephalogram) in freely moving mice. FPGA board, which performed complex real-time computation, was used for closed-loop DCN-DBS system. RESULTS: Closed-loop DCN-DBS was triggered only when symptomatic muscle EMG was detected in a real-time manner, which restored motor activities, electroencephalogram activities and neurospike properties completely in ataxia mice. Closed-loop DCN-DBS was more effective than an open-loop paradigm as it reduced the frequency of DBS. CONCLUSION: Our real-time FPGA-based DCN-DBS system could be a potential clinical strategy for alleviating cerebellar ataxia and other movement disorders.

Simple spike patterns and synaptic mechanisms encoding sensory and motor signals in Purkinje cells and the cerebellar nuclei.

Whisker stimulation in awake mice evokes transient suppression of simple spike probability in crus I/II Purkinje cells. Here, we investigated how simple spike suppression arises synaptically, what it encodes, and how it affects cerebellar output. In vitro, monosynaptic parallel fiber (PF)-excitatory postsynaptic currents (EPSCs) facilitated strongly, whereas disynaptic inhibitory postsynaptic currents (IPSCs) remained stable, maximizing relative inhibitory strength at the onset of PF activity. Short-term plasticity thus favors the inhibition of Purkinje spikes before PFs facilitate. In vivo, whisker stimulation evoked a 2-6 ms synchronous spike suppression, just 6-8 ms (∼4 synaptic delays) after sensory onset, whereas active whisker movements elicited broadly timed spike rate increases that did not modulate sensory-evoked suppression. Firing in the cerebellar nuclei (CbN) inversely correlated with disinhibition from sensory-evoked simple spike suppressions but was decoupled from slow, non-synchronous movement-associated elevations of Purkinje firing rates. Synchrony thus allows the CbN to high-pass filter Purkinje inputs, facilitating sensory-evoked cerebellar outputs that can drive movements.

Distant recurrence in the cerebellar dentate nucleus through the dentato-rubro-thalamo-cortical pathway in supratentorial glioma cases.

BACKGROUND: Distant recurrence can occur by infiltration along white matter tracts or dissemination through the cerebrospinal fluid (CSF). This study aimed to clarify the clinical features and mechanisms of recurrence in the dentate nucleus (DN) in patients with supratentorial gliomas. Based on the review of our patients, we verified the hypothesis that distant DN recurrence from a supratentorial lesion occurs through the dentato-rubro-thalamo-cortical (DRTC) pathway. METHODS: A total of 380 patients with supratentorial astrocytoma, isocitrate dehydrogenase (IDH)-mutant (astrocytoma), oligodendroglioma, IDH mutant and 1p/19q-codeleted (oligodendroglioma), glioblastoma, IDH-wild type (GB), and thalamic diffuse midline glioma, H3 K27-altered (DMG), who underwent tumor resection at our department from 2009 to 2022 were included in this study. Recurrence patterns were reviewed. Additionally, clinical features and magnetic resonance imaging findings before treatment, at the appearance of an abnormal signal, and at further progression due to delayed diagnosis or after salvage treatment of cases with recurrence in the DN were reviewed. RESULTS: Of the 380 patients, 8 (2.1%) had first recurrence in the DN, 3 were asymptomatic when abnormal signals appeared, and 5 were diagnosed within one month after the onset of symptoms. Recurrence in the DN developed in 8 (7.4%) of 108 cases of astrocytoma, GB, or DMG at the frontal lobe or thalamus, whereas no other histological types or sites showed recurrence in the DN. At the time of the appearance of abnormal signals, a diffuse lesion developed at the hilus of the DN. The patterns of further progression showed that the lesions extended to the superior cerebellar peduncle, tectum, tegmentum, red nucleus, thalamus, and internal capsule along the DRTC pathway. CONCLUSION: Distant recurrence along the DRTC pathway is not rare in astrocytomas, GB, or DMG at the frontal lobe or thalamus. Recurrence in the DN developed as a result of the infiltration of tumor cells through the DRTC pathway, not dissemination through the CSF.