Analysis of morphological measurements of the trigeminal nerve in the linac stereotactic radiosurgery simulation targeting the root entry zone in trigeminal neuralgia.

PURPOSE: To describe the anatomical measurements of the trigeminal nerve in patients with trigeminal neuralgia (TN) during Linac (linear accelerator)-based stereotactic radiosurgery (SRS) simulation, targeting the root entry zone (REZ), with a 30% isodose line tangential to the pons, using 4-mm and 6-mm collimators. METHODS: In this retrospective study, 53 TN patients, who underwent Fiesta sequence scanning prior to any treatment modality, were assessed. Bilateral measurements were obtained from the cisternal segment of the trigeminal nerve, the trigeminal-pontine angle, and the lateral width of the pontine cistern on the Fiesta MRI sequence. Linac-based SRS simulations were estimated with a radiation dosage of 90Gy to 30% isodose line tangential to the pons, with both 4- and 6-mm collimators. Distances from the calculated targets to the pons and the Gasserian ganglion were measured for later analysis. The statistical analysis was performed comparing the affected side against the unaffected side. RESULTS: Right trigeminal nerve was affected in 36 patients (67.9%), and left one in 17 (32.1%) patients. The mean length of the trigeminal nerve was 9.8mm (range: 4.6-16.8mm) on the affected side, and 10.5mm (range: 5.6-18.4mm) on the unaffected side (p=.02). The mean trigeminal-pontine angle was 12.5° (range: 5.4° to 19.5°) on the affected side, and 10.2° (range: 5.0° to 30.5°) on the unaffected side (p=.01). In the simulations, the distances from the estimated targets to the pons and the Gasserian ganglion were not statistically different between sides. The variation of target-pons and target-ganglion distances was statistically significant on the affected side with the change of collimators (p<.001). CONCLUSIONS: In this anatomical study, significant differences were identified in the length of the affected trigeminal nerve and trigeminal-pontine angle compared to the unaffected side in TN patients in Fiesta sequences prior to surgery or radiosurgery. Significant variation of the target location was found on the REZ between the 4- and 6-collimators during the Linac-based SRS simulations with the estimated radiation dosage of 90Gy and 30% isodose line tangential to the pons.

Hypofractionated Radiotherapy for Children With Diffuse Intrinsic Pontine Gliomas.

Children with diffuse intrinsic pontine gliomas have very poor outcomes, with nearly all children dying from disease. Standard therapy includes 6 weeks of radiation. There have been descriptions of using a shortened course of radiation. We describe our experience with a hypofractionated radiotherapy approach delivered over five treatments. In seven children, hypofractionated radiotherapy was well tolerated, but symptomatic radiation necrosis was seen in three of the children. Overall survival was slightly shorter than previously described in the literature. We are developing a prospective dose-finding protocol with the goal of tolerable short-course radiation treatment with outcomes comparable to conventional radiation.

Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma.

Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of PARP1 inhibition in preclinical models of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient samples and tumor-derived cell lines. The effects of PARP inhibitors veliparib, olaparib, and niraparib as monotherapy or as radiosensitizers on cell viability, DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell lines. Survival benefit of niraparib was examined in an orthotopic xenograft model of pHGA. About 85% of pHGAs and 76% of DIPG tissue microarray samples expressed PARP1. Six of 8 primary cell lines highly expressed PARP1. Interestingly, across multiple cell lines, some PARP1 protein expression was required for response to PARP inhibition; however, there was no correlation between protein level or PARP1 activity and sensitivity to PARP inhibitors. Niraparib was the most effective at reducing cell viability and proliferation (MTT and Ki67). Niraparib induced DNA damage (γH2AX foci) and induced growth arrest. Pretreatment of pHGA cells with a sublethal dose of niraparib (1 µmol/L) before 2 Gy of ionizing radiation (IR) decreased the rate of DNA damage repair, colony growth, and relative cell number. Niraparib (50 mg/kg) inhibited PARP1 activity in vivo and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 vs. 25 days). Our data provide in vitro and in vivo evidence that niraparib may be an effective radiosensitizer for pHGA and DIPG.

Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes.

Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C, and a lysine-to-isoleucine substitution (K27I) in H3F3A, also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 (H3F3A) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 (HIST1H3B/C). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.

Differences in brainstem fiber tract response to radiation: a longitudinal diffusion tensor imaging study.

PURPOSE: To determine whether radiation-induced changes in white matter tracts are uniform across the brainstem. METHODS AND MATERIALS: We analyzed serial diffusion tensor imaging data, acquired before radiation therapy and over 48 to 72 months of follow-up, from 42 pediatric patients (age 6-20 years) with medulloblastoma. FSL software (FMRIB, Oxford, UK) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivities. For a consistent identification of volumes of interest (VOIs), the parametric maps of each patient were transformed to a standard brain space (MNI152), on which we identified VOIs including corticospinal tract (CST), medial lemniscus (ML), transverse pontine fiber (TPF), and middle cerebellar peduncle (MCP) at the level of pons. Temporal changes of DTI parameters in VOIs were compared using a linear mixed effect model. RESULTS: Radiation-induced white matter injury was marked by a decline in FA after treatment. The decline was often accompanied by decreased axial diffusivity, increased radial diffusivity, or both. This implied axonal damage and demyelination. We observed that the magnitude of the changes was not always uniform across substructures of the brainstem. Specifically, the changes in DTI parameters for TPF were more pronounced than in other regions (P<.001 for FA) despite similarities in the distribution of dose. We did not find a significant difference among CST, ML, and MCP in these patients (P>.093 for all parameters). CONCLUSIONS: Changes in the structural integrity of white matter tracts, assessed by DTI, were not uniform across the brainstem after radiation therapy. These results support a role for tract-based assessment in radiation treatment planning and determination of brainstem tolerance.

Radiation necrosis of the pons after radiotherapy for nasopharyngeal carcinoma: diagnosis and treatment.

We report a case of radiation necrosis in an unusual location, the pons, in a patient who had received chemoradiation for nasopharyngeal carcinoma (NPC) over one year prior to presentation. This patient presented with subacute onset of ataxic hemiparesis and slurred speech. Initial magnetic resonance imaging (MRI) studies showed two 1-2 cm peripherally contrast-enhancing lesions in the pons with extensive surrounding edema. Proton magnetic resonance spectroscopy (MRS) played a key role in narrowing the differential diagnosis to radiation necrosis. The patient underwent biweekly bevacizumab therapy and has remained clinically stable with radiologic improvement of his lesion. In addition to this case, we present an overview of the use of advanced neuroimaging in distinguishing radiation necrosis of the central nervous system (CNS) from other entities as well as the role of bevacizumab in treatment.

Brain tumor therapy-induced changes in normal-appearing brainstem measured with longitudinal diffusion tensor imaging.

PURPOSE: To characterize therapy-induced changes in normal-appearing brainstems of childhood brain tumor patients by serial diffusion tensor imaging (DTI). METHODS AND MATERIALS: We analyzed 109 DTI studies from 20 brain tumor patients, aged 4 to 23 years, with normal-appearing brainstems included in the treatment fields. Those with medulloblastomas, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors (n = 10) received postoperative craniospinal irradiation (23.4-39.6 Gy) and a cumulative dose of 55.8 Gy to the primary site, followed by four cycles of high-dose chemotherapy. Patients with high-grade gliomas (n = 10) received erlotinib during and after irradiation (54-59.4 Gy). Parametric maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and spatially registered to three-dimensional radiation dose data. Volumes of interest included corticospinal tracts, medial lemnisci, and the pons. Serving as an age-related benchmark for comparison, 37 DTI studies from 20 healthy volunteers, aged 6 to 25 years, were included in the analysis. RESULTS: The median DTI follow-up time was 3.5 years (range, 1.6-5.0 years). The median mean dose to the pons was 56 Gy (range, 7-59 Gy). Three patterns were seen in longitudinal FA and apparent diffusion coefficient changes: (1) a stable or normal developing time trend, (2) initial deviation from normal with subsequent recovery, and (3) progressive deviation without evidence of complete recovery. The maximal decline in FA often occurred 1.5 to 3.5 years after the start of radiation therapy. A full recovery time trend could be observed within 4 years. Patients with incomplete recovery often had a larger decline in FA within the first year. Radiation dose alone did not predict long-term recovery patterns. CONCLUSIONS: Variations existed among individual patients after therapy in longitudinal evolution of brainstem white matter injury and recovery. Early response in brainstem anisotropy may serve as an indicator of the recovery time trend over 5 years after radiation therapy.

Predicting nonauditory adverse radiation effects following radiosurgery for vestibular schwannoma: a volume and dosimetric analysis.

PURPOSE: To define clinical and dosimetric predictors of nonauditory adverse radiation effects after radiosurgery for vestibular schwannoma treated with a 12 Gy prescription dose. METHODS: We retrospectively reviewed our experience of vestibular schwannoma patients treated between September 2005 and December 2009. Two hundred patients were treated at a 12 Gy prescription dose; 80 had complete clinical and radiological follow-up for at least 24 months (median, 28.5 months). All treatment plans were reviewed for target volume and dosimetry characteristics; gradient index; homogeneity index, defined as the maximum dose in the treatment volume divided by the prescription dose; conformity index; brainstem; and trigeminal nerve dose. All adverse radiation effects (ARE) were recorded. Because the intent of our study was to focus on the nonauditory adverse effects, hearing outcome was not evaluated in this study. RESULTS: Twenty-seven (33.8%) patients developed ARE, 5 (6%) developed hydrocephalus, 10 (12.5%) reported new ataxia, 17 (21%) developed trigeminal dysfunction, 3 (3.75%) had facial weakness, and 1 patient developed hemifacial spasm. The development of edema within the pons was significantly associated with ARE (p = 0.001). On multivariate analysis, only target volume is a significant predictor of ARE (p = 0.001). There is a target volume threshold of 5 cm3, above which ARE are more likely. The treatment plan dosimetric characteristics are not associated with ARE, although the maximum dose to the 5th nerve is a significant predictor of trigeminal dysfunction, with a threshold of 9 Gy. The overall 2-year tumor control rate was 96%. CONCLUSIONS: Target volume is the most important predictor of adverse radiation effects, and we identified the significant treatment volume threshold to be 5 cm3. We also established through our series that the maximum tolerable dose to the 5th nerve is 9 Gy.

Central pontine myelinolysis presented after prophylactic cranial irradiation in small cell lung cancer.

Prophylactic cranial irradiation (PCI) should now be considered as a part of the standard treatment of patients with small cell lung cancer (SCLC) in complete remission. The PCI has been offered in SCLC to reduce the incidence of brain metastasis and increase survival. The complications of PCI were reported brain necrosis, seizure or dementia. The complications were more frequent when chemotherapy was given at the time of cranial irradiation, or large radiation fraction size was employed. It is established that the pathophysiological reaction to irradiation in the normal brain tissue is necrosis, demyelinization, and diffuse changes due to wall thickening of the vascular structures. However, central pontine myelinolysis (CPM) of low dose irradiation like PCI is very rare. We report a patient with the classical syndrome of CPM following PCI for SCLC. The diagnosis was supported by typical features on magnetic resonance imaging.

Dedicated linear accelerator radiosurgery for trigeminal neuralgia: a single-center experience in 179 patients with varied dose prescriptions and treatment plans.

PURPOSE: Dedicated linear accelerator radiosurgery (D-LINAC) has become an important treatment for trigeminal neuralgia (TN). Although the use of gamma knife continues to be established, few large series exist using D-LINAC. The authors describe their results, comparing the effects of varied target and dose regimens. METHODS AND MATERIALS: Between August 1995 and January 2008, 179 patients were treated with D-LINAC radiosurgery. Ten patients (5.58%) had no clinical follow-up. The median age was 74.0 years (range, 32-90 years). A total of 39 patients had secondary or atypical pain, and 130 had idiopathic TN. Initially, 28 patients received doses between 70 and 85 Gy, with the 30% isodose line (IDL) touching the brainstem. Then, using 90 Gy, 82 consecutive patients were treated with a 30% IDL and 59 patients with a 50% IDL tangential to the pons. RESULTS: Of 169 patients, 134 (79.3%) experienced significant relief at a mean of 28.8 months (range, 5-142 months). Average time to relief was 1.92 months (range, immediate to 6 months). A total of 31 patients (19.0%) had recurrent pain at 13.5 months. Of 87 patients with idiopathic TN without prior procedures, 79 (90.8%) had initial relief. Among 28 patients treated with 70 Gy and 30% IDL, 18 patients (64.3%) had significant relief, and 10 (35.7%) had numbness. Of the patients with 90 Gy and 30% IDL at the brainstem, 59 (79.0%) had significant relief and 48.9% had numbness. Among 59 consecutive patients with similar dose but the 50% isodoseline at the brainstem, 49 patients (88.0%) had excellent/good relief. Numbness, averaging 2.49 on a subjective scale of 1 to 5, was experienced by 49.7% of the patients, CONCLUSIONS: Increased radiation dose and volume of brainstem irradiation may improve clinical outcomes with the trade-off of trigeminal dysfunction. Further study of the implications of dose and target are needed to optimize outcomes and to minimize complications.

Monitoring of tumor growth and post-irradiation recurrence in a diffuse intrinsic pontine glioma mouse model.

Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy because of its diffuse infiltrative growth pattern. Translational research suffers from the lack of a representative DIPG animal model. Hence, human E98 glioma cells were stereotactically injected into the pons of nude mice. The E98 DIPG tumors presented a strikingly similar histhopathology to autopsy material of a DIPG patient, including diffuse and perivascular growth, brainstem- and supratentorial invasiveness and leptomeningeal growth. Magnetic resonance imaging (MRI) was effectively employed to image the E98 DIPG tumor. [(18) F] 3'-deoxy-3'-[(18) F]fluorothymidine (FLT) positron emission tomography (PET) imaging was applied to assess the subcutaneous (s.c.) E98 tumor proliferation status but no orthotopic DIPG activity could be visualized. Next, E98 cells were cultured in vitro and engineered to express firefly luciferase and mCherry (E98-Fluc-mCherry). These cultured E98-Fluc-mCherry cells developed focal pontine glioma when injected into the pons directly. However, the diffuse E98 DIPG infiltrative phenotype was restored when cells were injected into the pons immediately after an intermediate s.c. passage. The diffuse E98-Fluc-mCherry model was subsequently used to test escalating doses of irradiation, applying the bioluminescent Fluc signal to monitor tumor recurrence over time. Altogether, we here describe an accurate DIPG mouse model that can be of clinical relevance for testing experimental therapeutics in vivo.

Repeat gamma knife radiosurgery for trigeminal neuralgia.

PURPOSE: Repeat gamma knife stereotactic radiosurgery (GKRS) for recurrent or persistent trigeminal neuralgia induces an additional response but at the expense of an increased incidence of facial numbness. The present series summarized the results of a repeat treatment series at Wake Forest University Baptist Medical Center, including a multivariate analysis of the data to identify the prognostic factors for treatment success and toxicity. METHODS AND MATERIALS: Between January 1999 and December 2007, 37 patients underwent a second GKRS application because of treatment failure after a first GKRS treatment. The mean initial dose in the series was 87.3 Gy (range, 80-90). The mean retreatment dose was 84.4 Gy (range, 60-90). The dosimetric variables recorded included the dorsal root entry zone dose, pons surface dose, and dose to the distal nerve. RESULTS: Of the 37 patients, 81% achieved a >50% pain relief response to repeat GKRS, and 57% experienced some form of trigeminal dysfunction after repeat GKRS. Two patients (5%) experienced clinically significant toxicity: one with bothersome numbness and one with corneal dryness requiring tarsorraphy. A dorsal root entry zone dose at repeat treatment of >26.6 Gy predicted for treatment success (61% vs. 32%, p = .0716). A cumulative dorsal root entry zone dose of >84.3 Gy (72% vs. 44%, p = .091) and a cumulative pons surface dose of >108.5 Gy (78% vs. 44%, p = .018) predicted for post-GKRS numbness. The presence of any post-GKRS numbness predicted for a >50% decrease in pain intensity (100% vs. 60%, p = .0015). CONCLUSION: Repeat GKRS is a viable treatment option for recurrent trigeminal neuralgia, although the patient assumes a greater risk of nerve dysfunction to achieve maximal pain relief.

A prospective study of temozolomide plus thalidomide during and after radiation therapy for pediatric diffuse pontine gliomas: preliminary results of the Korean Society for Pediatric Neuro-Oncology study.

This prospective study was performed to determine the efficacy and safety of temozolomide (TMZ) plus thalidomide during and after radiation therapy (RT) in pediatric patients with newly diagnosed diffuse pontine glioma (DPG). Seventeen patients with pediatric DPG were enrolled between November 2004 and March 2008. The median age was eight years (range, 3-16 years); seven patients were male and ten were female. With the exception of one glioblastoma case, which was diagnosed via open biopsy, all diagnoses were established using neuroradiological studies. The authors used the Korean Society for Pediatric Neuro-Oncology (KSPNO)-A053 protocol. The mean follow-up period was 12 months (range, 8.5-25 months). Five patients were withdrawn from the study. The rates of response to treatment and survival were analyzed in 12 patients. Ten out of the 12 patients showed a partial response (PR), whereas one patient exhibited stable disease (SD) and another patient had progressive disease (PD). The tumor control rate was 92% (11/12) and the response rate was 83% (10/12). The median progression-free survival (PFS) of the 12 patients was 7.2 months (95% confidence interval (CI), 3.6-10.7). Six-month and twelve-month PFS were 58.3 and 16.7%, respectively. Overall survival (OS) was 12.7 months (95% CI, 10.4-15.1). One and two-year survival were 58.3 and 25%, respectively. The main adverse effect was hematological toxicity, with four patients exhibiting grade 3 or 4 toxicity. All patients tolerated the regimen well enough to continue the adjuvant chemotherapy. No Pneumocystis jiroveci pneumonia was noted. The TMZ plus thalidomide regimen was safe and tolerated well enough to be administered on an outpatient basis. Larger studies are required to demonstrate the efficacy of this regimen.

Concurrent radiotherapy with temozolomide followed by adjuvant temozolomide and cis-retinoic acid in children with diffuse intrinsic pontine glioma.

The prognosis of children with diffuse intrinsic pontine glioma (DIPG) is very poor. Radiotherapy remains the standard treatment for these patients, but the median survival time is only 9 months. Currently, the use of concurrent radiotherapy with temozolomide (TMZ) has become the standard care for adult patients with malignant gliomas. We therefore investigated this approach in 12 children diagnosed with DIPG. The treatment protocol consisted of concurrent radiotherapy at a dose of 55.8-59.4 Gy at the tumor site with TMZ (75 mg/m(2)/day) for 6 weeks followed by TMZ (200 mg/m(2)/day) for 5 days with cis-retinoic acid (100 mg/m(2)/day) for 21 days with a 28-day cycle after concurrent radiotherapy. Ten of the 12 patients had a clinical response after the completion of concurrent radiotherapy. Seven patients had a partial response, four had stable disease, and one had progressive disease. At the time of the report, 9 of the 12 patients had died of tumor progression, one patient was alive with tumor progression, and two patients were alive with continuous partial response and clinical improvement. The median time to progression was 10.2 +/- 3.0 months (95% confidence interval [CI], 4.2-16.1 months). One-year progression-free survival was 41.7% +/- 14.2%. The median survival time was 13.5 +/- 3.6 months (95% CI, 6.4-20.5 months). One-year overall survival was 58% +/- 14.2%. The patients who had a partial response after completion of concurrent radiotherapy had a longer survival time (p = 0.036) than did the other patients (those with stable or progressive disease). We conclude that the regimen of concurrent radiotherapy and TMZ should be considered for further investigation in a larger series of patients.

Dendritic Ca2+ responses in neonatal lateral superior olive neurons elicited by glycinergic/GABAergic synapses and action potentials.

During development, GABA/glycinergic connections from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) gradually change from being depolarizing to being hyperpolarizing. Previous studies have shown that depolarizing MNTB-LSO synapses can trigger action potentials and increase the concentration of intracellular calcium. In the present study we used confocal calcium imaging combined with whole-cell patch clamp recordings to investigate how depolarizing MNTB inputs in neonatal rats and mice increase the calcium concentration in the dendrites of LSO neurons. Our results show that subthreshold synaptic responses can elicit local dendritic calcium responses while suprathreshold responses reliably generate global calcium responses that are observed in all dendritic processes. The amplitude of global dendritic calcium responses increased with distance from the soma. Global calcium responses were blocked by tetrodotoxin and could not be recovered by somatic injection of action potential waveforms indicating that global calcium responses are generated by back-propagating sodium action potentials.

Synaptic depression and short-term habituation are located in the sensory part of the mammalian startle pathway.

BACKGROUND: Short-term habituation of the startle response represents an elementary form of learning in mammals. The underlying mechanism is located within the primary startle pathway, presumably at sensory synapses on giant neurons in the caudal pontine reticular nucleus (PnC). Short trains of action potentials in sensory afferent fibers induce depression of synaptic responses in PnC giant neurons, a phenomenon that has been proposed to be the cellular correlate for short-term habituation. We address here the question whether both this synaptic depression and the short-term habituation of the startle response are localized at the presynaptic terminals of sensory afferents. If this is confirmed, it would imply that these processes take place prior to multimodal signal integration, rather than occurring at postsynaptic sites on PnC giant neurons that directly drive motor neurons. RESULTS: Patch-clamp recordings in vitro were combined with behavioral experiments; synaptic depression was specific for the input pathway stimulated and did not affect signals elicited by other sensory afferents. Concordant with this, short-term habituation of the acoustic startle response in behavioral experiments did not influence tactile startle response amplitudes and vice versa. Further electrophysiological analysis showed that the passive properties of the postsynaptic neuron were unchanged but revealed some alterations in short-term plasticity during depression. Moreover, depression was induced only by trains of presynaptic action potentials and not by single pulses. There was no evidence for transmitter receptor desensitization. In summary, the data indicates that the synaptic depression mechanism is located presynaptically. CONCLUSION: Our electrophysiological and behavioral data strongly indicate that synaptic depression in the PnC as well as short-term habituation are located in the sensory part of the startle pathway, namely at the axon terminals of sensory afferents in the PnC. Our results further corroborate the link between synaptic depression and short-term habituation of the startle response.

Extraocular muscle activity, rapid eye movements and the development of active and quiet sleep.

Rapid eye movements (REMs), traditionally measured using the electrooculogram (EOG), help to characterize active sleep in adults. In early infancy, however, they are not clearly expressed. Here we measured extraocular muscle activity in infant rats at 3 days of age (P3), P8 and P14-15 in order to assess the ontogeny of REMs and their relationship with other forms of sleep-related phasic activity. We found that the causal relationship between extraocular muscle twitches and REMs strengthened during the first two postnatal weeks, reflecting increased control of the extraocular muscles over eye movements. As early as P3, however, phasic bursts of extraocular muscle twitching occurred in synchrony with twitching in other muscle groups, producing waves of phasic activity interspersed with brief periods of quiescence. Surprisingly, the tone of the extraocular muscles, invisible to standard EOG measures, fluctuated in synchrony with the tone of other muscle groups; focal electrical stimulation within the dorsolateral pontine tegmentum, an area that has been shown to contain wake-on neurons in P8 rats, resulted in the simultaneous activation of high tone in both nuchal and extraocular muscles. Finally, when state-dependent neocortical electroencephalographic activity was observed at P14, it had already integrated fully with sleep and wakefulness as defined using electromyographic criteria alone; this finding is not consistent with the notion that active sleep in infants at this age is 'half-activated.' All together, these results indicate exquisite temporal organization of sleep soon after birth and highlight the possible functional implications of homologous activational states in striated muscle and neocortex.

Micturition-related neuronal firing in the periaqueductal gray area in cats.

The midbrain periaqueductal gray (PAG) is the area promoting emotional motor responses, reproductive behaviors and analgesia. Recent studies suggest that neurons in the PAG may be crucial for regulating the micturition reflex in both experimental animals and humans. We examined single neuronal activities in the PAG and the adjacent area in response to isovolumetric spontaneous micturition reflexes in 20 supracollicular decerebrated cats. In total, 84 neurons were recorded in the PAG that were related to urinary storage/micturition cycles. Of the neurons recorded, the most common were tonic storage neurons (43%), followed by tonic micturition neurons (29%), phasic storage neurons (15%) and phasic micturition neurons (13%). In addition to the tonic/phasic as well as storage/micturition classification, the neurons showed diverse discharge patterns: augmenting, constant and decrementing, with the constant discharge pattern being most common. Of the 16 neurons located within the PAG that had similar discharge patterns to those just ventral to the PAG, the micturition neurons were distributed in a broader area, whereas the storage neurons seemed to be concentrated in the middle part of the PAG (P0-1, Horsley-Clarke coordinate). High-frequency stimulation (HFS; 0.2-ms duration, 100 Hz) applied in the PAG elicited inhibition of the micturition reflex. Effective amplitude of the electrical stimulation for evoking inhibitory responses was less than 50 microA. In conclusion, the results of the present study showed that HFS of the PAG inhibited the micturition reflex and there were micturition-related neuronal firings in the PAG in cats, suggesting that the PAG is involved in neural control of micturition.

Nausea as a complication of low-frequency repetitive transcranial magnetic stimulation of the posterior fossa.

BACKGROUND: Transcranial magnetic stimulation (TMS) can non-invasively investigate the function of human brain. However, it can induce a focal pain at the stimulated site on the scalp or seizures when applied with high frequency (>1 Hz). Here we report an induction of nausea as a complication of low-frequency repetitive TMS (rTMS) of the cerebellum. SUBJECTS AND METHODS: Eight right-handed normal volunteers underwent low-frequency (0.9 Hz) rTMS of the right cerebellum. The stimulus intensity was set at 90% of the resting motor threshold determined by TMS to motor cortex. RESULTS: Nausea lasted as long as 10 min after the end of rTMS without apparent neurological deficit in two subjects. This symptom was replicated when the same protocol was applied on a different day in the same subjects. CONCLUSIONS: Low-frequency rTMS of cerebellum is still a safe procedure, but the experimenters should keep in mind the possibility of inducing nausea.

Radiation-induced rhombencephalopathy.

We report the case of a patient who underwent radiotherapy of the neck because of an epidermoid carcinoma in Rosenmuller's fossa. Eleven months later, T1-weighted brain magnetic resonance imaging (MRI) revealed a bulbo-pontine lesion, and the clinical course and sequential MRI results led to a diagnosis of radionecrosis-induced rhombencephalopathy. At a distance of more than three years, the lesion is no longer visible on MRI images but the severe neurological deficits remain. The clinical picture has not been improved by treatment with prednisone, hyperbaric oxygen, symptomatic therapies or anticoagulants.