Enlarging Perivascular Spaces Following Radiation Therapy in the Brain: A Report of 2 Cases and Literature Review.

BACKGROUND: Virchow-Robin or enlarged perivascular spaces (PVS) are benign pial-lined spaces that surround penetrating arteries and arterioles through the brain parenchyma. We present 2 cases of enlarging PVS in adults following whole-brain radiation therapy. CASE DESCRIPTION: Two patients underwent whole-brain radiation therapy for adult-onset medulloblastoma. Neither patient had enlarged PVS at the time of radiation treatment. The patients presented with PVS in the basal ganglia 6 and 8 years following the completion of radiation, respectively. One patient subsequently showed a decrease in size of PVS over time. Neither patient experienced symptoms, required surgical intervention, or had signs of tumor recurrence. CONCLUSIONS: Enlarging PVS can occur years after radiation therapy to the brain parenchyma. Recognition of these benign PVS is important so as not to mistake the changes for more sinister pathology that could lead to unnecessary intervention. Moreover, focal cystic changes more frequently seen surrounding areas of focal brain radiation therapy might represent enlarged PVS.

Focused ultrasound enhanced intranasal delivery of brain derived neurotrophic factor produces neurorestorative effects in a Parkinson's disease mouse model.

Focused ultrasound-enhanced intranasal (IN + FUS) delivery is a noninvasive approach that utilizes the olfactory pathway to administer pharmacological agents directly to the brain, allowing for a more homogenous distribution in targeted locations compared to IN delivery alone. However, whether such a strategy has therapeutic values, especially in neurodegenerative disorders such as Parkinson's disease (PD), remains to be established. Herein, we evaluated whether the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine catalysis, could be enhanced by IN + FUS delivery of brain-derived neurotrophic factor (BDNF) in a toxin-based PD mouse model. Mice were put on the subacute dosing regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), producing bilateral degeneration of the nigrostriatal pathway consistent with early-stage PD. MPTP mice then received BDNF intranasally followed by multiple unilateral FUS-induced blood-brain barrier (BBB) openings in the left basal ganglia for three consecutive weeks. Subsequently, mice were survived for two months and were evaluated morphologically and behaviorally to determine the integrity of their nigrostriatal dopaminergic pathways. Mice receiving IN + FUS had significantly increased TH immunoreactivity in the treated hemisphere compared to the untreated hemisphere while mice receiving only FUS-induced BBB opening or no treatment at all did not show any differences. Additionally, behavioral changes were only observed in the IN + FUS treated mice, indicating improved motor control function in the treated hemisphere. These findings demonstrate the robustness of the method and potential of IN + FUS for the delivery of bioactive factors for treatment of neurodegenerative disorder.

Inhibition of cytoplasmic p53 differentially modulates Ca(2+) signaling and cellular viability in young and aged striata.

The p53 protein, a transcription factor with many gene targets, can also trigger apoptosis in the cytoplasm. The disruption of cell homeostasis, such as Ca(2+) signaling and mitochondrial respiration, contributes to the loss of viability and ultimately leads to cell death. However, the link between Ca(2+) signaling and p53 signaling remains unclear. During aging, there are alterations in cell physiology that are commonly associated with a reduced adaptive stress response, thus increasing cell vulnerability. In this work, we examined the effects of a cytoplasmic p53 inhibitor (pifithrin µ) in the striatum of young and aged rats by evaluating Ca(2+) signaling, mitochondrial respiration, apoptotic protein expression, and tissue viability. Our results showed that pifithrin µ differentially modulated cytoplasmic and mitochondrial Ca(2+) in young and aged rats. Cytoplasmic p53 inhibition appeared to reduce the mitochondrial respiration rate in both groups. In addition, p53 phosphorylation and Bax protein levels were elevated upon cytoplasmic p53 inhibition and could contribute to the reduction of tissue viability. Following glutamate challenge, pifithrin µ improved cell viability in aged tissue, reduced reactive oxygen species (ROS) generation, and reduced mitochondrial membrane potential (ΔΨm). Taken together, these results indicate that cytoplasmic p53 may have a special role in cell viability by influencing cellular Ca(2+) homeostasis and respiration and may produce differential effects in the striatum of young and aged rats.

Oscilaciones cerebrales: papel fisiopatológico y terapéutico en algunas enfermedades neurológicas y psiquiátricas / Brain oscillations: pathophysiological and therapeutic role in some neurological and psychiatric diseases

Se usa el término «oscilación o actividad oscilatoria» para referirse a las fluctuaciones rítmicas de los potenciales postsinápticos de un grupo neuronal (potenciales de campo local) o de una región cortical (EEG, electrocorticografía) y también al patrón de descarga rítmico de los potenciales de acción de una neurona o un grupo neuronal. La actividad oscilatoria posibilita la sincronización entre grupos neuronales de la misma área cortical o de áreas distantes entre sí que intervienen en una acción motora, tarea cognitiva o perceptiva. Con frecuencia es motivo de confusión asociar la presencia de actividad oscilatoria con fenómenos de sincronización, ya que ambos fenómenos aunque relacionados no son equivalentes. En patologías neurológicas o psiquiátricas tan distintas como la enfermedad de Parkinson u otros movimientos anormales, la epilepsia o la esquizofrenia se han descrito anomalías de la actividad oscilatoria de distintas estructuras cerebrales o de su sincronización que podrían jugar un papel relevante en su fisiopatología. En esta revisión se discuten estos aspectos haciendo hincapié en su importancia por ser un mecanismo básico del funcionamiento cerebral y un nuevo mecanismo fisiopatólogico de la sintomatología de algunas enfermedades cerebrales (AU)

The terms «oscillations» or «oscillatory activity» are frequently used not only to define the rhythmic fluctuations of the postsynaptic potentials of a neuronal group (local field potentials) or a cortical region (EEG, MEG), but also to indicate the rhythmic discharge pattern of action potentials from a neuron or a small group of neurons. Oscillatory activity makes possible the synchronization of different neuronal groups from nearby or distant cortical regions that participate in the same motor, sensory or cognitive task. The presence of oscillatory activity is usually associated to the existence of synchronization, but both phenomena are not necessarily always equivalent. Abnormalities of oscillatory activities or synchronization within or between different brain structures have been described in several neurological and psychiatric diseases; these abnormalities might play a relevant pathophysiological role in Parkinson´s disease (and other movement disorders), schizophrenia or epilepsy. This review discusses all these aspects, with emphasis on their potential role both as a basic mechanism in brain function and as a pathophysiological substrate for some of the symptoms and signs observed in several diseases (AU)

Computational models simulating electrophysiological activity in the basal ganglia.

Modeling of the basal ganglia has played a substantial role in gaining insight into the mechanisms involved in the computational processes performed by this elusive group of nuclei. Models of the basal ganglia have undergone revolutionary changes over the last twenty years due to the rapid accumulation of neuroscientific data. In this chapter, we present distinct modeling approaches that can be used to enhance our understanding of the functional dynamics of information processing within the basal ganglia, and their interactions with the rest of the brain. Specific examples of recently developed models dealing with the analysis of computational processing issues at different structural levels of the basal ganglia are discussed.

Lacunar stroke attributable to radiation-induced intracranial arteriopathy.

We report the rare presentation of lacunar stroke syndrome secondary to single perforator mouth occlusion from radiation-induced middle cerebral artery (MCA) stem arteriopathy. A 30-year-old female had acute-onset right-sided ataxic hemiparesis and dysarthria. As a child, she had a medulloblastoma of the posterior fossa and had surgery followed by cranial radiotherapy. She had no significant vascular risk factors. Acute CT showed extensive bilateral basal ganglia and left thalamic calcification; DWI showed a left internal capsule lacunar infarct; and MRA and CTA showed a 50% stenosis of the proximal left MCA.

Gamma knife radiosurgery targeting protocols for the experiments with small animals.

BACKGROUND/AIMS: Manipulation of brain functions via Gamma Knife (GK) irradiation would have numerous applications in clinical and experimental neurology. METHODS: Alteration of brain functions in the unilaterally irradiated striatum was indexed through monitoring freely moving rat behaviors. Spontaneous activity and rotations on the apomorphine test, which can detect dopaminergic function imbalance, were indexed employing our behavior tracking system. The spatial distribution of necrotic lesions was explored using serial sections, and was assumed to represent the real foci of the GK target. RESULTS: Distinct behavioral alterations corresponded to the precise locations of the lesions in various areas of the basal ganglia. Displacement of the irradiation sites in the anteromedial direction increased spontaneous activity, and posterolateral shift provoked circling behavior on the apomorphine test. CONCLUSION: Accurate positioning of the target is crucial for experimental GK irradiation locally focused on domains of a small brain such as that of the rat. Here, we propose a protocol for converting the 'intended' focus, based on brain map coordinates, to a 'planned' focus on the MR imaging coordinate system with the Régis-Valliccioni stereotactic frame.

Improved naming after TMS treatments in a chronic, global aphasia patient--case report.

We report improved ability to name pictures at 2 and 8 months after repetitive transcranial magnetic stimulation (rTMS) treatments to the pars triangularis portion of right Broca's homologue in a 57 year-old woman with severe nonfluent/global aphasia (6.5 years post left basal ganglia bleed, subcortical lesion). TMS was applied at 1 Hz, 20 minutes a day, 10 days, over a two-week period. She received no speech therapy during the study. One year after her TMS treatments, she entered speech therapy with continued improvement. TMS may have modulated activity in the remaining left and right hemisphere neural network for naming.

High-frequency stimulation in Parkinson's disease: more or less?

Deep-brain stimulation at high frequency is now considered the most effective neurosurgical therapy for movement disorders. An electrode is chronically implanted in a particular area of the brain and, when continuously stimulated, it significantly alleviates motor symptoms. In Parkinson's disease, common target nuclei of high-frequency stimulation (HFS) are ventral thalamic nuclei and basal ganglia nuclei, such as the internal segment of the pallidum and the subthalamic nucleus (STN), with a preference for the STN in recent years. Two fundamental mechanisms have been proposed to underlie the beneficial effects of HFS: silencing or excitation of STN neurons. Relying on recent experimental data, we suggest that both are instrumental: HFS switches off a pathological disrupted activity in the STN (a 'less' mechanism) and imposes a new type of discharge in the upper gamma-band frequency that is endowed with beneficial effects (a 'more' mechanism). The intrinsic capacity of basal ganglia and particular STN neurons to generate oscillations and shift rapidly from a physiological to a pathogenic pattern is pivotal in the operation of these circuits in health and disease.

Measurement of radiation dose in cerebral CT perfusion study.

PURPOSE: To evaluate radiation dose in cerebral perfusion studies with a multi-detector row CT (MDCT) scanner on various voltage and current settings by using a human head phantom. MATERIALS AND METHODS: Following the CT perfusion study protocol, continuous cine scans (1 sec/rotation x60 sec) consisting of four 5-mm-thick contiguous slices were performed three times at variable tube voltages of 80 kV, 100 kV, 120 kV, and 140 kV with the same tube current setting of 200 mA and on variable current settings of 50 mA, 100 mA, 150 mA, and 200 mA with the same tube voltage of 80 kV. Radiation doses were measured using a total of 41 theroluminescent dosimeters (TLDs) placed in the human head phantom. Thirty-six TLDs were inside and three were on the surface of the slice of the X-ray beam center, and two were placed on the surface 3 cm caudal assuming the lens position. RESULTS: Average radiation doses of surface, inside, and lens increased in proportion to the increases of tube voltage and tube current. The lowest inside dose was 87.6+/-15.3 mGy, and the lowest surface dose was 162.5+/-6.7 mGy at settings of 80 kV and 50 mA. The highest inside dose was 1,591.5+/-179.7 mGy, and the highest surface dose was 2,264.6+/-123.7 mGy at 140 kV-200 mA. At 80 kV-50 mA, the average radiation dose of lens was the lowest at 5.5+/-0.0 mGy. At 140 kV-200 mA the radiation dose of lens was the highest at 127.2+/-0.6 mGy. CONCLUSION: In cerebral CT perfusion study, radiation dose can vary considerably. Awareness of the patient's radiation dose is recommended.

Sensory stimulation accelerates dopamine release in the basal ganglia.

We report herein the modulation of dopamine release in the basal ganglia during peripheral electrical stimulation in animals. The endogenous dopamine release during electrical stimulation was measured in anesthetized cats by positron emission tomography (PET) using the D2 receptor agonist [11C]-raclopride. Binding potential (BP) parametric maps were calculated using a simplified reference region model. The regional dopamine release evoked by electrical stimulation was estimated both by region of interest (ROI) analysis and statistical parametric mapping (SPM 99). Both ROI analysis and statistical parametric mapping showed significant release of endogenous dopamine in the nucleus accumbens and the striatum contralateral to the stimulated side as compared to the resting condition as well as the ipsilateral side. Accordingly, we suggest that the activity of the dopaminergic neurons in the midbrain projecting to the nucleus accumbens and the striatum is modulated by the input from the afferent nerves. This provides an in vivo evidence for the importance of the basal ganglia in the processing of peripheral information required for normal movement. This may also explain the clinically observed sensory system abnormalities in patients with movement disorders.

High frequency stimulation of the subthalamic nucleus eliminates pathological thalamic rhythmicity in a computational model.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) has recently been recognized as an important form of intervention for alleviating motor symptoms associated with Parkinson's disease, but the mechanism underlying its effectiveness remains unknown. Using a computational model, this paper considers the hypothesis that DBS works by replacing pathologically rhythmic basal ganglia output with tonic, high frequency firing. In our simulations of parkinsonian conditions, rhythmic inhibition from GPi to the thalamus compromises the ability of thalamocortical relay (TC) cells to respond to depolarizing inputs, such as sensorimotor signals. High frequency stimulation of STN regularizes GPi firing, and this restores TC responsiveness, despite the increased frequency and amplitude of GPi inhibition to thalamus that result. We provide a mathematical phase plane analysis of the mechanisms that determine TC relay capabilities in normal, parkinsonian, and DBS states in a reduced model. This analysis highlights the differences in deinactivation of the low-threshold calcium T -current that we observe in TC cells in these different conditions. Alternative scenarios involving convergence of thalamic signals in the cortex are also discussed, and predictions associated with these results, including the occurrence of rhythmic rebound bursts in certain TC cells in parkinsonian states and their drastic reduction by DBS, are stated. These results demonstrate how DBS could work by increasing firing rates of target cells, rather than shutting them down.

Melatonin receptor density in Area X of European starlings is correlated with reproductive state and is unaffected by plasma melatonin concentration.

Several of the song control nuclei of songbirds, including HVc (higher vocal center) and Area X, contain melatonin receptor (MelR). In laboratory-housed male starlings, the densities of MelR in Area X change markedly according to reproductive state. MelR are down-regulated when starlings are photostimulated (in full breeding condition) and are subsequently up-regulated when starlings become photorefractory (reproductively quiescent). However, seasonal regulation of MelR densities in Area X has only been investigated during the light phase of the light:dark cycle. Variation in MelR densities are physiologically relevant only if they also occur during the dark phase, when melatonin is present in the circulation. Brains from male starlings that were in different reproductive states but exposed to the same 18L:6D photoperiod were collected during either the mid-point of the light phase or the dark phase. Melatonin receptor distribution was assessed in vitro by 125Iodomelatonin (IMEL) receptor autoradiography. All photostimulated birds exhibited down-regulation of MelR in Area X, and all photorefractory birds exhibited high MelR density in Area X, regardless of time of sampling or plasma melatonin concentration. Thus, within each reproductive state, MelR density in Area X did not differ over the course of a circadian cycle. The functional significance of seasonal regulation of MelR in this song control nucleus remains unclear, but it is likely to involve a release of cellular inhibition by melatonin during photostimulation, with possible consequences for song learning, memory consolidation or regulation of the context of song production.

Biodistribution and radiation dosimetry of the dopamine transporter ligand.

UNLABELLED: 18F-labeled 2 beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(-2-fluoroethyl)nortropane ([18F]FECNT) is a recently developed dopamine transporter ligand with potential applications in patients with Parkinson's disease and cocaine addiction. METHODS: Estimates of the effective dose equivalent and doses for specific organs were made using biodistribution data from 16 Sprague-Dawley rats and nine rhesus monkeys. PET images from two rhesus monkeys were used to calculate the residence time for the basal ganglia. The computer program MIRDOSE3 was used to calculate the dosimetry according to the methodology recommended by MIRD. RESULTS: The basal ganglia were the targeted tissues receiving the highest dose, 0.11 mGy/MBq (0.39 rad/mCi). The effective dose equivalent was 0.018 mSv/MBq (0.065 rem/mCi), and the effective dose was 0.016 mSv/MBq (0.058 rem/mCi). CONCLUSION: Our data show that a 185-MBq (5-mCi) injection of [18F]FECNT leads to an estimated effective dose of 3 mSv (0.3 rem) and an estimated dose to the target organ or tissue of 19.4 mGy (1.93 rad).

A patient with improvement in short-term memory disturbance brought about by radiation therapy for germinoma involving Papez circuit.

A 27-year-old male presented with memory loss. With magnetic resonance imaging (MRI), enhanced masses on the right side of hypothalamus, right side of anterior basal ganglia, and left side of hypothalamus were found. Histological analysis of the tumor by stereotactic biopsy proved it to be a germinoma. When related to the map of the thalamic nuclei, the tumor involved anterior column of the fornix and anterior nuclei of the thalamus. Neuropsychological tests prior to radiation therapy disclosed only short-term memory disturbance. The patient received radiation therapy to a total dose of 55 Gy to the primary lesion. After the completion of radiation therapy, the enhanced effect disappeared on gadolinium enhanced T1-weighted MRI. Single photon emission computed tomography indicated improvement in blood flow in the anterior portion of the bilateral thalami. Neuropsychological tests after radiation therapy showed improvement in short-term memory compared with baseline. Test results have remained stable for two and half years. This case indicates the possibility of improvement in memory function by treatment for tumor when it involves part of Papez circuit. Nevertheless, a decrease in intellectual ability by irradiation remains the major problem. Better approaches not only for cure but also to reduce the late effects should be undertaken when radiation therapy is the treatment of choice.

Cosmic ray hit frequencies in critical sites in the central nervous system.

One outstanding question to be addressed in assessing the risk of exposure to space travelers from galactic cosmic rays (GCR) outside the geomagnetosphere is to ascertain the effects of single heavy-ion hits on cells in critical regions of the central nervous system (CNS). As a first step toward this end, it is important to determine how many "hits" might be received by a neural cell in several critical CNS areas during an extended mission outside the confines of the earth's magnetic field. Critical sites in the CNS: the macula, and an interior brain point (typical of the genu, thalamus, hippocampus and nucleus basalis of Meynert) were chosen for the calculation of hit frequencies from galactic cosmic rays for a mission to Mars during solar minimum (i.e., at maximum cosmic-ray intensity). The shielding at a given position inside the body was obtained using the Computerized Anatomical Man (CAM) model, and a radiation transport code which includes nuclear fragmentation was used to calculate yearly fluences at the point of interest. Since the final Mars spacecraft shielding configuration has not yet been determined, we considered the minimum amount of aluminum required for pressure vessel-wall requirements in the living quarters of a spacecraft, and a typical duty area as a pressure vessel plus necessary equipment. The conclusions are: (1) variation of the position of the "target site" within the head plays only a small role in varying hit frequencies; (2) the average number of hits depends linearly on the cross section of the critical portion of the cell assumed in the calculation; (3) for a three-year mission to Mars at solar minimum (i.e., assuming the 1977 spectrum of galactic cosmic rays), 2% or 13% of the "critical sites" of cells in the CNS would be directly hit at least once by iron ions, depending on whether 60 micrometers2 or 471 micrometers2 is assumed as the critical cross sectional area; and (4) roughly 6 million out of some 43 million hippocampal cells and 55 thousand out of 1.8 million thalamus cell nuclei would be directly hit by iron ions at least once on such a mission for space travelers inside a simple pressure vessel. Also, roughly 20 million out of 43 million hippocampal cells and 230 thousand out of 1.8 million thalamus cell nuclei would be directly hit by one or more particles with z > or = 15 on such a mission.

Cerebral radiation necrosis complicating stereotactic radiosurgery for arteriovenous malformation.

A patient presented with symptoms and signs of raised intracranial pressure and increasing focal deficit 13 months after stereotactic radiosurgical treatment of an arteriovenous malformation (AVM). Computed Tomography (CT) showed a mass lesion at the site of the previous abnormality typical of radiation necrosis, but with features identical to those of a malignant neoplasm. Biopsy confirmed cerebral radiation necrosis. The radiation dose was 25 Gray to the periphery of two overlapping 14 mm collimator fields, delivered in a single dose. Treatment with steroids led to improvement in the symptoms and signs of raised intracranial pressure, but not the focal deficit. Radiation necrosis is a consequence of the large doses required to obliterate AVMs and is a limiting factor in their treatment. It is important for clinicians referring patients for stereotactic radiosurgery to be aware of this complication, and to be able to recognise and treat it.

[Trigeminal neuralgia. Classical clinical and therapeutic aspects. Advantages of a modern method: controlled differential heat coagulation]. / Nevralgia del trigemino. Aspetti clinici ed aspetti terapeutici classici. Vantaggi di un moderno metodo: la termocoagulazione controllata differenziale.

The main clinical aspects of essential trigeminal neuralgia are reported and traditional medical and surgical therapy reviewed. Results obtained in 114 patients treated with a modern method, controlled differential thermocoagulation, are then analysed. This consists of percutaneous infiltration of Gasser's ganglion and/or retrogasserian roots and in causing thermolesions by means of radiofrequency, i.e. using constantly controlled and steadily increasing temperatures which selectively damage the finer painful facial fibres without affecting the more resistant tactile fibres. While the principal advantage of this method lies in the elimination of pain with partial saving of facial tactile sensitivity, other practical advantages are of no less importance: these include the fact that the method is so harmless that all patients, even those of advanced age, could leave hospital at the latest one day after treatment.