Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery.

The blood-brain barrier (BBB) is a major anatomical and physiological barrier limiting the passage of drugs into brain. Central nervous system tumors can impair the BBB by changing the tumor microenvironment leading to the formation of a leaky barrier, known as the blood-tumor barrier (BTB). Despite the change in integrity, the BTB remains effective in preventing delivery of chemotherapy into brain tumors. Focused ultrasound is a unique noninvasive technique that can transiently disrupt the BBB and increase accumulation of drugs within targeted areas of the brain. Herein, we summarize the current understanding of different types of targeted ultrasound mediated BBB/BTB disruption techniques. We also discuss influence of the tumor microenvironment on BBB opening, as well as the role of immunological response following disruption. Lastly, we highlight the gaps between evaluation of the parameters governing opening of the BBB/BTB. A deeper understanding of physical opening of the BBB/BTB and the biological effects following disruption can potentially enhance treatment strategies for patients with brain tumors.

Attenuation and amino acid changes in infectious bronchitis virus Iranian 793/B serotype during serial passaging in embryonated chicken eggs.

The use of live attenuated vaccine (LAV) is the main method for controlling infectious bronchitis (IB). It is advisable to develop a LAV using a dominant serotype in the region in the case of vaccine failure. Since 793/B serotype is one of the most predominant circulating IB viruses in Iran, attenuation of three Iranian 793/B isolates (IR/773/2001, IR/794/2002 and IR/520/2002) was done by serial passaging in specific pathogen free (SPF) embryonated chicken eggs up to 90 passages to assess the degree of their attenuation to achieve a native LAV in the future. Virulence and pathogenicity of passage levels 15 and 90 of isolates 773 and 794 were compared using histopathology, ciliostasis and potency tests. The results showed a decrease in the virulence and pathogenicity of the isolates at passage 90 compared to passage 15, although this decrease in pathogenicity was very mild and viruses after passage 90 were not adequately attenuated. Each isolate underwent some amino acid changes at passage 90. In case of isolate 773 it was 5 aa changes, while in isolate 794 it was 19 aa changes. Some amino acid changes resulted in change into amino acid with different hydrophobicity characteristics. No amino acid change was found at passage level 15 compared to wild type viruses. Interestingly, we did not find previously reported change in amino acid 95 in passage levels 15 and 90. Keywords: infectious bronchitis; live attenuated vaccine; 793/B serotype; pathogenicity; attenuation; nucleotide sequencing.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience.

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a 'learning curve' both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior-posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Behavioural improvements with thalamic stimulation after severe traumatic brain injury.

Widespread loss of cerebral connectivity is assumed to underlie the failure of brain mechanisms that support communication and goal-directed behaviour following severe traumatic brain injury. Disorders of consciousness that persist for longer than 12 months after severe traumatic brain injury are generally considered to be immutable; no treatment has been shown to accelerate recovery or improve functional outcome in such cases. Recent studies have shown unexpected preservation of large-scale cerebral networks in patients in the minimally conscious state (MCS), a condition that is characterized by intermittent evidence of awareness of self or the environment. These findings indicate that there might be residual functional capacity in some patients that could be supported by therapeutic interventions. We hypothesize that further recovery in some patients in the MCS is limited by chronic underactivation of potentially recruitable large-scale networks. Here, in a 6-month double-blind alternating crossover study, we show that bilateral deep brain electrical stimulation (DBS) of the central thalamus modulates behavioural responsiveness in a patient who remained in MCS for 6 yr following traumatic brain injury before the intervention. The frequency of specific cognitively mediated behaviours (primary outcome measures) and functional limb control and oral feeding (secondary outcome measures) increased during periods in which DBS was on as compared with periods in which it was off. Logistic regression modelling shows a statistical linkage between the observed functional improvements and recent stimulation history. We interpret the DBS effects as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain. These findings provide evidence that DBS can promote significant late functional recovery from severe traumatic brain injury. Our observations, years after the injury occurred, challenge the existing practice of early treatment discontinuation for patients with only inconsistent interactive behaviours and motivate further research to develop therapeutic interventions.

Neuropsychological functioning following bilateral subthalamic nucleus stimulation in Parkinson's disease.

The cognitive effects of subthalamic nucleus (STN) stimulation in Parkinson's disease (PD) have been examined. However, there are no reported studies that evaluate, by incorporating a disease control group, whether neuropsychological performance in surgical patients changes beyond the variability of the assessment measures. To examine this issue, 17 PD patients were tested before and after bilateral STN stimulator implantation, both on and off stimulation. Eleven matched PD controls were administered the same repeatable neuropsychological test battery twice. Relative to changes seen in the controls, the surgery for electrode placement mildly adversely affected attention and language functions. STN stimulation, per se, had little effect on cognition. The STN DBS procedure as a whole resulted in a mild decline in delayed verbal recall and language functions. There were no surgery, stimulation, or procedure effects on depression scale scores. In contrast to these group findings, one DBS patient demonstrated significant cognitive decline following surgery.

Brain stimulation: history, current clinical application, and future prospects.

The dramatic effects of chronic brain stimulation in the treatment of movement disorders have spurred a renewed interest in this technique for treating a variety of other conditions. This technique has only recently begun to reach its vast clinical potential, due to a number of significant advances in basic and clinical neurosciences. Current image-guided navigation systems and intraoperative physiological mapping techniques offer more efficient, consistent, and precise targeting. Advances in neurophysiology have helped elucidate the pathophysiology of a number of disease states and thus provided for rational target selection for therapy. The latest generation of stimulation equipment allows for precise tailoring of stimulation parameters to maximize clinical benefit. These techniques are now being applied to a variety of other conditions including chronic pain, epilepsy, and psychiatric disorders.

MR safety in patients with implanted deep brain stimulation systems (DBS).

INTRODUCTION: While it is desirable to perform MRI examinations in patients with deep brain stimulators (DBS), a major safety concern exists regarding the potential for excessive heating secondary to magnetically induced electrical currents. This study was designed to determine the safety of MRI and DBS. METHODS: Standard configurations of DBS systems were tested. In vitro testing was performed using a 1.5-Tesla MR system, a gel-filled phantom, and the body and head RF coils with varying levels of RF energy (SAR). A fluoroptic thermometry system was used to record temperatures. RESULTS: Using the 1.5-T MRI and body RF transmit coil, the temperature changes ranged from 2.5 to 25.3 degrees C. Using the 1.5-T MRI and head RF transmit coil, the temperature changes ranged from 2.3 to 7.1 degrees C. CONCLUSIONS: Excessive heating does occur with certain MR imaging conditions. Under certain conditions determined in this study, patients with DBS may safely undergo anatomical MR imaging. In the future, standardized testing and more comprehensive studies will be needed to ensure the MR safety of neurostimulation systems.

Neurophysiological modulation of the subthalamic nucleus by pallidal stimulation in Parkinson's disease.

OBJECTIVES: Current models of basal ganglia dysfunction in Parkinson's disease suggest a pivotal role of subthalamic nucleus (STN) hyperactivity. There is a direct excitatory output to the globus pallidus internus (GPi), which in turn hyperinhibits the motor thalamus and leads to a lack of cortical facilitation. The model, however, does not address the reciprocal influence of GPi on STN activity. METHODS: Measurement of immediate changes in STN single cell activity after GPi deep brain stimulation (DBS). RESULTS: An opposite effect of GPi DBS in the dorsal versus ventral STN was found. There was an almost exclusive reduction of firing rate in the dorsal region of the STN, whereas the cells in the ventral region exhibited facilitation similar to the recordings from the substantia nigra pars reticulata. CONCLUSION: Although these findings require confirmation, they suggest that the current theories of GPi DBS action, which do not include a GPi-STN modulation, are most likely incomplete.

Epidural motor cortex stimulation with functional imaging guidance.

Chronic epidural motor cortex stimulation (MCS) has been shown to have promise in the treatment of patients with refractory deafferentation pain. Precise placement of the electrode over the motor cortex region corresponding to the area of pain is essential for the success of this procedure. Whereas standard anatomical landmarks have been used in the past in conjunction with image guidance, the use of functional brain imaging can be beneficial in the precise surgical planning. The authors report the use of functional imaging-guided frameless stereotactic surgery for epidural MCS. Five patients underwent MCS in which functional imaging guidance was used. Prior to surgery, patients underwent magnetic resonance (MR) imaging with skin fiducial markers placed on standard anatomical reference prints, followed by magnetoencephalography (MEG) mapping of the sensory and motor cortices. In two patients, functional MR imaging was also performed using a motor task paradigm. The functional imaging data were integrated into a frameless stereotactic database by using a three-dimensional coregistration algorithm. Subsequently, a frameless stereotactic craniotomy was performed using the integrated anatomical and functional imaging data for surgical planning. Intraoperative somatosensory evoked potentials (SSEPs) and direct stimulation were used to confirm the target and final placement of the electrode. Direct stimulation and SSEPs performed intraoperatively confirmed the accuracy of the functional imaging data. Trial periods of stimulation successfully reduced pain in three of the five patients who then underwent permanent internal placement of the system. At a mean 6-month follow up, these patients reported an average reduction in pain of 55% on a visual analog scale. The integration of functional and anatomical imaging data allows for precise and efficient surgical planning and may reduce the time necessary for intraoperative physiological verification.

Complications of deep brain stimulation surgery.

Although technological advances have reduced device-related complications, DBS surgery still carries a significant risk of transient and permanent complications. We report our experience in 86 patients and 149 DBS implants. Patients with Parkinson's disease, essential tremor and dystonia were treated. There were 8 perioperative, 8 postoperative, 9 hardware-related complications and 4 stimulation-induced side effects. Only 5 patients (6%) sustained some persistent neurological sequelae, however, 26 of the 86 patients undergoing 149 DBS implants in this series experienced some untoward event with the procedure. Although there were no fatalities or permanent severe disabilities encountered, it is important to extend the informed consent to include all potential complications.

Deep brain stimulation in epilepsy.

Since the pioneering studies of Cooper et al. to influence epilepsy by cerebellar stimulation, numerous attempts have been made to reduce seizure frequency by stimulation of deep brain structures. Evidence from experimental animal studies suggests the existence of a nigral control of the epilepsy system. It is hypothesized that the dorsal midbrain anticonvulsant zone in the superior colliculi is under inhibitory control of efferents from the substantia nigra pars reticulata. Inhibition of the subthalamic nucleus (STN) could release the inhibitory effect of the substantia nigra pars reticulata on the dorsal midbrain anticonvulsant zone and thus activate the latter, raising the seizure threshold. Modulation of the seizure threshold by stimulation of deep brain structures-in particular, of the STN-is a promising future treatment option for patients with pharmacologically intractable epilepsy. Experimental studies supporting the existence of the nigral control of epilepsy system and preliminary results of STN stimulation in animals and humans are reviewed, and alternative mechanisms of seizure suppression by STN stimulation are discussed.

Woven vascular microsurgical prostheses in our experimental practice.

The authors have been concerned for six years with the development of woven microsurgical prostheses in experiments on laboratory rats, beagle dogs and domestic white pigs. In rats, in 224 experiments employing 38 types of prostheses with an inner diameter of 2 mm, a reliable prosthesis was selected, described as No. 36, with a 100% patency after insertion of a 1 cm long portion into a defect in the abdominal aorta in 40 experiments. The follow-up of this type of prosthesis lasted 12 months. In large animals this type of prosthesis was implanted into a defect of the radial artery and cephalic vein in dogs and into the femoral artery and the artery of a vascular pedicle of groin and lateral thigh flap. These experiments on large animals are not yet complete and will be the subject of a separate paper.

Comparison of anatomic and neurophysiological methods for subthalamic nucleus targeting.

OBJECTIVE: The subthalamic nucleus (STN) has recently become the surgical target of choice for the treatment of medically refractory idiopathic Parkinson's disease. A number of anatomic and physiological targeting methods have been used to localize the STN. We retrospectively reviewed the various anatomic targeting methods and compared them with the final physiological target in 15 patients who underwent simultaneous bilateral STN implantation of deep brain stimulators. METHODS: The x, y, and z coordinates of our localizing techniques were analyzed for 30 STN targets. Our final targets, as determined by single-cell microelectrode recording, were compared with the following: 1) targets selected on coronal magnetic resonance inversion recovery and T2-weighted imaging sequences, 2) the center of the STN on a digitized scaled Schaltenbrand-Wahren stereotactic atlas, 3) targeting based on a point 13 mm lateral, 4 mm posterior, and 5 mm inferior to the midcommissural point, and 4) a composite target based on the above methods. RESULTS: All anatomic methods yielded targets that were statistically significantly different (P < 0.001) from the final physiological targets. The average distance error between the final physiological targets and the magnetic resonance imaging-derived targets was 2.6 +/- 1.3 mm (mean +/- standard deviation), 1.7 +/- 1.1 mm for the atlas-based method, 1.5 +/- 0.8 mm for the indirect midcommissural method, and 1.3 +/- 1.1 mm for the composite method. Once the final microelectrode-refined target was determined on the first side, the final target for the contralateral side was 1.3 +/- 1.2 mm away from its mirror image. CONCLUSION: Although all anatomic targeting methods provide accurate STN localization, a combination of the three methods offers the best correlation with the final physiological target. In our experience, direct magnetic resonance targeting was the least accurate method.

A neuromodulation strategy for rational therapy of complex brain injury states.

We review initial efforts at neuromodulation in the vegetative state and organize several aspects of recent studies of the underlying neurobiology of catastrophic brain injuries. An innovative strategy for patient and target selection for neuromodulation of impaired cognitive function is outlined. Scientific and ethical issues that will attend future efforts to appropriately risk-stratify patients and initiate interventions with therapeutic intent are considered.

Neurostimulation and functional brain imaging.

Recent advancements in functional neuroimaging have furthered our understanding of the normal and pathological brain. These non-invasive imaging modalities have allowed us to study the human brain in vivo. Concurrently, the revival of neurostimulation in the treatment of pain, movement disorders, and epilepsy has allowed the synergistic combination of these two technologies. Several studies focusing on the use of functional imaging in patients with implanted neurostimulation devices are reviewed. The anticipated roles of these two disciplines are discussed.

Tremor arrest with thalamic microinjections of muscimol in patients with essential tremor.

Six patients undergoing stereotactic procedures for essential tremor received microinjections of muscimol (a gamma-aminobutyric acid-A [GABA(A)] agonist) into the ventralis intermedius thalamus in areas where tremor-synchronous cells were identified electrophysiologically with microelectrode recordings and where tremor reduction occurred with electrical microstimulation. Injections of muscimol but not saline consistently reduced tremor in each patient. The effect had a mean latency of 7 minutes and lasted an average of 9 minutes. We propose that GABA-mediated thalamic neuronal inhibition may represent a mechanism underlying the effectiveness of surgery for tremor and that GABA analogues could potentially be used therapeutically.