Lead cap localization using ultrasound in deep brain stimulation surgery: technical note.

In deep brain stimulation (DBS) surgery, after intracranial lead implantation, lead caps are tunneled into the subgaleal space for later connection to internal pulse generator (IPG) extension wires. In the subsequent IPG implantation procedure, the lead cap must be localized by palpation in order to plan an incision in the scalp to complete this connection. However, if the IPG implantation is done the same day as the intracranial lead implantation, palpation of the lead cap may be challenging in a thick or postoperatively edematous scalp. Manufacturers suggest using fluoroscopy in these instances, but fluoroscopy provides poor soft tissue visualization, requires further unnecessary radiation exposure to both the patient and the surgical team, and can be cumbersome. Portable ultrasound (US) machines are readily available in many operating rooms, and can be used to easily and accurately localize the lead cap prior to IPG implantation.

Tinnitus modulation by deep brain stimulation in locus of caudate neurons (area LC).

Tinnitus is an auditory disorder characterized by perception of internally generated phantom auditory sensations without corresponding mechanical stimuli arising from the body or external environment. Current auditory based treatment approaches, sometimes in conjunction with nonauditory based strategies, such as Tinnitus Retraining Therapy and Cognitive Behavioral Therapy, have been helpful in mitigating symptoms for the majority of patients. Yet there are over 1 million tinnitus sufferers who still endure troublesome chronic, continuous head noises that are debilitating and interfere with activities of daily living. Here we show that application of deep brain stimulation (DBS) therapy to a locus of caudate neurons (area LC) in the body of the nucleus, a subsite of the striatum that is not part of the classical auditory pathway, can decrease or increase tinnitus loudness perception. The DBS lead traversed through or was adjacent to area LC in six Parkinson's disease and essential tremor subjects with concomitant tinnitus who underwent implantation of the subthalamic or ventral intermediate nucleus. In five subjects where the DBS lead tip traversed area LC, tinnitus loudness in both ears was suppressed to a nadir of level 2 or lower on a 0-10 rating scale. In one subject where the DBS lead was outside area LC, tinnitus was not modulated. In three subjects with preoperative and postoperative audiograms, hearing thresholds were unchanged by area LC stimulation. Neuromodulation of area LC may be interrupting perceptual integration of phantom sensations generated in the central auditory system. This new, basal ganglia based approach to tinnitus modulation warrants further investigation and may be ultimately refined to treat patients with refractory symptoms.

Physiological identification of the human pedunculopontine nucleus.

BACKGROUND: The pedunculopontine nucleus (PPN) is a brainstem structure with widespread connections to the basal ganglia. Despite the recent introduction of PPN deep brain stimulation (DBS) for the treatment of gait disorders, little is known about its physiology in humans. METHODS: Single unit discharge characteristics of neurons in the PPN region were analysed in four patients and PPN local field potentials (LFP) in one patient, recorded during the course of DBS implantation. Two patients had Parkinson disease, and two had non-sinemet responsive parkinsonism. Cell locations were plotted in the coordinate system of a human brainstem atlas. RESULTS: Fifty-six units in the PPN region were studied, of which 32 mapped to within PPN boundaries. The mean (SD) discharge rate of neurons in the PPN was 23.2 (15.6) Hz. Spontaneous neuronal firing rate and burst discharge rate were significantly different between neurons in the region dorsal to PPN and those in the PPN. Responses to passive movement of contralateral and ipsilateral limbs were found. Theta and beta band oscillations were present in the PPN LFP. CONCLUSION: PPN discharge characteristics may prove useful in the electrophysiological identification of PPN during DBS implantation surgery.

Safety and tolerability of putaminal AADC gene therapy for Parkinson disease.

BACKGROUND: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial. METHODS: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [(18)F]fluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression. RESULTS: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort. CONCLUSION: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Quantitative analysis of allele imbalance supports atypical ductal hyperplasia lesions as direct breast cancer precursors.

It remains unclear whether hyperplastic breast lesions, especially with atypia, are cancer precursors or markers of increased cancer risk. Quantified comparisons of genomic alterations in coexisting lesions could address this question. Therefore, we examined allele imbalance (AI), also known as loss of heterozygosity (LOH), at 20 microsatellite markers on nine chromosome arms, in DNA from 106 samples microdissected from 17 randomly selected cancer-containing breast specimens: 13 simple (DH) and 45 atypical ductal hyperplastic (ADH) lesions, 30 in situ (DCIS) and 18 invasive ductal carcinomas (IDC). Data were analysed using regression models and generalized estimating equations. We found that AI increased as histology became more aberrant and varied with histology across the chromosome arms (p<0.0001). ADH had more AIs on 1q (p=0.03) and 16q (p=0.02) and fewer AIs on 17p (p=0.06) and 17q (p<0.0001) than on other arms. In cancers, AIs remained high on 1q and 16q, and became frequent on 17p and 17q. Concordance between AIs in ADHs and cancers exceeded the 50% expected if the lesions were separate clones in 16/20 (80%) ADHs (p=0.05), from 9/11 (82%) cases (p=0.03), and involved 41/51 (80%) evaluable markers (p=0.05). The occurrence of any AI in ADH predicted greater AI (p=0.009) and possibly lower grade (p=0.05) in coexisting cancers. Nevertheless, ADHs were not genetically identical to cancers or to each other. We found AIs discordant between ADHs and cancers (always on 1q and 16q), AIs unique to ADH (usually on 11q) and some genetic heterogeneity among coexisting ADHs. We conclude that ADH lesions are genetically advanced, with frequent alterations on 1q and 16q, and are often direct cancer precursors. Their global genetic characteristics predict features of cancers in the same breast. Nevertheless, the genetic heterogeneity detected suggests that hyperplasias and cancers may arise on a field at generalized increased cancer risk.

Frameless stereotactic neurosurgery using intraoperative magnetic resonance imaging: stereotactic brain biopsy.

OBJECTIVE: To assess the application accuracy of intraoperative magnetic resonance imaging for frameless stereotactic surgery, and to evaluate the performance of intraoperative magnetic resonance imaging for the brain biopsy, a standard stereotactic procedure. METHODS: A series of spatial coordinate and phantom experiments were performed to analyze the application accuracy of the system. A prospective analysis of 68 consecutive patients undergoing stereotactic brain biopsy was then performed. RESULTS: The spatial coordinate experiments revealed a mean overall error in acquisition of 0.2 mm. The phantom experiments demonstrated a 1:1 correlation between the magnetic resonance image of a stereotactically guided probe and its relationship to a target and the actual relationship of the probe and target. Sixty-eight brain biopsies were successfully performed in all intracranial compartments except the sella. The radiographic abnormality was localized successfully in all patients (100%). Sixty-six (97.1%) of the biopsies yielded diagnostic tissue. Two biopsies (2.9%) were complicated by intraparenchymal hemorrhage. One expanding temporal lobe hemorrhage was evacuated by immediate craniotomy in the magnet with no postoperative sequelae. A deep hemorrhage from a lymphoma was managed conservatively with interval resolution of symptoms. There were no infections. There was no perioperative mortality. CONCLUSION: Intraoperative magnetic resonance imaging allows excellent target localization, provides true real-time imaging to account for anatomic changes during surgery, and permits intraoperative confirmation that the biopsy needle has reached the targeted lesion. Immediate postoperative imaging in the operating room allows assessment of adverse events and the potential for immediate management of hemorrhagic complications.

Traumatic intracranial aneurysms.

Traumatic intracranial aneurysms are rare, occurring in fewer than 1% of patients with cerebral aneurysms. They can occur following blunt or penetrating head trauma and are more common in the pediatric population. Traumatic aneurysms can be categorized histologically as true, false, or mixed, with false aneurysms being the most common. These aneurysms can present in a variety of ways, but are typically associated with an acute episode of delayed intracranial hemorrhage with an average time from initial trauma to aneurysm hemorrhage of approximately 21 days. The mortality rate for patients harboring these aneurysms may be as high as 50%. Prompt diagnosis based on arteriography and aggressive surgical management are associated with better outcome than conservative treatment. The authors describe a classification scheme for traumatic aneurysms based on their anatomical location and conclude that 1) posttraumatic aneurysm must be considered in patients with acute neurological deterioration following closed head injury; 2) they can occur following mild closed head injury; 3) they occur more commonly in children than in adults; and 4) surgical clipping and/or endovascular occlusion is the definitive treatment.

DNA alterations in tumor scrapes vs. biopsies of squamous-cell carcinomas of the head and neck.

Genetic abnormalities in SCCHNs are frequent and may be useful for screening, follow-up and prognosis. A biopsy or resection generally is utilized to identify these alterations but analysis of scraped or exfoliated tumor cells has been proposed as simpler and more versatile. It is unknown how well genetic abnormalities in scrapes reflect those in the tumor. Therefore, we compared DNA alterations in tumor scrapes obtained prior to treatment with alterations in microdissected tumor biopsies. Eight primary squamous-cell carcinomas of the head and neck (SCCHNs) were examined at 14 loci to determine loss of heterozygosity (LOH) at sites on 3p, 9p, 11p, 11q and 17p and amplification of cyclin D1 (CCND1). All biopsies contained DNA alterations, but only 3/8 scrapes contained unequivocal abnormalities; 4/8 contained subtle alterations that could not have been definitively identified without comparison to the paired biopsies. Overall, 22 alterations were detected in the biopsies: 8/22 were found unequivocally in the scrapes; 7/22 were identifiable in scrapes only after the biopsy alterations were defined and 7/22 were absent from scrapes. One LOH in scrape, but not biopsy, DNA was found. Discrepancies between scrapes and tumors tended to increase if multiple tumor samples were examined. We conclude that DNA alterations can be detected in scrapes of SCCHNs but may inaccurately reflect the tumor's complex genetic abnormalities. This may be due to contamination of scrapes with normal cells or to genetic heterogeneity within the tumor not represented in the scrape. Although examining scrapes of SCCHNs is an attractive technique, its clinical utility may have limitations.

Lack of correlation between morphometric analysis and presence of microsatellite alterations in proliferative ductal lesions of the breast.

OBJECTIVE: To apply morphometric studies using an image analyzer to a previously reported group of proliferative duct lesions and to compare results to see if there was a correlation between nuclear size range and monoclonality. STUDY DESIGN: Fifteen proliferative lesions of the breast from 12 subjects who had no history of breast malignancy were retrieved from archival pathology specimens. Evidence of monoclonality was studied using a panel of polymerase chain reaction primers to examine microsatellite alterations on microdissected paraffin-embedded specimens. Variation in nuclear size was studied using an image analyzer. RESULTS: Of six proliferative breast lesions with demonstrated genetic instability, three showed cytologic evidence of uniformity in nuclear size, a cytologic feature of malignancy. One of the six, which showed microsatellite alterations at three loci, demonstrated a wide range of nuclear size variation. Of the eight proliferative lesions that showed no genetic instability, three showed very uniform nuclear size, and five showed significant variations in nuclear size. One lesion, which fell into the "uncertain but probably genetic instable" category, showed diverse nuclear size ranges. CONCLUSION: This study demonstrated that there is no correlation between monoclonality and monomorphic cell cytology of histologic proliferative breast lesions.

Loss of heterozygosity at 11q23 in squamous cell carcinoma of the head and neck is associated with recurrent disease.

Loss of heterozygosity (LOH) at chromosome 11q23 has been found in a variety of epithelial human neoplasms, suggesting that this region contains a tumor suppressor gene(s) important to tumorigenesis. We investigated whether LOH at 11q23 could be detected in squamous cell carcinoma of the head and neck (SCCHN), and whether loss at this site was associated with specific clinical parameters. Fifty-six matched blood and SCCHN tumor samples taken at the time of diagnosis were evaluated for LOH at three microsatellite markers at 11q23. Multiplex PCRs with [alpha-32P]dCTP labeling of the amplified DNA strands were performed. Clinical data were obtained from medical record review. LOH at 11q23 was found in 13 of 52 (25%) evaluable tumors. There was no association between LOH at 11q23 and amplification of the CCND1 (cyclin D1) oncogene or inactivation of the p53 gene, which had been determined previously. With a mean follow-up of 24 months, an association independent of tumor size or stage was found between LOH at 11q23 and recurrent disease (P = 0.04). Among subjects who received radiotherapy (RT) as a component of their treatment, LOH at 11q23 was associated with persistent or recurrent locoregional disease (P = 0.05). LOH at 11q23 occurs in a subset of SCCHN. It is associated with a higher likelihood of recurrent disease, perhaps related to resistance to RT. The specific gene(s) and mechanism(s) responsible remain to be identified. Until then, LOH at 11q23 might become a marker identifying patients likely to do poorly with conventional therapy.

Genetically abnormal clones in histologically normal breast tissue.

Breast cancer is believed to develop as multiple genetic abnormalities accumulate, each conferring some growth advantage, but the timing and nature of the earliest steps in this progression are not yet elucidated. Proliferative breast lesions, associated with an increased risk of breast cancer although considered benign, recently were shown to contain clonal genetic abnormalities. Therefore, we hypothesized that clonal genetic abnormalities might be detectable before any phenotypic abnormalities are evident, ie, in histologically normal breast tissue. We examined DNA extracted from 95 normal-appearing breast ducts or terminal ductal-lobular units from 20 individuals at varying degrees of risk (those undergoing reduction mammoplasties, those with atypical hyperplastic proliferative lesions, and those already diagnosed with breast cancer). Using nine microsatellite markers, we sought evidence of genetic instability or of allelic imbalance (most likely representing loss of heterozygosity). We found genetically abnormal clones in 21/95 (22%) seemingly normal samples from 10/20 (50%) women from all three risk groups. In women under age 50, trends toward increased rates of abnormalities were noted with increased cancer risk. The abnormalities identified were more likely to be at sites of known or postulated tumor suppressor genes rather than at random or neutral loci. Our data indicate that genetic abnormalities potentially critical to breast tumorigenesis accumulate before pathological detection even of high-risk lesions and are detectable in tissue that is not only histologically benign but also completely normal.

Microsatellite alterations indicating monoclonality in atypical hyperplasias associated with breast cancer.

One model of breast tumorigenesis postulates a sequential evolution from normal to proliferative epithelium and eventually to neoplasia, but genetic data to support this progression have been limited. We wished to determine whether atypical hyperplasia (AH), a proliferative lesion conventionally classified and treated as benign, but associated with an increased risk of developing carcinoma, might show evidence of genetic abnormalities. Using the polymerase chain reaction (PCR), we examined DNA extracted from 12 separate AH lesions, from six breast cancer patients' paraffin-embedded tissue specimens, for alterations in microsatellite repeat sequences. Five of 12 AH lesions, from three of six patients, demonstrated alterations in microsatellite sequences in patterns indicating that the AH lesions are monoclonal or contain a substantial monoclonal component. We conclude that a subset of AH lesions from patients with breast cancer are characterized by monoclonal microsatellite alterations; therefore, they may already be neoplastic. This finding lends support to one postulated sequence of breast tumorigenesis and suggests that some type of genetic instability may play a role early in breast tumor development.

Visuomotor learning in cerebellar patients.

The aim of the present study was to demonstrate that patients with pathology affecting substantial regions of the cerebellum can improve their performance in a series of two-dimensional tracing tasks, thus supporting the view that this type of motor behavior can be acquired even when the integrity of this structure is compromised. Eight patients with chronic, isolated cerebellar lesions and eight age- and sex-matched healthy controls were tested. Three patients had mild, five had moderate upper limb ataxia. The experiment was divided into two parts. In the first, subjects traced an irregularly shaped outline over 20 consecutive trials ('Trace 1' task). Next, subjects were asked to redraw the object without any underlying template as a guide ('Memory 1' task). In the second part of the study, subjects were asked to trace a different, irregularly shaped outline over 20 consecutive trials ('Trace 2' task). Next, they were required to redraw it by memory with its axis rotated 90 degrees ('Memory 2' task). In each of the memory tasks the template was placed over the drawn image after each trial and shown to the subjects. The error of performance was determined by calculating three different measurements, each focused on different aspects of the task. Based on these measurements, the cerebellar patients showed improvement in both memory tasks. In the 'Memory 1' task the calculated error decreased significantly for the patients with mild ataxia. In the 'Memory 2' task all cerebellar patients improved their performance substantially enough to reduce significantly the magnitude of all three error measurements. The experiments demonstrate that patients with cerebellar lesions are capable of improving substantially their performance of a complex motor task involving the recall of memorized shapes and the visuomotor control of a tracing movement.

Detection of monoclonal microsatellite alterations in atypical breast hyperplasia.

Atypical hyperplastic (AH) breast lesions are currently classified and treated as benign proliferative disorders, but their presence is associated with a four- to fivefold increased risk of developing breast cancer. Currently, it is not known if an AH lesion is a marker of increased risk, or is itself a premalignant lesion. To investigate this question, we used a series of 15 microsatellite loci to analyze 15 separate AH lesions microdissected from the archived pathology specimens of subjects with no coincident or previous breast malignancy. We found that a significant subset (6/15, or 40%) of these AH lesions demonstrated evidence of monoclonal microsatellite alterations, both length variation and allele loss. These monoclonal alterations suggest that the AH lesion has already undergone genetic changes conferring a growth advantage. Thus, these AH lesions may actually be early neoplasms. We also noted that monoclonality characterized AH lesions in younger as compared with older women (44 vs. 59 yrs, P < 0.05) and that a subset of monoclonal lesions (4/6) demonstrated microsatellite alterations at more than one locus, suggesting that an undetermined type of genetic instability may play a role early in the development of abnormal breast proliferations. These findings contribute to our understanding of the pathogenesis of AH lesions and may have implications regarding their relationship to breast tumors.

Real time operations of the cerebellar cortex.

This manuscript reviews a series of experiments which support the notion that the cerebellum and more specifically the cerebellar cortex is principally involved in real time operations required for the regulation of coordinated motor activity. Experiments are reviewed which illustrate: (1) that the climbing fiber inputs to Purkinje cells can induce a short-lasting enhancement of their responses to mossy fiber-granule cell-parallel fiber inputs, (2) that the cerebellum is not essential for the acquisition and performance of the classically conditioned nictitating membrane reflex (NMR) of the rabbit, and (3) that the observations resulting from the microinjection of lidocaine and multiple single unit recordings within the brainstem support the notion that cell populations in this region may participate in establishing the modifications in neuronal interactions required for the acquisition of the conditioned NMR. In addition, preliminary data are shown comparing the capacity of a normal subject and a patient with a massive ipsilateral cerebellar stroke to learn certain tracing tasks and to redraw these learned tracing movements 90 degrees to the orientation of the original image. The data support the notion that the cerebellum is essential, not for the initial learning of the tracing movement, but rather for performing the learned movement with the required rotation of the original image.

Modulation of c-myc gene expression in rat livers by aflatoxin B1 exposure and age.

A single dose of aflatoxin B1 (AFB1) caused a rapid and transient induction in c-myc mRNA levels in livers derived from adult male Fischer 344 rats. The inducibility of c-myc expression by AFB1 increased with age as c-myc mRNA levels from untreated livers declined from 18-fold in 29-day-old animals to 1-fold in 39-day-old animals, relative to untreated 43-day-old control animals. A dose-dependent increase in c-myc mRNA was found when 53- and 76-day-old rats were administered various AFB1 doses whereas 29-day-old animals exhibited essentially no change in c-myc mRNA levels for the doses examined. Rats were treated with multiple doses of AFB1 to induce hepatocellular carcinomas. C-myc mRNA levels were measured in rat liver samples taken during and subsequent to chronic AFB1 exposure. Characterization of the c-myc induction response at the time of AFB1 exposure revealed that a transient elevation of c-myc mRNA occurred during each (5-day) dosing period for the first 3 weeks, consistent with the acute exposure studies. RNA prepared from hepatocellular carcinomas exhibited elevated levels of c-myc mRNA compared to vehicle-treated control animals. Examination of tumors isolated from the 28-day-old animals showed that the increased c-myc mRNA observed was not the result of gene amplification or gene rearrangement. A comparison of tumor data showed that the 28-day-old animals had a 100% liver tumor incidence while the 38-day-old rats had a 20% liver tumor incidence.(ABSTRACT TRUNCATED AT 250 WORDS)