Adam N. Mamelak

Humans with hippocampus damage display severe spatial memory impairments in a virtual Morris water task

For nonhumans, it has been shown that the hippocampus (HPC) is critical for spatial memory. We tested patients with unilateral HPC resections on a virtual analogue of a classic spatial task to assess HPC functioning in nonhumans: the Morris water task. We found that when humans are required to use spatial cues to navigate to a hidden escape platform in a pool, patients with HPC resections display severe impairments in spatial navigation relative to age-matched controls and age-matched patients who have had extra-HPC resections. This effect occurred for every patient tested and was evident regardless of side of surgery. Hence, it is apparent across species and irrespective of which hemisphere is damaged that the human HPC is critical for spatial/relational memory.

Online detection and sorting of extracellularly recorded action potentials in human medial temporal lobe recordings, in vivo

Understanding the function of complex cortical circuits requires the simultaneous recording of action potentials from many neurons in awake and behaving animals. Practically, this can be achieved by extracellularly recording from multiple brain sites using single wire electrodes. However, in densely packed neural structures such as the human hippocampus, a single electrode can record the activity of multiple neurons. Thus, analytic techniques that differentiate action potentials of different neurons are required. Offline spike sorting approaches are currently used to detect and sort action potentials after finishing the experiment. Because the opportunities to record from the human brain are relatively rare, it is desirable to analyze large numbers of simultaneous recordings quickly using online sorting and detection algorithms. In this way, the experiment can be optimized for the particular response properties of the recorded neurons. Here we present and evaluate a method that is capable of detecting and sorting extracellular single-wire recordings in realtime. We demonstrate the utility of the method by applying it to an extensive data set we acquired from chronically implanted depth electrodes in the hippocampus of human epilepsy patients. This dataset is particularly challenging because it was recorded in a noisy clinical environment. This method will allow the development of closed-loop experiments, which immediately adapt the experimental stimuli and/or tasks to the neural response observed.

Poor drug distribution as a possible explanation for the results of the PRECISE trial

OBJECTnConvection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial.nnnMETHODSnData on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution.nnnRESULTSnOnly 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score.nnnCONCLUSIONSnThe potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Lack of association of cytomegalovirus with human brain tumors

Cytomegalovirus (CMV) is thought to possess oncogenic properties and has been linked with a number of human malignancies. CMV infection was recently described in association with malignant gliomas. The intent of the present study was to further investigate the reported association between CMV and malignant gliomas. Tissue from 22 brain tumors of various histologic types and grades, four normal brains, six breast carcinomas, six colon carcinomas, six lung carcinomas, and six sarcomas were evaluated for the presence of CMV by polymerase chain reaction (PCR), in situ hybridization, and immunohistochemical methods. None of the brain tumors or normal brain tissue tested demonstrated evidence of CMV pp65 or early nuclear proteins by immunohistochemistry. In addition, no CMV RNA or DNA was detected in these cases by in situ hybridization and PCR. None of the carcinomas or sarcomas evaluated were positive for CMV by immunohistochemistry, in situ hybridization, or PCR. The findings of the present study suggest that CMV is not significantly associated with brain tumors in humans.

Efficacy of proton magnetic resonance spectroscopy in clinical decision making for patients with suspected malignant brain tumors.

We wished to determine the utility of single voxel proton (1H) magnetic resonance spectroscopy (MRS) when used as an alternative or adjunct to brain biopsy in patients harboring lesions suggestive of brain tumors identified by MRI scan. Fifteen patients (age 7–58 years) with MRI scans and clinical histories suggestive of primary brain tumors underwent single voxel 1H-MRS. MRS (16 regions of interest in 15 patients) was used to aid in differentiation between tumor and other pathologies such as stroke or demyelinating plaque (n=6), radiation necrosis (n=5), or edema (n=5). Spectra were quantified to determine absolute molar values of N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), lactate (LAC), and myo-inositol (mI), metabolite ratios relative to Cr were calculated, and spectra were interpreted based on metabolite ratios. Subsequent clinical management was based on MRS interpretation, and patients were then followed to determine if MRS interpretation accurately predicted clinical outcome or surgical findings. Mean follow-up was 12.5 months (range 3–28 months). MRS suggested the presence of recurrent tumor in 7 cases, all of which were subsequently ‘confirmed’ by tumor resection (n=4) or disease progression (n=3). MRS suggested the presence of new tumor in 1 case, subsequently confirmed by surgical resection. MRS suggested the presence of necrosis in 3 patients; all 3 remained radiographically stable during the follow-up period, and one was confirmed by stereotactic biopsy. MRS suggested non-neoplastic lesions in 4 cases, 3 of whom were followed until radiographic resolution of lesions and one of which was confirmed as a pyogenic abscess via stereotactic aspiration. Overall, MRS accurately predicted the pathological nature and clinical outcome of lesions in 15/16 (96%) situations, influenced clinical decision making in 12 cases, and altered surgery planning in 7 patients. In appropriate circumstances MRS can reduce the need for biopsy and provide an important guide for clinical decision-making in difficult cases.

Long-range temporal correlations in the spontaneous spiking of neurons in the hippocampal-amygdala complex of humans.

The spontaneous or background discharge patterns of in vivo single neuron is mostly considered as neuronal noise, which is assumed to be devoid of any correlation between successive inter-spike-intervals (ISI). Such random fluctuations are modeled only statistically by stochastic point process, lacking any temporal correlation. In this study, we have investigated the nature of spontaneous irregular fluctuations of single neurons from human hippocampus-amygdala complex by three different methods: (i) detrended fluctuation analysis (DFA), (ii) multiscale entropy (MSE), (iii) rate estimate convergence. Both the DFA and MSE analysis showed the presence of long-range power-law correlation over time in the ISI sequences. Moreover, we observed that the individual spike trains presented non-random structure on longer time-scales and showed slow convergence of rate estimates with increasing counting time. This power-law correlation and the slow convergence of statistical moments were eliminated by randomly shuffling the ISIs even though the distributions of ISIs were preserved. Thus the power-law relationship arose from long-term correlations among ISIs that were destroyed by shuffling the data. Further, we found that neurons which showed long-range correlations also showed statistically significant correlated firing as measured by correlation coefficient or mutual information function. The presence of long-range correlations indicates the history-effect or memory in the firing pattern by the associative formation of a neuronal assembly.

Vagus nerve stimulation therapy: 2-year prospective open-label study of 40 subjects with refractory epilepsy and low IQ who are living in long-term care facilities.

Treating seizures among patients with mental retardation/developmental disabilities (MR/DD) is difficult owing in large part to the presence of additional comorbidities and the resulting need for polytherapy. Therefore, a nonpharmacological treatment option is needed for this population. This prospective, open-label study documented the long-term outcome of 40 low-IQ (<70) patients living in long-term care facilities who received vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy. Subjects were seen every 1 to 3 months by their neurologist (R.H.). Seizure frequency, antiepileptic medication, and quality-of-life information were documented preimplantation and quarterly thereafter through 2 years. The surgery and therapy were well tolerated. Seizures were reduced by at least 50% for 11 subjects. Antiepileptic medications were reduced from 3.3 per subject at baseline to an average of 2.3 per subject after 2 years. According to caregiver reports, overall quality of life improved for the majority of subjects; also, using the Client Development Evaluation Report (CDER), statistically significant improvements were reported at both 1 and 2 years in attention span, word usage, clarity of speech, standing balance, washing dishes, and household chores. VNS is a viable treatment option for low-IQ patients with pharmacoresistant epilepsy who are living in long-term care facilities.

Novel method for visualizing and modeling the spatial distribution of neural stem cells within intracranial glioma

Neural stem cells (NSCs) hold great promise for glioma therapy due to their inherent tumor-tropic properties, enabling them to deliver therapeutic agents directly to invasive tumor sites. In the present study, we visualized and quantitatively analyzed the spatial distribution of tumor-tropic NSCs in a mouse model of orthotopic glioma in order to predict the therapeutic efficacy of a representative NSC-based glioma therapy. U251.eGFP human glioma was established in the brain of athymic mice, followed by stereotactic injection of CM-DiI-labeled human NSCs posterior-lateral to the tumor site. Confocal microscopy, three-dimensional modeling and mathematical algorithms were used to visualize and characterize the spatial distribution of NSCs throughout the tumor. The pattern of NSC distribution showed a gradient with higher densities toward the centroid of the tumor mass. We estimate that NSC-mediated therapy would eradicate 70-90% of the primary tumor mass and the majority of invasive tumor foci. Our method may serve as a model for optimizing the efficacy of NSC-based glioma therapy.

Quantification of B0 homogeneity variation with head pitch by registered three-dimensional field mapping

In this study, we quantify the extent to which B(0) homogeneity in adult humans is dependent on head pitch relative to the B(0) vector. Three-dimensional, whole-brain B(0) field maps were acquired in five normal subjects for three generalized head pitch angles. Optimal first- and second-order shimming of the experimental B(0) maps were simulated numerically. The spatial B(0) distribution within the brain was analyzed following automated volumetric co-registration of all data. Increasing head pitch improves both the resonance offset and local homogeneity in the inferior frontal lobes, but introduces inhomogeneities in other regions of the brain which cannot be compensated by first-order shimming but are further improved by second-order shimming.

Hematopoietic potential of neural stem cells: plasticity versus heterogeneity.

Organ-specific stem cells have been identified in a variety of mammalian tissues. These cells hold great promise for cellular therapy if they can reliably produce functional progeny of specific lineages. A central dogma in development has been that organ-specific stem cells are restricted to making the differentiated cell types of the tissue from which they are isolated. However, a substantial body of evidence exists that stem-cell populations from neural and hematopoietic tissues can generate the other cell types, suggesting that adult organ-specific stem cells may have a broader differentiation potential than originally thought. It remains unclear whether this apparent stem cell plasticity is attributable to transdifferentiation of tissue specific stem cells, the co-existence of multiple stem cells with different potentials, or resident totipotent stem cells in these tissues. Recent evidence, in fact, indicates that there may be a fourth explanation for the apparent plasticity of stem cells: cell fusion. Here, the authors critically examine the existing data to assess the extent of phenotypic conversion of bone marrow-to-brain and brain-to-blood and discuss some of the contentious issues surrounding these studies. We conclude that there is strong evidence for a multipotent neurohematopoietic stem-cell population in human and mouse brain, although further characterization of these cells will be required if the goal of engineering tissues for therapeutic applications is to be realized.