Neal Prakash

Optical Doppler tomography

Optical Doppler tomography (ODT) is an imaging modality that takes advantage of the short coherence length of a broad-band light sources to perform micrometer-scale, cross-sectional imaging of tissue structure and blood flow dynamics simultaneously. The authors review in this paper the principal of ODT and its applications. Results from in vitro and in vivo model studies demonstrated that ODT can map the blood flow velocity profile with high spatial resolution in scattering medium. ODT detection mechanisms are illustrated using Monte Carlo simulations. The application of ODT to image brain hemodynamics is demonstrated. Finally, the authors discuss the limitations of the current technology and application of a phase resolved technique to improve image speed and quality.

A mapping label required for normal scale of body representation in the cortex

The neocortical primary somatosensory area (S1) consists of a map of the body surface. The cortical area devoted to different regions, such as parts of the face or hands, reflects their functional importance. Here we investigated the role of genetically determined positional labels in neocortical mapping. Ephrin-A5 was expressed in a medial > lateral gradient across S1, whereas its receptor EphA4 was in a matching gradient across the thalamic ventrobasal (VB) complex, which provides S1 input. Ephrin-A5 had topographically specific effects on VB axon guidance in vitro. Ephrin-A5 gene disruption caused graded, topographically specific distortion in the S1 body map, with medial regions contracted and lateral regions expanded, changing relative areas up to 50% in developing and adult mice. These results provide evidence for within-area thalamocortical mapping labels and show that a genetic difference can cause a lasting change in relative scale of different regions within a topographic map.

Nanoplatforms for constructing new approaches to cancer treatment, imaging, and drug delivery: What should be the policy?

Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1-100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law-healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines.

Visualizing and quantifying evoked cortical activity assessed with intrinsic signal imaging

Intrinsic signal imaging (ISI) measures changes in light reflectance from the illuminated cortex (intrinsic signals or IS) attributed to various vascular and metabolic sources that, when using illumination in the 600 nm range, appear to co-localize with neuronal activity. Given the multiple sources contributing to the collected IS, the common practice of averaging across an extended post-stimulus time epoch before dividing by baseline data typically visualizes evoked IS overlying both the cortical tissue and the large surface blood vessels. In rat PMBSF, the contribution from these vessels are problematic as they do not co-localize with known PMBSF function. Determining a means for quantifying the evoked IS area poses an additional challenge. Here, we describe how exploiting IS collected shortly after stimulus onset (within 1.5 s), which coincides with fast oxygen consumption of active neurons, visualizes evoked IS overlying the cortical tissue without the large surface vessels. We also describe how the use of absolute thresholds combined with a baseline determined from data collected immediately prior to stimulus onset (within 1 s) targets most precisely a specific evoked IS amplitude, a method that should be especially useful when evoked areas are expected to occupy a substantial portion of the total imaged area and/or when peak activity is expected to differ between subjects.

Patterns of fractional anisotropy changes in white matter of cerebellar peduncles distinguish spinocerebellar ataxia-1 from multiple system atrophy and other ataxia syndromes

AIM To determine prospectively if qualitative and quantitative diffusion tensor imaging (DTI) metrics of white matter integrity are better than conventional magnetic resonance imaging (MRI) metrics for discriminating cerebellar diseases. METHODS Conventional MRI images from 31 consecutive patients with ataxia and 12 controls were interpreted by a neuroradiologist given only a clinical indication of ataxia. An expert ataxologist, blinded to radiological findings, determined the clinical diagnosis, as well as ataxia severity and asymmetry for each patient. For qualitative analysis, a comparison of the cerebellar white matter in ataxic vs. control patients was made by visual inspection of directionally encoded color (DEC) images. For quantitative analysis, segmentation of the cerebellar white matter in the inferior, middle, and superior cerebellar peduncles (ICP, MCP, and SCP) was attempted using three methods: a region of interest method, a deterministic DTI tractography (DDT) method, and a probabilistic DTI tractography (PDT) method. A statistical comparison of the average fractional anisotropy (FA) in these tracts was made between subject groups, and correlated to clinical diagnosis, severity, and asymmetry. RESULTS Of the 31 consecutive patients with ataxia, the two largest subgroups had a clinical diagnosis of multiple system atrophy (cerebellar subtype; MSA-C), and spinocerebellar ataxia-1 (SCA1). Conventional MRI features, such as degree of pontocerebellar atrophy, correlated with ataxia severity, but were neither sensitive nor specific for the ataxia subtypes. PDT was the most accurate and least variable method of the three methods used for determining FA, especially in the ICP. Average FA in all ataxic patients was significantly decreased in the MCP, SCP and ICP and this decrease correlated to disease severity. Asymmetric ataxia correlated to proportionately larger contralateral MCP, ICP and SCP FA values. MCP, ICP, and SCP FA difference values formed distinct clusters that distinguished MSA-C from SCA-1, and other ataxia syndromes. CONCLUSIONS Qualitative and quantitative reductions in DTI metrics of white matter integrity in the cerebellar peduncles correlated better to clinical features of patients with sporadic and hereditary ataxias than conventional structural MRI measures of pontocerebellar atrophy.

Current Trends in Intraoperative Optical Imaging for Functional Brain Mapping and Delineation of Lesions of Language Cortex

Resection of a cerebral arteriovenous malformation (AVM), epileptic focus, or glioma, ideally has a prerequisite of microscopic delineation of the lesion borders in relation to the normal gray and white matter that mediate critical functions. Currently, Wada testing and functional magnetic resonance imaging (fMRI) are used for preoperative mapping of critical function, whereas electrical stimulation mapping (ESM) is used for intraoperative mapping. For lesion delineation, MRI and positron emission tomography (PET) are used preoperatively, whereas microscopy and histological sectioning are used intraoperatively. However, for lesions near eloquent cortex, these imaging techniques may lack sufficient resolution to define the relationship between the lesion and language function, and thus not accurately determine which patients will benefit from neurosurgical resection of the lesion without iatrogenic aphasia. Optical techniques such as intraoperative optical imaging of intrinsic signals (iOIS) show great promise for the precise functional mapping of cortices, as well as delineation of the borders of AVMs, epileptic foci, and gliomas. Here we first review the physiology of neuroimaging, and then progress towards the validation and justification of using intraoperative optical techniques, especially in relation to neurosurgical planning of resection AVMs, epileptic foci, and gliomas near or in eloquent cortex. We conclude with a short description of potential novel intraoperative optical techniques.

In Vivo Modulation of a Cortical Functional Sensory Representation Shortly After Topical Cholinergic Agent Application

The aim of the present study was to determine whether cholinergic increase in the size of a functional representation (collective evoked response from a large population of neurons) can be observed shortly (within an hour) after treatment onset and whether nicotinic receptors can participate in this type of modulation. Cholinergic agonist application has been found previously to increase the response of a single cortical neuron to a stimulus. Also, pairing cholinergic basal forebrain stimulation with delivery of a tone has been reported to increase the size of that tones functional representation. Whereas the increase in a single cortical neuron response can occur within seconds after cholinergic agonist application, to date the increase in the size of a functional representation has only been investigated within one to several weeks after the onset of pairing basal forebrain stimulation with tone delivery. Furthermore, primarily muscarinic receptors have been implicated in these types of changes in cortical activity. By using optical imaging of intrinsic signals in vivo, we found that the size of a whiskers functional representation in the primary somatosensory cortex of the rat increases substantially within 69 or 46 minutes after topical application of either a muscarinic or nicotinic agonist to the exposed cortex, respectively, and decreases within 23 minutes after topical application of a muscarinic antagonist. For each cholinergic agent, we verified that delivery of a cholinergic agent by means of topical application can lead to the agents successful penetration through the cortical layers in the time allotted to complete an imaging experiment. Furthermore, the time course of penetration for each agent was characterized. Based on the combined imaging/penetration results, we speculate on potential sites of cholinergic action in the cortex. Irrespective of the exact mechanism of action, we demonstrate here that an increase in the size of a functional sensory representation can occur shortly by means of activation of either nicotinic or muscarinic receptors. J. Comp. Neurol. 452:38–50, 2002.

Temporal profiles and 2-dimensional oxy-, deoxy-, and total-hemoglobin somatosensory maps in rat versus mouse cortex

BACKGROUND Mechanisms of neurovascular coupling-the relationship between neuronal chemoelectrical activity and compensatory metabolic and hemodynamic changes-appear to be preserved across species from rats to humans despite differences in scale. However, previous work suggests that the highly cellular dense mouse somatosensory cortex has different functional hemodynamic changes compared to other species. METHODS We developed novel hardware and software for 2-dimensional optical spectroscopy (2DOS). Optical changes at four simultaneously recorded wavelengths were measured in both rat and mouse primary somatosensory cortex (S1) evoked by forepaw stimulation to create four spectral maps. The spectral maps were converted to maps of deoxy-, oxy-, and total-hemoglobin (HbR, HbO, and HbT) concentration changes using the modified Beer-Lambert law and phantom HbR and HbO absorption spectra. RESULTS : Functional hemodynamics were different in mouse versus rat neocortex. On average, hemodynamics were as expected in rat primary somatosensory cortex (S1): the fractional change in the log of HbT concentration increased monophasically 2 s after stimulus, whereas HbO changes mirrored HbR changes, with HbO showing a small initial dip at 0.5 s followed by a large increase 3.0 s post stimulus. In contrast, mouse S1 showed a novel type of stimulus-evoked hemodynamic response, with prolonged, concurrent, monophasic increases in HbR and HbT and a parallel decrease in HbO that all peaked 3.5-4.5 s post stimulus onset. For rats, at any given time point, the average size and shape of HbO and HbR forepaw maps were the same, whereas surface veins distorted the shape of the HbT map. For mice, HbO, HbR, and HbT forepaw maps were generally the same size and shape at any post-stimulus time point. CONCLUSIONS 2DOS using image splitting optics is feasible across species for brain mapping and quantifying the map topography of cortical hemodynamics. These results suggest that during physiologic stimulation, different species and/or cortical architecture may give rise to different hemodynamic changes during neurovascular coupling.

Cortical Sensory Plasticity in a Model of Migraine with Aura

The migraine attack is characterized by alterations in sensory perception, such as photophobia or allodynia, which have in common an uncomfortable amplification of the percept. It is not known how these changes arise. We evaluated the ability of cortical spreading depression (CSD), the proposed mechanism of the migraine aura, to shape the cortical activity that underlies sensory perception. We measured forepaw- and hindpaw-evoked sensory responses in rat, before and after CSD, using multielectrode array recordings and two-dimensional optical spectroscopy. CSD significantly altered cortical sensory processing on a timescale compatible with the duration of the migraine attack. Both electrophysiological and hemodynamic maps had a reduced surface area (were sharpened) after CSD. Electrophysiological responses were potentiated at the receptive field center but suppressed in surround regions. Finally, the normal adaptation of sensory-evoked responses was attenuated at the receptive field center. In summary, we show that CSD induces changes in the evoked cortical response that are consistent with known mechanisms of cortical plasticity. These mechanisms provide a novel neurobiological substrate to explain the sensory alterations of the migraine attack.

What Has Intrinsic Signal Optical Imaging Taught Us About NGF-Induced Rapid Plasticity in Adult Cortex and Its Relationship to the Cholinergic System?

Intrinsic signal optical imaging (ISI) is a high-resolution functional brain mapping technique that is being used to further our understanding of the neocortex and its interaction with drugs. Recent studies using combination ISI and in vivo pharmacology have advanced our insight into the actions of both acetylcholine and neurotrophins on inducing rapid and large-scale cortical plasticity. In particular, it appears that acetylcholine (ACh), nicotinic ACh receptors, nerve growth factor (NGF), and NGF receptors (TrkA and p75) are involved in an important feedback loop between the basal forebrain cholinergic system (BFCS) and the neocortex. Specifically, recent data suggest that NGF expressed in the cortex may act on multiple time scales on the BFCS: acutely to increase BFCS release of acetylcholine, intermediately to induce sprouting of BFCS axons, and long-term to change gene expression of BFCS neurons. In this article, advances in understanding the links in vivo between the BFCS, neocortex, nicotinic ACh receptors, and NGF are reviewed.