Measuring visual stimulation and attention signals in human superior colliculus using high-resolution fMRI

textThe superior colliculus (SC) is a laminated oculomotor structure in the midbrain. In non-human primates SC has long been known to contain a retinotopically-organized map of visual stimulation in its superficial layers, which is aligned to a map of saccadic eye movements in the deeper layers. Microstimulation and electrophysiology experiments have shown that SC also plays a key role in covert visuospatial attention and suggest that attentional modulation also occurs in a retinotopic manner. Retinotopic organization of the visual field can be non-invasively mapped in humans using functional MRI with a technique called phase-encoded retinotopy. In this technique, rotating wedges and expanding rings of visual stimuli are used to map the polar angle and eccentricity dimensions of a polar coordinates system, respectively. A similar technique can also be used to map spatial attention by keeping the visual stimulus constant and cueing subjects to attend to apertures of rotating wedges and expanding rings within the stimulus. A previous study using fMRI has shown the polar angle representation of visual stimulation in human SC but was unable to find a representation of eccentricity. This work uses high-resolution fMRI along with special surface analysis techniques developed in our lab to demonstrate maps of both polar angle and eccentricity for visual stimulation. Moreover, visual attention is also shown to be topographically organized within SC and in registration with visual stimulation. Finally, in human visual cortex, fMRI is known to show activity for sustained spatial attention even in the absence of a significant visual stimulus, an attentional "base response". In this work, SC is shown to exhibit a similar sustained attention base response using a threshold-contrast detection paradigm. This base response was compared with a response for attention with visual stimulation. The peak amplitude of the base response occurred more deeply within SC tissue than the peak for attention with stimulation. It is proposed that this reflects the specific attentional enhancement of the deeper visuomotor neurons, which are hypothesized to be a direct neuronal correlate of the oculomotor theory of attention.Psycholog

THE LEFT HEMISPHERE’S STRUCTURAL CONNECTIVITY FOR THE INFERIOR FRONTAL GYRUS, STRIATUM, AND THALAMUS, AND INTRA-THALAMIC TOPOGRAPHY

The neuroanatomy of language cognition has an extensive history of scientific interest and inquiry. Over a century of behavioral lesion studies and decades of functional neuroimaging research have established the left hemisphere’s inferior frontal gyrus (IFG) as a critical region for speech and language processing. This region’s subcortical projections are thought to be instrumental for supporting and integrating the cognitive functions of the language network. However, only a subset of these projections have been shown to exist in humans, and structural evidence of pars orbitalis’ subcortical circuitry has been limited to non-human primates. This thesis demonstrates direct, intra-structural connectivity of each of the left IFG’s gyral regions with the thalamus and the putamen in humans, using high-angular, deterministic tractography. Novel processing and analysis methods elucidated evidence of predominantly segregated cortical circuits within the thalamus, and suggested the presence of parallel circuits for motor/language integration along the length of the putamen

Imaging the subthalamic nucleus in Parkinson’s disease

This thesis is comprised of a set of work that aims to visualize and quantify the anatomy, structural variability, and connectivity of the subthalamic nucleus (STN) with optimized neuroimaging methods. The study populations include both healthy cohorts and individuals living with Parkinson's disease (PD). PD was chosen specifically due to the involvement of the STN in the pathophysiology of the disease. Optimized neuroimaging methods were primarily obtained using ultra-high field (UHF) magnetic resonance imaging (MRI). An additional component of this thesis was to determine to what extent UHF-MRI can be used in a clinical setting, specifically for pre-operative planning of deep brain stimulation (DBS) of the STN for patients with advanced PD. The thesis collectively demonstrates that i, MRI research, and clinical applications must account for the different anatomical and structural changes that occur in the STN with both age and PD. ii, Anatomical connections involved in preparatory motor control, response inhibition, and decision-making may be compromised in PD. iii. The accuracy of visualizing and quantifying the STN strongly depends on the type of MR contrast and voxel size. iv, MRI at a field strength of 3 Tesla (T) can under certain circumstances be optimized to produce results similar to that of 7 T at the expense of increased acquisition time

Functional and Structural Magnetic Resonance Imaging of Humans and Macaques

Magnetic resonance imaging (MRI) is a technique which finds use in the neurosciences both as an anatomical and functional localization tool. The traditional uses of MRI for structural analysis, such as are commonly found in medicine, can be adapted to serve in place of histological studies for identifying areas of interest in the cortex. Functional MRI (fMRI) is a rapidly developing tangent of MRI which can be used alone or in tandem with classical electrophysiological experiments to investigate neural activity. Although developed intensely for clinical and scientific studies in human subjects, MRI and fMRI have been used increasingly in the non-human primate. This document contains work exemplifying the use of fMRI in both species and methods for pre- and post-surgical anatomical MRI in the non-human primate. Serving as a solid foundation for learning the principles of block-design fMRI, a classic visual illusion, the motion aftereffect, is studied in the human by means of a hemifield visual stimulus using conventional blood oxygen level dependent (BOLD) fMRI. Primary response and levels of motion aftereffect are analyzed in visual cortex, areas pMT and pMST. A novel use of iron oxide nanoparticles as an intravascular contrast agent in the non-human primate is investigated as a method of boosting fMRI contrast, yielding an ultimate gain in contrast-to-noise at the expense of temporal resolution. While anatomical imaging served as a necessary tool for the localization of functional response in the human, further novel techniques were investigated in the non-human primate. A technique for MRI-guided implantation of multiple electrode arrays is considered, to aid the localization of sites of interest in the cortex. The use of MRI as a replacement for histological preparations for purposes of reconstructing electrode penetration sites is documented. These studies exist to aid in bridging the gap between human and non-human MRI and fMRI. Further application of these principles could be extended to the eventual placement of intracortical recording devices in the human, to benefit a patient population needing devices such as a neural prosthesis

Creation of Computerized 3D MRI-Integrated Atlases of the Human Basal Ganglia and Thalamus

Functional brain imaging and neurosurgery in subcortical areas often requires visualization of brain nuclei beyond the resolution of current magnetic resonance imaging (MRI) methods. We present techniques used to create: (1) a lower resolution 3D atlas, based on the Schaltenbrand and Wahren print atlas, which was integrated into a stereotactic neurosurgery planning and visualization platform (VIPER); and (2) a higher resolution 3D atlas derived from a single set of manually segmented histological slices containing nuclei of the basal ganglia, thalamus, basal forebrain, and medial temporal lobe. Both atlases were integrated to a canonical MRI (Colin27) from a young male participant by manually identifying homologous landmarks. The lower resolution atlas was then warped to fit the MRI based on the identified landmarks. A pseudo-MRI representation of the high-resolution atlas was created, and a non-linear transformation was calculated in order to match the atlas to the template MRI. The atlas can then be warped to match the anatomy of Parkinson's disease surgical candidates by using 3D automated non-linear deformation methods. By way of functional validation of the atlas, the location of the sensory thalamus was correlated with stereotactic intraoperative physiological data. The position of subthalamic electrode positions in patients with Parkinson's disease was also evaluated in the atlas-integrated MRI space. Finally, probabilistic maps of subthalamic stimulation electrodes were developed, in order to allow group analysis of the location of contacts associated with the best motor outcomes. We have therefore developed, and are continuing to validate, a high-resolution computerized MRI-integrated 3D histological atlas, which is useful in functional neurosurgery, and for functional and anatomical studies of the human basal ganglia, thalamus, and basal forebrain

Comprehensive in vivo Mapping of the Human Basal Ganglia and Thalamic Connectome in Individuals Using 7T MRI

Basal ganglia circuits are affected in neurological disorders such as Parkinson's disease (PD), essential tremor, dystonia and Tourette syndrome. Understanding the structural and functional connectivity of these circuits is critical for elucidating the mechanisms of the movement and neuropsychiatric disorders, and is vital for developing new therapeutic strategies such as deep brain stimulation (DBS). Knowledge about the connectivity of the human basal ganglia and thalamus has rapidly evolved over recent years through non-invasive imaging techniques, but has remained incomplete because of insufficient resolution and sensitivity of these techniques. Here, we present an imaging and computational protocol designed to generate a comprehensive in vivo and subject-specific, three-dimensional model of the structure and connections of the human basal ganglia. High-resolution structural and functional magnetic resonance images were acquired with a 7-Tesla magnet. Capitalizing on the enhanced signal-to-noise ratio (SNR) and enriched contrast obtained at high-field MRI, detailed structural and connectivity representations of the human basal ganglia and thalamus were achieved. This unique combination of multiple imaging modalities enabled the in-vivo visualization of the individual human basal ganglia and thalamic nuclei, the reconstruction of seven white-matter pathways and their connectivity probability that, to date, have only been reported in animal studies, histologically, or group-averaged MRI population studies. Also described are subject-specific parcellations of the basal ganglia and thalamus into sub-territories based on their distinct connectivity patterns. These anatomical connectivity findings are supported by functional connectivity data derived from resting-state functional MRI (R-fMRI). This work demonstrates new capabilities for studying basal ganglia circuitry, and opens new avenues of investigation into the movement and neuropsychiatric disorders, in individual human subjects

USPIO-labeling nei macrofagi M1 e M2: studio in vitro con risonanza magnetica

Purpose: Tumor-associated macrophages (TAM) are recruited to the tumor site and programmed by tumor-derived factors in tumor-supportive M2-polarized macrophages, although M1-polarized TAM with anti-tumor activity have been described in several types of cancer. Aim of the present study was to evaluate if ultrasmall superparamagnetic iron oxide (USPIO) magnetic resonance (MR) could be used to depict distinct population of macrophages. Materials and Methods: Human monocytic cell line THP-1 were differentiated into macrophages using PMA and polarized according to the Tjiu method. A control population of macrophages, was developed from THP-1 cells with PMA (M0 macrophages). M1-polarized, M2-polarized and the M0 were incubated with USPIO research prototype (P904, CheMatech, Guerbet Research)(200 μg Fe/mL) for 36 hours. A M0 without P904 was the control non-treated population. M0, M0+P904, M1+P904 and M2+P904 were analyzed in gel phantoms containing at least 1x106 cells/milliliter with a 3.0T MR scan (Discovery MR750). Optical and electron microscopy was used as gold standard to evaluate the iron uptake. Results: M2+P904 showed a much greater T1 signal compared to the other population (p<0.0001), and the T2* signal was significantly lower compared to the other groups (p<0.0001); the R* was significantly higher for the M2+ P904 compared to the other populations (p<0.0001). Hystological analysis demonstrated higher iron content in the M2+P904 as compared to both the M1+904 (p=0.04) and the M0+P904 population (p=0.003). Ultrastructure analysis with a electron microscope demonstrated ubiquitous localization of P904 within the cellular compartments. Those results were confirmed with human macrophages. Conclusion: Avid and selective USPIO-labeling for M2-like population was demonstrated with a 3.0T clinical scan. Clinical relevance: USPIO-RM is able to depict M2 macrophage population. Further studies on same topic would be highly desirable to investigate the possible role of non-invasive diagnosis in inflammation and cancer imaging