Tammar Kushnir

Differential Processing of Objects under Various Viewing Conditions in the Human Lateral Occipital Complex

The invariant properties of human cortical neurons cannot be studied directly by fMRI due to its limited spatial resolution. Here, we circumvented this limitation by using fMR adaptation, namely, reduction of the fMR signal due to repeated presentation of identical images. Object-selective regions (lateral occipital complex [LOC]) showed a monotonic signal decrease as repetition frequency increased. The invariant properties of fMR adaptation were studied by presenting the same object in different viewing conditions. LOC exhibited stronger fMR adaptation to changes in size and position (more invariance) compared to illumination and viewpoint. The effect revealed two putative subdivisions within LOC: caudal-dorsal (LO), which exhibited substantial recovery from adaptation under all transformations, and posterior fusiform (PF/LOa), which displayed stronger adaptation. This study demonstrates the utility of fMR adaptation for revealing functional characteristics of neurons in fMRI studies.

A sequence of object-processing stages revealed by fMRI in the human occipital lobe.

Functional magnetic resonance imaging was used in combined functional selectivity and retinotopic mapping tests to reveal object‐related visual areas in the human occpital lobe. Subjects were tested with right, left, up, or down hemivisual field stimuli which were composed of images of natural objects (faces, animals, man‐made objects) or highly scrambled (1,024 elements) versions of the same images. In a similar fashion, the horizontal and vertical meridians were mapped to define the borders of these areas. Concurrently, the same cortical sites were tested for their sensitivity to image‐scrambling by varying the number of scrambled picture fragments (from 16–1,024) while controlling for the Fourier power spectrum of the pictures and their order of presentation. Our results reveal a stagewise decrease in retinotopy and an increase in sensitivity to image‐scrambling. Three main distinct foci were found in the human visual object recognition pathway (Ungerleider and Haxby [1994]: Curr Opin Neurobiol 4:157–165): 1) Retinotopic primary areas V1–3 did not exhibit significant reduction in activation to scrambled images. 2) Areas V4v (Sereno et al., [1995]: Science 268:889–893) and V3A (DeYoe et al., [1996]: Proc Natl Acad Sci USA 93:2382–2386; Tootell et al., [1997]: J Neurosci 71:7060–7078) manifested both retinotopy and decreased activation to highly scrambled images. 3) The essentially nonretinotopic lateral occipital complex (LO) (Malach et al., [1995]: Proc Natl Acad Sci USA 92:8135–8139; Tootell et al., [1996]: Trends Neurosci 19:481–489) exhibited the highest sensitivity to image scrambling, and appears to be homologous to macaque the infero‐temporal (IT) cortex (Tanaka [1996]: Curr Opin Neurobiol 523–529). Breaking the images into 64, 256, or 1,024 randomly scrambled blocks reduced activation in LO voxels. However, many LO voxels remained significantly activated by mildly scrambled images (16 blocks). These results suggest the existence of object‐fragment representation in LO. Hum. Brain Mapping 6:316–328, 1998.

Toward direct visualization of the internal shape representation space by fMRI

Reports of columnar organization of the macaque inferotemporal cortex (Tanaka, 1992, 1993a) indicate that ensembles of cells responding to particular objects may be both sufficiently extensive and properly localized to allow their detection and discrimination by means of functional magnetic resonance imaging (fMRI). A recently developed theory of object representation by ensembles of coarsely tuned units (Edelman, 1998; Edelman & Duvdevani-Bar, 1997b) and its implementation as a computer model of recognition and categorization (Cutzu & Edelman, 1998; Edelman & Duvdevani-Bar, 1997a) provide a computational framework in which such findings can be interpreted in a straightforward fashion. Taken together, these developments in the study of object representation and recognition suggest that direct visualization of the internal representations may be easier than was previously thought. In this paper, we show how fMRI techniques can be used to investigate the internal representation of objects in the human visual cortex. Our initial results reveal that the activation of most voxels in object-related areas remains unaffected by a coarse scrambling of the natural images used as stimuli and that a map of the representation space of object categories in individual subjects can be derived from the distributed pattern of voxel activation in those areas.

Shape-selective stereo processing in human object-related visual areas

Object related areas in the human ventral stream were previously shown to be activated, in a shape‐selective manner, by luminance, motion, and texture cues. We report on the preferential activation of these areas by stereo cues defining shape. To assess the relationship of this activation to object recognition, we employed a perceptual stereo effect, which profoundly affects object recognition. The stimuli consisted of stereo‐defined line drawings of objects that either protruded in front of a flat background (“front”), or were sunk into the background (“back”). Despite the similarity in the local feature structure of the two conditions, object recognition was superior in the “front” compared to the “back” configuration. We measured both recognition rates and fMRI signal from the human visual cortex while subjects viewed these stimuli. The results reveal shape selective activation from images of objects defined purely by stereoscopic cues in the human ventral stream. Furthermore, they show a significant correlation between recognition and fMRI signal in the object‐related occipito‐temporal cortex (lateral occipital complex). Hum. Brain Mapping 15:67–79, 2001.

Abnormal olfactory function demonstrated by manganese-enhanced MRI in mice with experimental neuropsychiatric lupus.

Mice with experimental neuropsychiatric lupus (NPSLE), induced by anti‐ribosomal‐P antibodies, developed depression‐like behavior and a diminished sense of smell. Manganese‐enhanced MRI (MEMRI) allows in vivo mapping of functional neuronal connections in the brain, including the olfactory tract. The aim of this study was to analyze and describe, via the MEMRI technique, the effect of the anti‐ribosomal‐P injection on the olfactory pathway. Twenty mice were intra‐cerebra‐ventricular injected to the right hemisphere: 10 with human anti‐ribosomal‐P antibodies and 10 with human IgG antibodies (control). Depression was addressed by forced swimming test and smell function was evaluated by smelling different concentrations of menthol. MEMRI was used to investigate the olfactory system in these mice. Passive transfer of anti‐ribosomal‐P to mice resulted in a depression‐like behavior, accompanied with a significant deficit in olfactory function. MEMRI of these mice demonstrated significant reduction (P < 0.001) in normalized manganese enhancement ratios of olfactory structures, compared to control mice. We concluded that an impaired olfactory neuronal function in mice with experimental depression, mediated by passive transfer of human‐anti‐ribosomal‐P, can be demonstrated by MEMRI.

Macrophages dictate the progression and manifestation of hypertensive heart disease

BACKGROUND Inflammation has been implicated in the initiation, progression and manifestation of hypertensive heart disease. We sought to determine the role of monocytes/macrophages in hypertension and pressure overload induced left ventricular (LV) remodeling. METHODS AND RESULTS We used two models of LV hypertrophy (LVH). First, to induce hypertension and LVH, we fed Sabra salt-sensitive rats with a high-salt diet. The number of macrophages increased in the hypertensive hearts, peaking at 10 weeks after a high-salt diet. Surprisingly, macrophage depletion, by IV clodronate (CL) liposomes, inhibited the development of hypertension. Moreover, macrophage depletion reduced LVH by 17% (p<0.05), and reduced cardiac fibrosis by 75%, compared with controls (p=0.001). Second, to determine the role of macrophages in the development and progression of LVH, independent of high-salt diet, we depleted macrophages in mice subjected to transverse aortic constriction and pressure overload. Significantly, macrophage depletion, for 3 weeks, attenuated LVH: a 12% decrease in diastolic and 20% in systolic wall thickness (p<0.05), and a 13% in LV mass (p=0.04), compared with controls. Additionally, macrophage depletion reduced cardiac fibrosis by 80% (p=0.006). Finally, macrophage depletion down-regulated the expression of genes associated with cardiac remodeling and fibrosis: transforming growth factor beta-1 (by 80%) collagen type III alpha-1 (by 71%) and atrial natriuretic factor (by 86%). CONCLUSIONS Macrophages mediate the development of hypertension, LVH, adverse cardiac remodeling, and fibrosis. Macrophages, therefore, should be considered as a therapeutic target to reduce the adverse consequences of hypertensive heart disease.

Mast Cell Inhibition Attenuates Myocardial Damage, Adverse Remodeling, and Dysfunction During Fulminant Myocarditis in the Rat

Background: Myocarditis is a life-threatening heart disease characterized by myocardial inflammation, necrosis, and chronic fibrosis. While mast cell inhibition has been suggested to prevent fibrosis in rat myocarditis, little is known about its effectiveness in attenuating cardiac remodeling and dysfunction in myocarditis. Thus, we sought to test the hypothesis that mast cell inhibition will attenuate the inflammatory reaction and associated left ventricular (LV) remodeling and dysfunction after fulminant autoimmune myocarditis. Methods and Results: To induce experimental autoimmune myocarditis, we immunized 30 rats with porcine cardiac myosin (PCM) twice at a 7-day interval. On day 8 animals were randomized into treatment with either an intraperitoneal (IP) injection of 25mg/kg of cromolyn sodium (n = 13) or an equivalent volume (∼0.5 mL IP) of normal saline (n = 11). All animals were scanned by serial echocardiography studies before treatment (baseline echocardiogram) and after 20 days of cromolyn sodium (28 days after immunization). Furthermore, serial cardiac magnetic resonance was performed in a subgroup of 12 animals. After 20 days of treatment (28 days from first immunization), hearts were harvested for histopathological analysis. By echocardiography, cromolyn sodium prevented LV dilatation and attenuated LV dysfunction, compared with controls. Postmortem analysis of hearts showed that cromolyn sodium reduced myocardial fibrosis, as well as the number and size of cardiac mast cells in the inflamed myocardium, compared with controls. Conclusions: Our study suggests that mast cell inhibition with cromolyn sodium attenuates adverse LV remodeling and dysfunction in myocarditis. This mechanism-based therapy is clinically relevant and could improve the outcome of patients at risk for inflammatory cardiomyopathy and heart failure.

A new method to record and control for 2D-movement kinematics during functional magnetic resonance imaging (fMRI).

The recording of movement kinematics during functional magnetic resonance imaging (fMRI) experiments is complicated due to technical constraints of the imaging environment. Nevertheless, to study the functions of brain areas related to motor control, reliable and accurate records of movement trajectories and speed profiles are needed. We present a method designed to record and characterize the kinematic properties of drawing- and handwriting-like forearm movements during fMRI studies by recording pen stroke trajectories. The recording system consists of a translucent plastic board, a plastic pen containing fiber optics and a halogen light power source, a CCD camera, a video monitor and a PC with a video grabber card. Control experiments using a commercially available digitizer tablet have demonstrated the reliability of the data recorded during fMRI. Since the movement tracking signal is purely optical, there is no interaction with the MR (echoplanar) images. Thus, the method allows to obtain movement records with high spatial and temporal resolution which are suitable for the kinematic analysis of hand movements in fMRI studies.

Non-invasive assessment of experimental autoimmune myocarditis in rats using a 3 T clinical MRI scanner

AIMS The aim of this study was to assess the use of a 3 T clinical cardiac magnetic resonance (CMR) scanner to detect injury to the heart in experimental autoimmune myocarditis (EAM). METHODS AND RESULTS The use of 3 T CMR for the detection of cardiac injury was assessed in EAM (n = 55) and control (n = 10) male Lewis rats. Animals were evaluated with serial CMR imaging studies, using a 3 T scanner, and with 2D echocardiography before, and at 2 and 5 weeks after EAM induction. By CMR, regional wall motion abnormalities were noted in seven out of eight rats with myocarditis 5 weeks after induction. Subsequently, the rats developed significant left ventricular (LV) dilatation, wall thickening, and pericardial effusion. Average LV systolic and diastolic volumes increased from 131 ± 10 to 257 ± 20 µL (P = 0.0008), and from 309 ± 14 to 412 ± 24 µL (P < 0.0001), and ejection fraction markedly deteriorated (from 58 ± 2 to 37 ± 5%; P = 0.0003). Areas of fibrosis were located by late gadolinium enhancement (LGE) CMR at the subepicardium, mainly within the anterior, lateral, and inferior walls. The extent and location of LGE were highly correlated (r = 0.94; P < 0.0001) with areas of myocardial fibrosis by histopathology, with 85% sensitivity and 86% specificity. CONCLUSION A clinical 3 T CMR scanner enables accurate detection, quantification, and monitoring of experimental myocarditis in rats, and could be used for translational research to study the pathophysiology of the disease and evaluate novel therapies.

Alteration learning in social anxiety disorder: an fMRI study.

The present study attempts to challenge the orbitofrontal cortex by using a learning paradigm which is specifically subserved by this cortical region. We implemented a version of alternation learning specifically designed for fMRI and assessed the cognitive performance and fMRI response in wide range of social anxiety disorder (SAD) severity (n=15). The main regions that were activated by the alternation learning task included portions of frontal and orbitofrontal cortex as well as the calcarine fissure. Correlations between brain activation and performance of the alternation learning task were found, among other regions, in the left and right orbitofrontal cortex. Highest correlations between degree of activation and the anxiety scores as assessed by the Leibovitch Social Anxiety Scale (LSAS) were obtained in the left temporal region as well as orbitofrontal cortex. This study supports the involvement of the orbitofrontal cortex in emotion and cognitive regulation in SAD.