topographical-estimation-of-visual-population-receptive-fields-by-fmri

Topographical Estimation of Visual Population Receptive Fields by fMRI

Visual cortex is retinotopically organized so that neighboring populations of cells map to neighboring parts of the visual field. Functional magnetic ...

Baylor College of Medicine

Neurons in area V4 of the macaque are generally not selective for direction of motion, as judged from their response to directional stimuli presented after a baseline condition devoid of movement. We used motion adaptation to investigate whether stimulation history influences direction-of-motion selectivity. We found that classically nondirectional V4 neurons develop direction-of-motion selectivity after adaptation, an observation that underscores the dynamic nature of functional cortical architecture.

Neurons in macaque area V4 acquire directional tuning after adaptation to motion stimuli.

Several aspects of cortical organization are thought to remain plastic into adulthood, allowing cortical sensorimotor maps to be modified continuously by experience. This dynamic nature of cortical circuitry is important for learning, as well as for repair after injury to the nervous system. Electrophysiology studies suggest that adult macaque primary visual cortex (V1) undergoes large-scale reorganization within a few months after retinal lesioning, but this issue has not been conclusively settled. Here we applied the technique of functional magnetic resonance imaging (fMRI) to detect changes in the cortical topography of macaque area V1 after binocular retinal lesions. fMRI allows non-invasive, in vivo, long-term monitoring of cortical activity with a wide field of view, sampling signals from multiple neurons per unit cortical area. We show that, in contrast with previous studies, adult macaque V1 does not approach normal responsivity during 7.5 months of follow-up after retinal lesions, and its topography does not change. Electrophysiology experiments corroborated the fMRI results. This indicates that adult macaque V1 has limited potential for reorganization in the months following retinal injury.

Lack of long-term cortical reorganization after macaque retinal lesions.

Simultaneous electroencephalography (EEG)/functional magnetic resonance imaging (fMRI) acquisition can identify the brain networks involved in generating specific EEG patterns. Yet, the combination of these methodologies is hampered by strong artifacts that arise due to electromagnetic interference during magnetic resonance (MR) image acquisition. Here, we report corrections of the gradient-induced artifact in phantom measurements and in experiments with an awake behaving macaque monkey during fMRI acquisition at a magnetic field strength of 4.7 T. Ninety-one percent of the amplitude of a 10 microV, 10 Hz phantom signal could successfully be recovered without phase distortions. Using this method, we were able to extract the monkey EEG from scalp recordings obtained during MR image acquisition. Visual evoked potentials could also be reliably identified. In conclusion, simultaneous EEG/fMRI acquisition is feasible in the macaque monkey preparation at 4.7 T and holds promise for investigating the neural processes that give rise to particular EEG patterns.

Simultaneous EEG and fMRI in the macaque monkey at 4.7 Tesla.

Intravascular contrast agents are used in functional magnetic resonance imaging to obtain cerebral blood volume (CBV) maps of cortical activity. Cerebral blood volume imaging with MION (monocrystalline-iron-oxide-nanoparticles) increases the sensitivity of functional imaging compared with the blood oxygenation level-dependent (BOLD) signal (Leite et al, 2002; Mandeville et al, 1998; Vanduffel et al, 2001). It therefore represents an attractive method for obtaining detailed maps of cortical organization (Vanduffel et al, 2001; Zhao et al, 2005). However, it remains to be determined how the spatial profile of CBV maps of cortical activity derived with MION compares with the profile of BOLD activation maps under a variety of different stimulation conditions. We used several stimulation paradigms to compare the spatial specificity of CBV versus BOLD activation maps in macaque area V1 at 4.7 T. We observed that: (1) CBV modulation is relatively stronger in deep cortical layers compared with BOLD, in agreement with studies in cats (Harel et al, 2006) and rodents (Lu et al, 2004; Mandeville and Marota, 1999) and (2) surprisingly, under large surround stimulation conditions, CBV maps extend along the cortical surface to cover large (>10 mm) regions of the cortex that are devoid of significant BOLD modulation. We conclude that the spatial profiles of BOLD and CBV activity maps do not coregister across all stimulus conditions, and therefore do not necessarily represent equivalent transforms of the neural response. Cerebral blood volume maps should be interpreted with care, in the context of the particular experimental paradigm applied.

Spatial specificity of BOLD versus cerebral blood volume fMRI for mapping cortical organization.

Creating focal lesions in primary visual cortex (V1) provides an opportunity to study the role of extra-geniculo-striate pathways for activating extrastriate visual cortex. Previous studies have shown that more than 95% of neurons in macaque area V2 and V3 stop firing after reversibly cooling V1. However, no studies on long term recovery in areas V2, V3 following permanent V1 lesions have been reported in the macaque. Here we use macaque fMRI to study area V2, V3 activity patterns from 1 to 22 months after lesioning area V1. We find that visually driven BOLD responses persist inside the V1-lesion projection zones (LPZ) of areas V2 and V3, but are reduced in strength by approximately 70%, on average, compared to pre-lesion levels. Monitoring the LPZ activity over time starting one month following the V1 lesion did not reveal systematic changes in BOLD signal amplitude. Surprisingly, the retinotopic organization inside the LPZ of areas V2, V3 remained similar to that of the non-lesioned hemisphere, suggesting that LPZ activation in V2, V3 is not the result of input arising from nearby (non-lesioned) V1 cortex. Electrophysiology recordings of multi-unit activity corroborated the BOLD observations: visually driven multi-unit responses could be elicited inside the V2 LPZ, even when the visual stimulus was entirely contained within the scotoma induced by the V1 lesion. Restricting the stimulus to the intact visual hemi-field produced no significant BOLD modulation inside the V2, V3 LPZs. We conclude that the observed activity patterns are largely mediated by parallel, V1-bypassing, subcortical pathways that can activate areas V2 and V3 in the absence of V1 input. Such pathways may contribute to the behavioral phenomenon of blindsight.

Visually driven activation in macaque areas V2 and V3 without input from the primary visual cortex.

This review argues that one reason why a functional visuo-cortical prosthetic device has not been developed to restore even minimal vision to blind individuals is because there is no animal model to guide the design and development of such a device. Over the past 8 years we have been conducting electrical microstimulation experiments on alert behaving monkeys with the aim of better understanding how electrical stimulation of the striate cortex (area V1) affects oculo- and skeleto-motor behaviors. Based on this work and upon review of the literature, we arrive at several conclusions: (1) As with the development of the cochlear implant, the development of a visuo-cortical prosthesis can be accelerated by using animals to test the perceptual effects of microstimulating V1 in intact and blind monkeys. (2) Although a saccade-based paradigm is very convenient for studying the effectiveness of delivering stimulation to V1 to elicit saccadic eye movements, it is less ideal for probing the volitional state of monkeys, as they perceive electrically induced phosphenes. (3) Electrical stimulation of V1 can delay visually guided saccades generated to a punctate target positioned in the receptive field of the stimulated neurons. We call the region of visual space affected by the stimulation a delay field. The study of delay fields has proven to be an efficient way to study the size and shape of phosphenes generated by stimulation of macaque V1. (4) An alternative approach to ascertain what monkeys see during electrical stimulation of V1 is to have them signal the detection of current with a lever press. Monkeys can readily detect currents of 1-2 microA delivered to V1. In order to evoke featured phosphenes currents of under 5 microA will be necessary. (5) Partially lesioning the retinae of monkeys is superior to completely lesioning the retinae when determining how blindness affects phosphene induction. We finish by proposing a future experimental paradigm designed to determine what monkeys see when stimulation is delivered to V1, by assessing how electrical fields generated through multiple electrodes interact for the production of phosphenes, and by depicting a V1 circuit that could mediate electrically induced phosphenes.

Microstimulation of visual cortex to restore vision.

It is important to understand the balance between cortical plasticity and stability in various systems and across spatial scales in the adult brain. Here we review studies of adult plasticity in primary visual cortex (V1), which has a key role in distributing visual information. There are claims of plasticity at multiple spatial scales in adult V1, but a number of inconsistencies in the supporting data raise questions about the extent and nature of such plasticity. Our understanding of the extent of plasticity in V1 is further limited by a lack of quantitative models to guide the interpretation of the data. These problems limit efforts to translate research findings about adult cortical plasticity into significant clinical, educational and policy applications.

Plasticity and stability of visual field maps in adult primary visual cortex.

PURPOSE: Animal models are powerful tools to broaden our understanding of disease mechanisms and to develop future treatment strategies. Here we present detailed structural and functional findings of a rhesus macaque suffering from a naturally occurring bilateral macular dystrophy (BMD), partial optic atrophy and corresponding reduction of central V1 signals in visual fMRI experiments when compared to data in a healthy macaque (CTRL) of similar age. METHODS: Retinal imaging included infrared and autofluorescence recordings, fluorescein and indocyanine green angiography and spectral domain optical coherence tomography (OCT) on the Spectralis HRA + OCT platform. Electroretinography included multifocal and Ganzfeld-ERG recordings. Animals were killed and eyes analyzed by immunohistochemistry. RESULTS: Angiography showed reduced macular vascularization with significantly larger foveal avascular zones (FAZ) in the affected animal (FAZ(BMD) = 8.85 mm(2) vs. FAZ(CTRL) = 0.32 mm(2)). OCT showed bilateral thinning of the macula within the FAZ (total retinal thickness, TRT(BMD) = 174 ± 9 µm) and partial optic nerve atrophy when compared to control (TRT(CTRL) = 303 ± 45 µm). Segmentation analysis revealed that inner retinal layers were primarily affected (inner retinal thickness, IRT(BMD) = 33 ± 9 µm vs. IRT(CTRL) = 143 ± 45 µm), while the outer retina essentially maintained its thickness (ORT(BMD) = 141 ± 7 µm vs. ORT(CTRL) = 160 ± 11 µm). Altered macular morphology corresponded to a preferential reduction of central signals in the multifocal electroretinography and to a specific attenuation of cone-derived responses in the Ganzfeld electroretinography, while rod function remained normal. CONCLUSION: We provided detailed characterization of a primate macular disorder. This study aims to stimulate awareness and further investigation in primates with macular disorders eventually leading to the identification of a primate animal model and facilitating the preclinical development of therapeutic strategies.

Detailed functional and structural characterization of a macular lesion in a rhesus macaque.

The neonatal intraventricular injection of adeno-associated virus has been shown to transduce neurons widely throughout the brain, but its full potential for experimental neuroscience has not been adequately explored. We report a detailed analysis of the method's versatility with an emphasis on experimental applications where tools for genetic manipulation are currently lacking. Viral injection into the neonatal mouse brain is fast, easy, and accesses regions of the brain including the cerebellum and brainstem that have been difficult to target with other techniques such as electroporation. We show that viral transduction produces an inherently mosaic expression pattern that can be exploited by varying the titer to transduce isolated neurons or densely-packed populations. We demonstrate that the expression of virally-encoded proteins is active much sooner than previously believed, allowing genetic perturbation during critical periods of neuronal plasticity, but is also long-lasting and stable, allowing chronic studies of aging. We harness these features to visualise and manipulate neurons in the hindbrain that have been recalcitrant to approaches commonly applied in the cortex. We show that viral labeling aids the analysis of postnatal dendritic maturation in cerebellar Purkinje neurons by allowing individual cells to be readily distinguished, and then demonstrate that the same sparse labeling allows live in vivo imaging of mature Purkinje neurons at a resolution sufficient for complete analytical reconstruction. Given the rising availability of viral constructs, packaging services, and genetically modified animals, these techniques should facilitate a wide range of experiments into brain development, function, and degeneration.

Viral transduction of the neonatal brain delivers controllable genetic mosaicism for visualising and manipulating neuronal circuits in vivo.

Emerging subspecialties: neuroinformatics.

We introduce a new method for measuring visual population receptive fields (pRF) with functional magnetic resonance imaging (fMRI). The pRF structure is modeled as a set of weights that can be estimated by solving a linear model that predicts the Blood Oxygen Level-Dependent (BOLD) signal using the stimulus protocol and the canonical hemodynamic response function. This method does not make a priori assumptions about the specific pRF shape and is therefore a useful tool for uncovering the underlying pRF structure at different spatial locations in an unbiased way. We show that our method is more accurate than a previously described method (Dumoulin and Wandell, 2008) which directly fits a 2-dimensional isotropic Gaussian pRF model to predict the fMRI time-series. We demonstrate that direct-fit models do not fully capture the actual pRF shape, and can be prone to pRF center mislocalization when the pRF is located near the border of the stimulus space. A quantitative comparison demonstrates that our method outperforms the direct-fit methods in the pRF center modeling by achieving higher explained variance of the BOLD signal. This was true for direct-fit isotropic Gaussian, anisotropic Gaussian, and difference of isotropic Gaussians model. Importantly, our model is also capable of exploring a variety of pRF properties such as surround suppression, receptive field center elongation, orientation, location and size. Additionally, the proposed method is particularly attractive for monitoring pRF properties in the visual areas of subjects with lesions of the visual pathways, where it is difficult to anticipate what shape the reorganized pRF might take. Finally, the method proposed here is more efficient in computation time than direct-fit methods, which need to search for a set of parameters in an extremely large searching space. Instead, this method uses the pRF topography to constrain the space that needs to be searched for the subsequent modeling.

A new method for estimating population receptive field topography in visual cortex.

The visual field is retinotopically represented in early visual areas. It has been suggested that when adult primary visual cortex (V1) is deprived of normal retinal input it is capable of large-scale reorganisation, with neurons inside the lesion projection zone (LPZ) being visually driven by inputs from intact retinal regions. Early functional magnetic resonance imaging (fMRI) studies in humans with macular degeneration (MD) report > 1 cm spread of activity inside the LPZ border, whereas recent results report no shift of the LPZ border. Here, we used fMRI population receptive field measurements to study, for the first time, the visual cortex organisation of one macaque monkey with MD and to compare it with normal controls. Our results showed that the border of the V1 LPZ remained stable, suggesting that the deafferented area V1 zone of the MD animal has limited capacity for reorganisation. Interestingly, the pRF size of non-deafferented V1 voxels increased slightly (~20% on average), although this effect appears weaker than that in previous single-unit recording reports. Area V2 also showed limited reorganisation. Remarkably, area V5/MT of the MD animal showed extensive activation compared to controls stimulated over the part of the visual field that was spared in the MD animal. Furthermore, population receptive field size distributions differed markedly in area V5/MT of the MD animal. Taken together, these results suggest that V5/MT has a higher potential for reorganisation after MD than earlier visual cortex.

Visual cortex organisation in a macaque monkey with macular degeneration.

MECP2 duplication syndrome is a childhood neurological disorder characterized by intellectual disability, autism, motor abnormalities, and epilepsy. The disorder is caused by duplications spanning the gene encoding methyl-CpG-binding protein-2 (MeCP2), a protein involved in the modulation of chromatin and gene expression. MeCP2 is thought to play a role in maintaining the structural integrity of neuronal circuits. Loss of MeCP2 function causes Rett syndrome and results in abnormal dendritic spine morphology and decreased pyramidal dendritic arbor complexity and spine density. The consequences of MeCP2 overexpression on dendritic pathophysiology remain unclear. We used in vivo two-photon microscopy to characterize layer 5 pyramidal neuron spine turnover and dendritic arborization as a function of age in transgenic mice expressing the human MECP2 gene at twice the normal levels of MeCP2 (Tg1; Collins et al., 2004). We found that spine density in terminal dendritic branches is initially higher in young Tg1 mice but falls below control levels after postnatal week 12, approximately correlating with the onset of behavioral symptoms. Spontaneous spine turnover rates remain high in older Tg1 animals compared with controls, reflecting the persistence of an immature state. Both spine gain and loss rates are higher, with a net bias in favor of spine elimination. Apical dendritic arbors in both simple- and complex-tufted layer 5 Tg1 pyramidal neurons have more branches of higher order, indicating that MeCP2 overexpression induces dendritic overgrowth. P70S6K was hyperphosphorylated in Tg1 somatosensory cortex, suggesting that elevated mTOR signaling may underlie the observed increase in spine turnover and dendritic growth.

Dendritic arborization and spine dynamics are abnormal in the mouse model of MECP2 duplication syndrome.

Shared, trial-to-trial variability in neuronal populations has a strong impact on the accuracy of information processing in the brain. Estimates of the level of such noise correlations are diverse, ranging from 0.01 to 0.4, with little consensus on which factors account for these differences. Here we addressed one important factor that varied across studies, asking how anesthesia affects the population activity structure in macaque primary visual cortex. We found that under opioid anesthesia, activity was dominated by strong coordinated fluctuations on a timescale of 1-2 Hz, which were mostly absent in awake, fixating monkeys. Accounting for these global fluctuations markedly reduced correlations under anesthesia, matching those observed during wakefulness and reconciling earlier studies conducted under anesthesia and in awake animals. Our results show that internal signals, such as brain state transitions under anesthesia, can induce noise correlations but can also be estimated and accounted for based on neuronal population activity.

State dependence of noise correlations in macaque primary visual cortex.

Injury to the primary visual cortex (V1) typically leads to loss of conscious vision in the corresponding, homonymous region of the contralateral visual hemifield (scotoma). Several studies suggest that V1 is highly plastic after injury to the visual pathways, whereas others have called this conclusion into question. We used functional magnetic resonance imaging (fMRI) to measure area V1 population receptive field (pRF) properties in five patients with partial or complete quadrantic visual field loss as a result of partial V1+ or optic radiation lesions. Comparisons were made with healthy controls deprived of visual stimulation in one quadrant ["artificial scotoma" (AS)]. We observed no large-scale changes in spared-V1 topography as the V1/V2 border remained stable, and pRF eccentricity versus cortical-distance plots were similar to those of controls. Interestingly, three observations suggest limited reorganization: (i) the distribution of pRF centers in spared-V1 was shifted slightly toward the scotoma border in 2 of 5 patients compared with AS controls; (ii) pRF size in spared-V1 was slightly increased in patients near the scotoma border; and (iii) pRF size in the contralesional hemisphere was slightly increased compared with AS controls. Importantly, pRF measurements yield information about the functional properties of spared-V1 cortex not provided by standard perimetry mapping. In three patients, spared-V1 pRF maps overlapped significantly with dense regions of the perimetric scotoma, suggesting that pRF analysis may help identify visual field locations amenable to rehabilitation. Conversely, in the remaining two patients, spared-V1 pRF maps failed to cover sighted locations in the perimetric map, indicating the existence of V1-bypassing pathways able to mediate useful vision.

Population receptive field analysis of the primary visual cortex complements perimetry in patients with homonymous visual field defects.

The small GTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processes including synapse development. While precise spatiotemporal regulation of Rac1 is necessary for its function, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs) to act in concert to regulate Rac1 signaling. Here, we identify a regulatory complex composed of a Rac-GEF (Tiam1) and a Rac-GAP (Bcr) that cooperate to control excitatory synapse development. Disruption of Bcr function within this complex increases Rac1 activity and dendritic spine remodeling, resulting in excessive synaptic growth that is rescued by Tiam1 inhibition. Notably, EphB receptors utilize the Tiam1-Bcr complex to control synaptogenesis. Following EphB activation, Tiam1 induces Rac1-dependent spine formation, whereas Bcr prevents Rac1-mediated receptor internalization, promoting spine growth over retraction. The finding that a Rac-specific GEF/GAP complex is required to maintain optimal levels of Rac1 signaling provides an important insight into the regulation of small GTPases.

Article	Year
Neurons in macaque area V4 acquire directional tuning after adaptation to motion stimuli. Nature neuroscience\| PubMed ID: 15834417	2005
Lack of long-term cortical reorganization after macaque retinal lesions. Nature\| PubMed ID: 15902248	2005
Simultaneous EEG and fMRI in the macaque monkey at 4.7 Tesla. Magnetic resonance imaging\| PubMed ID: 16677938	2006
Spatial specificity of BOLD versus cerebral blood volume fMRI for mapping cortical organization. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism\| PubMed ID: 17213863	2007
Visually driven activation in macaque areas V2 and V3 without input from the primary visual cortex. PloS one\| PubMed ID: 19436733	2009
Microstimulation of visual cortex to restore vision. Progress in brain research\| PubMed ID: 19660667	2009
Plasticity and stability of visual field maps in adult primary visual cortex. Nature reviews. Neuroscience\| PubMed ID: 19904279	2009
Detailed functional and structural characterization of a macular lesion in a rhesus macaque. Documenta ophthalmologica. Advances in ophthalmology\| PubMed ID: 22923360	2012
Viral transduction of the neonatal brain delivers controllable genetic mosaicism for visualising and manipulating neuronal circuits in vivo. The European journal of neuroscience\| PubMed ID: 23347239	2013
Emerging subspecialties: neuroinformatics. Neurology\| PubMed ID: 23569003	2013
A new method for estimating population receptive field topography in visual cortex. NeuroImage\| PubMed ID: 23684878	2013
Visual cortex organisation in a macaque monkey with macular degeneration. The European journal of neuroscience\| PubMed ID: 24033706	2013
Dendritic arborization and spine dynamics are abnormal in the mouse model of MECP2 duplication syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 24336718	2013
State dependence of noise correlations in macaque primary visual cortex. Neuron\| PubMed ID: 24698278	2014
Population receptive field analysis of the primary visual cortex complements perimetry in patients with homonymous visual field defects. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 24706881	2014
Dynamic control of excitatory synapse development by a Rac1 GEF/GAP regulatory complex. Developmental cell\| PubMed ID: 24960694	2014

Stelios M. Smirnakis

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