Name: measuring connectivity in the primary visual pathway in human albinism using diffusion tensor imaging and tractography
Uploaded: 2016-08-11T13:00:00
Description: Watch this Scientific Journal Video about Measuring Connectivity in the Primary Visual Pathway in Human Albinism Using Diffusion Tensor Imaging and Tractography at JoVE.com

The work is supported in part by the Natural Sciences and Engineering Research Council of Canada (NSERC). The authors thank the participants, Dr. Rick Thompson for his assistance in recruiting the albinism patients, Denis Romanovsky for his help running some of the analyses and modifying a figure, M&#243;nica Giraldo Chica for her knowledge and advice with tractography, Joy Williams for her help in MRI acquisition, and Aman Goyal for his MRI analysis expertise.

Ethics Statement: The current research study has been approved by the Human Participants Review Committee (HPRC) at York University, Toronto. All participants gave informed written consent.
1. Subject Preparation
Note: Eleven participants with OCA, aged 36 &#177; 4 years (6 females) were compared to ten age-matched controls, aged 32 &#177; 4 years (6 females). Participant history is recorded in Table 1.
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	<li>Montoliu, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Increasing+the+complexity:+new+genes+and+new+types+of+albinism.">Increasing the complexity: new genes and new types of albinism.</a> Pigment Cell Melanoma Res. 27, 11-18 (2013).</li><li>Martinez-Garcia, M., Montoliu, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Albinism+in+Europe.">Albinism in Europe.</a> J. Dermatol. 40 (5), 319-324 (2013).</li><li>Gottlob, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Albinism:+a+model+of+adaptation+of+the+brain+in+congenital+visual+disorders.">Albinism: a model of adaptation of the brain in congenital visual disorders.</a> Br. J. Opthalmol. 91 (4), 411-412 (2007).</li><li>Wilk, M. 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Altered WM and, more specifically, decreased connectivity in albinism compared to controls were expected. Thus, the reduced FA in the right hemisphere of albinism compared to controls as well as the decreased connectivity in male patients with albinism reported here are in line with our prediction. Gender and hemisphere effects are not completely clear, although research on the healthy brain that suggests decreased WM complexity in the left hemisphere of males compared to females30-31 could explain some of the...

Albinism is a genetic condition primarily characterized by overt hypopigmentation observed in affected individuals. It is caused by inherited mutations to genes involved in melanin synthesis1. Albinism appears in two main forms: oculo-cutaneous albinism (OCA), an autosomal recessive trait presenting both ocular and cutaneous features; and ocular albinism (OA), an X-linked trait more prevalent in males and characterized primarily by the ocular symptoms2. Melanin in the retinal pigment epithelium (RPE) is crucial for proper development of the central visual pathway. Its absence in albinism therefore results in visual impairments, including photophobia, nystagmus, reduced visual acuity and loss of binocular vision2-3. Visual acuity has been linked to foveal morphology, which is altered in albinism4. In humans, a retinal line of decussation lies along the nasotemporal border through the fovea, with fibers from nasal retina crossing to the other hemisphere and those from temporal retina extending ipsilaterally. The degree of reduced visual function in albinism has been linked to the level of hypopigmentation. Specifically, pigmentation is inversely proportional to the shift into temporal retina of the line of decussation5. As a result of the shift in line of decussation into the temporal retina, crossing of optic nerve fibers is increased&#160;&#8211; a characteristic common across all species3.
Structural MRI studies on humans have shown narrower optic chiasms in albinism compared to controls, which is likely the result of increased crossing of RGCs observed in albinism6-8. The retina and optic chiasm express axonal guidance cues such as Eph family receptors and their ligands9 and are therefore candidate sites for misrouting10.
A study on monkeys with induced glaucoma revealed a significant decrease in the number of LGN parvalbumin-immunoreactive relay neurons and LGN volume11. This suggests a correlation between LGN size and the number of white matter (WM) trajectories traveling through the OR to V1. A post mortem study on human albinism also revealed smaller LGN with fused M and P layers12. High-resolution structural MRI confirmed significant reduction in volume of LGN in albinism8. Taken together, these findings suggest that decreased LGN volume may result in a reduced number of neurons in the LGN, and in turn in decreased connectivity between LGN and V1.
Examining patterns of anatomical connectivity in humans has been limited. Dissection, tracer injection and lesion induction are invasive techniques that can only be used post mortem, and usually involve a very small number of patients. Previous studies using carbocyanine dye DiI injections demonstrated neuronal connectivity between V1 and V2 (secondary visual cortex)13, as well as within the hippocampal complex in aldehyde-fixed post-mortem human brains14. Labeling fibers in this way is restricted to distances of only tens of millimeters from the point of injection14. Diffusion tensor imaging, DTI, is an MRI modality developed in early-mid 1990s to identify fiber tract direction and organization. It is a non-invasive method that allows mapping of large WM pathways in the living brain. DTI is sensitive to the diffusion of water molecules in biological tissue15. In the brain, the diffusion of water is anisotropic (uneven) due to barriers such as membranes and myelin. WM has high diffusion anisotropy, meaning the diffusion is greater parallel to than perpendicular to the orientation of the fibers16. Fractional anisotropy (FA) is a scalar quantity that describes the preference of molecules to diffuse in an anisotropic manner. FA values range from 0-1, from low to high anisotropy (cerebrospinal fluid (CSF) &#60;gray matter (GM) &#60;WM)16.
Streamline (deterministic) and probabilistic fiber tracking are two different algorithms for 3D path reconstruction. Deterministic tractography uses a line propagation method, connecting neighboring voxels in a defined seed region. Two stop criteria used in this algorithm are the turning angle and the FA value. Therefore, tract tracing between neighbouring voxels is unlikely at large turning angles. The algorithm would therefore also progresses only if the FA in a voxel exceeds a specific threshold, limiting its effectiveness in accurately defining pathways near gray matter, where anisotropy drops. Probabilistic tractography, on the other hand, yields a connectivity map describing the probability of a voxel to be part of a tract between two regions of interest (ROIs) and thus progresses into gray matter such as V117. Using this MRI application, key WM structures like the OR can be delineated, as shown in previous studies18-20.
This study therefore uses diffusion data and tractography to explore the effect of axonal misrouting on retino-geniculo-cortical connectivity. Based on previously reported reductions in LGN volumes in human albinism8, we predict that fiber projections from LGN to V1 are also reduced (Figure 1).

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Magnetom Tim Trio 3T MRI</td>
			<td>Siemens (Erlangen, Germany)</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>FMRIB&#8217;s Software Library (FSL)</td>
			<td></td>
			<td></td>
			<td>http://www.fmrib.ox.ac.uk/fsl/</td>
		</tr>
		<tr>
			<td>FreeSurfer</td>
			<td></td>
			<td></td>
			<td>http://surfer.nmr.mgh.harvard.edu</td>
		</tr>
		<tr>
			<td>DSI Studio</td>
			<td></td>
			<td></td>
			<td>http://dsi-studio.labsolver.org</td>
		</tr>
		<tr>
			<td>SPSS</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

measuring connectivity in the primary visual pathway in human albinism using diffusion tensor imaging and tractography

In albinism, the number of ipsilaterally projecting retinal ganglion cells (RGCs) is significantly reduced. The retina and optic chiasm have been proposed as candidate sites for misrouting. Since a correlation between the number of lateral geniculate nucleus (LGN) relay neurons and LGN size has been shown, and based on previously reported reductions in LGN volumes in human albinism, we suggest that fiber projections from LGN to the primary visual cortex (V1) are also reduced. Studying structural differences in the visual system of albinism can improve the understanding of the mechanism of misrouting and subsequent clinical applications. Diffusion data and tractography are useful for mapping the OR (optic radiation). This manuscript describes two algorithms for OR reconstruction in order to compare brain connectivity in albinism and controls.An MRI scanner with a 32-channel head coil was used to acquire structural scans. A T1-weighted 3D-MPRAGE sequence with 1 mm3 isotropic voxel size was used to generate high-resolution images for V1 segmentation. Multiple proton density (PD) weighted images were acquired coronally for right and left LGN localization. Diffusion tensor imaging (DTI) scans were acquired with 64 diffusion directions. Both deterministic and probabilistic tracking methods were run and compared, with LGN as the seed mask and V1 as the target mask. Though DTI provides relatively poor spatial resolution, and accurate delineation of OR may be challenging due to its low fiber density, tractography has been shown to be advantageous both in research and clinically. Tract based spatial statistics (TBSS) revealed areas of significantly reduced white matter integrity within the OR in patients with albinism compared to controls. Pairwise comparisons revealed a significant reduction in LGN to V1 connectivity in albinism compared to controls. Comparing both tracking algorithms revealed common findings, strengthening the reliability of the technique.

This section provides a summary of results obtained using two different algorithms of tractography, deterministic and probabilistic. LGN volumes in PD space in which masks were originally drawn, as well as in all other spaces used in this study, are recorded in Table 2, and LGN tracing is illustrated in Figure 4. The results reported here are based on runs that used a standard sphere as the LGN ROI. Standard LGN volume was 461 mm3</s...

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Measuring Connectivity in the Primary Visual Pathway in Human Albinism Using Diffusion Tensor Imaging and Tractography

This manuscript describes deterministic and probabilistic algorithms for white matter (WM) reconstruction, used to examine differences in optic radiation (OR) connectivity between albinism and controls. Although probabilistic tractography follows the true course of nerve fibers more closely, deterministic tractography was run to compare the reliability and reproducibility of both techniques.

In albinism, the number of ipsilaterally projecting retinal ganglion cells (RGCs) is significantly reduced. The retina and optic chiasm have been proposed ...

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Magnetic resonance imaging (MRI) is the state of the art approach for assessing the status of the spinal cord noninvasively, and can be used as a ...

Simultaneous ex vivo Functional Testing of Two Retinas by in vivo Electroretinogram System

Simultaneous ex vivo Functional Testing of Two Retinas by in vivo Electroretinogram System

An In vivo electroretinogram (ERG) signal is composed of several overlapping components originating from different retinal cell types, as well as noise ...

Assessing Primary Neurogenesis in Xenopus Embryos Using Immunostaining

Assessing Primary Neurogenesis in Xenopus Embryos Using Immunostaining

Primary neurogenesis is a dynamic and complex process during embryonic development that sets up the initial layout of the central nervous system. During ...

Analyzing Dendritic Morphology in Columns and Layers

In many regions of the central nervous systems, such as the fly optic lobes and the vertebrate cortex, synaptic circuits are organized in layers and ...

Imaging Neural Activity in the Primary Somatosensory Cortex Using Thy1-GCaMP6s Transgenic Mice

Imaging Neural Activity in the Primary Somatosensory Cortex Using Thy1-GCaMP6s Transgenic Mice

The mammalian brain exhibits marked symmetry across the sagittal plane. However, detailed description of neural dynamics in symmetric brain regions in ...

Analyzing Neural Activity and Connectivity Using Intracranial EEG Data with SPM Software

Measuring neural activity and connectivity associated with cognitive functions at high spatial and temporal resolutions is an important goal in cognitive ...

Diffusion Tensor Magnetic Resonance Imaging in Chronic Spinal Cord Compression

Chronic spinal cord compression is the most common cause of spinal cord impairment in patients with nontraumatic spinal cord damage. Conventional magnetic ...