Educational Exhibit NJR 2011; 1(1):78 – 91;Available online at www.nranepal.org

Insights into the Connectivity of the Human Using DTI

S Kollias

Institute of Neuroradiology, University Hospital of Zurich, Switzerland.

Abstract

Diffusion tensor imaging (DTI) is a neuroimaging MR technique, which allows in vivo and non-destructive visualization of myeloarchitectonics in the neural tissue and provides quantitative estimates of WM integrity by measuring molecular diffusion. It is based on the phenomenon of diffusion anisotropy in the nerve tissue, in that water molecules diffuse faster along the neural fibre direction and slower in the fibre-transverse direction. On the basis of their topographic location, trajectory, and areas that interconnect the various fibre systems of the mammalian brain are divided into commissural, projectional and association fibre systems. DTI has opened an entirely new window on the anatomy with both clinical and scientific applications. Its utility is found in both the localization and the quantitative assessment of specific neuronal pathways. The potential of this technique to address connectivity in the is not without a few methodological limitations. A wide spectrum of diffusion imaging paradigms and computational tractography algorithms has been explored in recent years, which established DTI as promising new avenue, for the non-invasive in vivo mapping of structural connectivity at the macroscale level. Further improvements in the spatial resolution of DTI may allow this technique to be applied in the near future for mapping connectivity also at the mesoscale level.

Key words: Diffusion Tensor Imaging, human brain, white matter anatomy

Definitions diffusion coefficients for the cellular compartments. Diffusion tensor imaging (DTI) is a neuroimaging MR technique, which allows The anisotropic diffusion of coherently in vivo and non-destructive visualization of oriented axonal fibers can be exploited for myeloarchitectonics in the neural tissue and anatomic mapping and quantitative provides quantitative estimates of WM characterization of white matter tracts. This integrity by measuring molecular diffusion. is done by depicting and measuring the It is based in the phenomenon of diffusion diffusion tensor within the imaging voxels of anisotropy in the nerve tissue, in that water the diffusion acquisition. Provided that 6 molecules diffuse faster along the neural diffusion-encoded images sets are acquired fiber direction and slower in the fiber- along noncollinear directions, the diffusion transverse direction (Fig. 1) The hindrance of tensor can be calculated. Diffusion tensor, is water diffusion in white matter is putative ______due to the diffusion barrier represented by Correspondence to: Prof. Dr. med. Spyros the cell membrane and the sheath Kollias, Chief of MRI, Institute of however, it is governed by several other, yet Neuroradiology, University Hospital of not completely elucidated, parameters related Zurich, Switzerland to the diffusion physics and biophysical E-mail: [email protected] properties of the tissue such as, the cell membrane permeability and the free

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Figure 1: Schematic representation of water Figure 2: graphic representation of the diffusion proton anisotropic diffusion along the long axis of ellipsoid. The long axis of the ellipsoid indicates myelinated white mater fibers. The displacement the preferred direction of diffusion. Its value varies of the protons in the 3D space is faster along the from 0 (isotropic diffusion) up to maximum 1, direction of the fibers. Estimation of the direction indicating perfectly linear (anisotropic) diffusion of faster diffusion indicates the along the primary eigenvector. a mathematical model of the 3D pattern of The fiber orientation information inherent in diffusion trsjectories (a 3X3 matrix of the primary eigenvector can be visualized on vectors) within the white matter tracts. The 2D images by assigning a color to each of three principal axes of the diffusion tensor the 3 mutually orthogonal axes, typically red are termed the eigenvectors. The largest for left-right, green for anteroposterior and eigenvector is termed the primary blue for superior-inferior. The orientation of eigenvector and indicates the direction and the primary eigenvector within each voxel magnitude of greatest water diffusion. It is gives the color in the specific voxel (Fig. 3). important for fiber tractography because it This way, white matter tissue can be further indicates the orientation of axonal fiber parcellated into specific white matter tracts bundles. The degree of directionality of according to their orientation in the 3D space intravoxel diffusivity is measured by the (Fig. 4). fractional anisotropy (FA) index. When the The orientation information can also be used value of the primary eigenvector is higher for 3D fiber tracking of specific white matter than the values of the second and third tracts (Fig 5). The objective of fiber tracking eigenvectors the FA will be high, indicating is to determine intervoxel connectivity by diffusion along a preferred direction. The using the diffusion tensor of each voxel to graphic representation of the three follow an axonal tract in 3D from voxel to eigenvectors corresponds to a prolate shape voxel through the neural tissue. Several fiber of diffusion ellipsoid with the long axis of tracking algorithms have been developed the ellipsoid indicating the preferred over the last years for anatomical direction of diffusion (Fig. 2). Its value reconstruction and quantitative varies from 0 (isotropic diffusion) up to characterization of white matter tracts. maximum 1, indicating perfectly linear Grossly, these algorithms can be divided into diffusion along the primary eigenvector. deterministic and probabilistic methods. Deterministic, “streamline” tractography, Visualization of white matter architecture infers the continuity of fiber bunbles from using DTI voxel-to-voxel. User-defined regions of interest, as well as constrains on the maximum turning angle of the fiber

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trajectory between voxels and on the minimum FA within a voxel for propagation of the streamline, are applied to restrict the fiber tracts to a specific pathway based on prior anatomical knowledge and thus to create realistic representations of the white matter pathways. Probabilistic methods, incorporate the expected uncertainty into the tracking algorithm and can be used to produce a connectivity metric for each voxel. They focus on the connectivity probabilities rather the actual WM pathways between Figure 4: 2D DTI overlaid on a coronal inversion voxels. Definition of a “probability density recovery (IR) anatomical MR image. Large white function” allows estimation of the matter tracts of the projectional (blue), uncertaintity of both intravoxel orientation commissural (red) and association (green) fiber systems are distinguished from each other on the and its propagation. These algorithms have DT image. the potential to delineate a greater portion of a white matter tract.

Figure 3: 2D DTI color-coded according the orientation in the 3D space of the primary eigenvector within each voxel of the image (red for left-right, green for anterior-posterior and blue for Figure 5: 3D reconstruction of fiber systems using superior-inferior). The direction of the main the Fiber Assignment by Continuous Tracking eigenvector indicates the fiber orientation within (FACT) algorithm. Based on the localization and the specific voxel. the specific main orientation we can virtually reconstruct individual fiber systems of the WM in great detail. We indentify the mediolaterally oriented commisural (red) the Methods to improve determination of the vertically oriented projectional systems of the diffusion tensor corona radiata and internal caspule (blue) and the anteroposterior oriented long Much progress has also been achieved over systems of the superior occipito-frontal fasciculus and arcuate fasciculus (green). the last years in improving the acquisition schemes of DTI data collection for better characterization of the water molecule (DSI) although, this approach is time diffusion. These include: a) increasing the consuming and difficult to transfer in the angular resolution of the diffusion- clinical setting, c) performing measurements sensitizing gradients, b) performing a direct at many directions but one gradient strength measurement of water diffusion in all only, referred as Q-ball imaging, with an directions and at different gradient strengths, acquisition time more compatible with referred to as Diffusion Spectrum Imaging clinical requirements. Certainly, the quality

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of the DTI is greatly facilitated by the use of information between the cerebral higher field strength magnets (3-7 T), the use hemispheres. It was demonstrated that of specialized surface coils and the anterior and body callosal connections are development of parallel imaging acquisition essential to perform temporally independent schemes. bimanual finger movements, whereas the The clinical and scientific utility of DTI fiber posterior corpus callosum plays an important tracking is found not only in the anatomical role in visual and visuospatial integration. delineation and localization of specific Moreover, CC plays an important role higher neuronal pathways but also in their order cognition including social, attentional quantitative assessment. Quantitative and emotional well functioning and has been analysis examines the microstructure of the the focus of intense research in certain tracts according to the underlying FA values psychiatric disorders such as schizophrenia, in the voxels contained within the tracts. autism, Tourette‟s syndrome, attention deficit hyperactivity disorder (ADHD), Topographic-anatomic classification of dyslexia, depression, genetic disorders (i.e., major fiber systems in the cerebral white Down‟s syndrome), and demyelination (MS, matter of the primate brain HIV). Corpus Callosum (CC): is the largest On the basis of their topographic location, connective structure in the brain. It consists trajectory, and areas that interconnect the of over 200-300 million that transfer various fiber systems of the mammalian information between the two cerebral brain are divided into: a) commissural, b) hemispheres. The interhemispheric projectional and c) association fiber systems. connections between major neopalial On the basis of the known functional role of portions of the two hemispheres are in the the areas that are interconnected by a fiber majority homotopic however, heterotopic pathway, we can also make some general connections also exist. There has been a annotations regarding the possible functional debate whether the connections are primarily role of the specific fiber system: excitatory (integrating information across hemispheres) or inhibitory (allowing the a) Commissural fiber systems: are hemispheres to inhibit each other in order to bihemispheric, interconnecting cortical areas maximize independent function) but the between the two hemispheres. The two major consensus seems to be that the connections commissural fiber systems in the are primarily excitatory. The fiber mamamalian brain are the corpus callosum distribution in the CC shows an and the . The also anteroposterior topographical organization has a small commissural component that is consistent with the topography of the (hippocampal commissure) however, due to and is particularly precise in its predominant association fibers is included primates. Connections of the prefrontal in the association fiber systems. The cortex are located within the genu and commissural system plays an important role anterior part of the body, premotor cortical in interhemispheric functional integration connections in the midbody region, communicating perceptual, cognitive, immediately posterior are the M1 and S1 learned, and volitional information. The tracts, and immediately posterior to S1 tracts corpus callosum facilitates interhemispheric are posterior parietal cortical connections. interactions and integration. It is important Tracts connecting the temporal and occipital for the performance of visual and tactile cortices occupy the splenium of the CC (Fig tasks that require transfer of sensory 6 A and B). A more detailed topographical –

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somatotopical organization has been recently fasciculus), and more posterior subdivisions reported by Wahl et al., showing cortical connecting the inferior temporal, motor fibers connecting defined body parahippocampal and fusiform gyri as well representations of M1 crossing the CC onto as the inferior occipital cortex (following the somatotopically organized circumscribed course of the inferior longitudinal fasciculus) regions. Another important finding of this (Fig. 7). study was that the FA of the hand fibers correlated linearly with interhemispheric inhibition, induced by TMS, which suggested that microstructural information as measured by DTI can be directly linked to functional connectivity.

Figure 7: 3D DTI reconstruction of the anterior commissure including its anterior, olfactory, as well as its anterior and posterior, non-olfactory Figure 6: Lateral (A) and superior (B) view of DTI fiber subcomponents. reconstructions of the corpus callosum. Connections of the prefrontal cortex (purple) are located within the genu and anterior part of the b) Projectional fiber systems: include the body, premotor cortical connections (cyan) in the internal capsule, the coronal radiation midbody region, immediately posterior are the M1 and S1 tracts (blue), and immediately posterior to including the corticospinal tract, and the S1 tracts are posterior parietal cortical connections geniculocalcarine tract. (magenta). Tracts connecting the temporal Internal capsule (IC): The majority of (yellow)and occipital (green) cortices occupy the connections between the cerebral cortex and splenium of the CC. subcortical structures travel through the internal capsule. It is composed of two major Anterior commissure (AC): is a familiar components: a) thalamic radiations, which landmark on sagittal and coronal radiate anteriorly to frontal cortex, superiorly conventional MR images where it crosses the to parietal cortex, posteriorly to parietal and midline as a compact cylindrical bundle occipital cortex, and inferolateraly to between anterior and posterior columns of temporal cortex and b) motor projections the fornix beneath the septum pelucidum and connecting frontoparietal areas with anterior to the third ventricle, shaped like the subcortical nuclei and the spinal cord. The handlebars of a bicycle. On DTI topographic organization of tracts within the reconstructions two types of fibers can be IC is related to the anteroposterior part of recognised: a) olfactory fibers, connecting their cortical connections irrespective from the olfactory bulb, anterior olfactory nucleus their afferent or efferent nature. The anterior and anterior perforated substance, and b) limb carries thalamic projections to the non-olfactory fibers, which are further frontal lobes and fronto-pontine motor fibers, subdivided in anterior subdivisions the genu contains thalamic projections to the connecting the amygdale and temporal pole parietal lobe and corticonuclear motor (following the course of the uncinate projections, and the posterior limb contains

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posterior and inferolateral thalamic in healthy individuals and is not significantly projections and corticospinal, corticopontine, different from zero across individuals. and corticotegmental motor fibers (Fig 8). Geniculocalcarine tract: the human visual Coronal Radiation and Corticospinal Tracts system comprises elongated fiber pathways (CS): the coronal radiation is not a specific that represent a serious challenge for DTI. Reconstruction of the optic nerves and chiasm are compromised by the adjacent sinuses, eye muscles and bone. Crossing of the fibers in the optic chiasm represents also a challenge for traditional deterministic

Figure 8: 2D DTI of the internal capsule. The different colours in the anterior limb, genu and posterior limb indicate the specific orientation of the thalamic radiations and motor projections connecting various areas of the cerebral cortex with subcortical structures. The most prominent structure is the corticospinal tract in the posterior Figure 9: 3D DTI reconstruction of the coronal limb coloured in dark blue, which indicates its radiation. The blue-coloured fibers indicate the more vertically oriented fibers. more vertically oriented fibers of the corticospinal tract. tract per se, however, is one of the most reconstruction techniques. The optic easily identified structures on directional radiation connects the LGN to the occipital DTI color maps due to its coronally directed (primary visual) cortex. The optic radiation fibers that give him a distinct color (blue) is dissected into: a) the anterior ventral from the adjacent tracts, which are primarily bundle (Meyer‟s loop), running anterior directed left-right (i.e., CC) or anterior- around the tip of the temporal horn and then posterior (i.e., SLF) (Fig. 4). The passing posterior along the lateral wall of the corticospinal tract is easily reconstructed ventricle to terminate on the lower lip of the within the coronal radiation connecting calcarine fissure, b) the central bundle, primary motor areas with the spinal cord and leaving the LGN in a lateral direction and passing through the internal capsule (Fig 9). then turning posterior along the lateral wall In comparison with non-human primates, the of the ventricle to radiate into the visual sensorimotor tracts in humans are shifted cortex, and c) the dorsal bundle, running more posterior (in the posterior third of the straight into a posterior direction forming a posterior limb) as a consequence of the thick compact lamina terminating posteriorly prominent development of the prefrontal in the upper calcarine lip. (fig. 10) cortex and its projections through the IC. There is a small asymmetry between left and right CS tracts however, it tends to be small

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Figure 10: 3D, DTI reconstruction of the human Figure 11: selective reconstruction of short visual system including optic nerves (blue), tracts association fibers around the central sulcus. (red) and optic radiations (magenta). The anterior ventral bundle (Meyer’s loop), the central bundle, interchangeably in their descriptions. Non- and the dorsal bundle, have different trajectories human primate studies showed that these are connecting the LGN with the occipital cortex. two separate entities. Traditionally the SLF c) Association fiber systems: interconnect is considered to be a major association fiber cortical areas in each hemisphere and define pathway that connects the postrolandic large scale networks that subserve cognitive regions (parietotemporal association areas) functions. They can be grossly divided into with the frontal lobe and vice versa. It stems short and long association fiber systems. from the caudal part of the superior temporal Short association fibers connect cortical gyrus, arches around the sylvial fissure and areas around of a sulcus within the same lobe advances forward to end within the frontal or in adjacent lobes (Fig. 11). They are most lobe. Recent, detailed DTI studies in notable in the frontal and lateral occipital monkeys and humans identified three lobes in proximity to the long association subcomponents of the SLF: subcomponent I) superior and inferior longitudinal fascicles, located more suberior and medial, it courses which suggests that they could be part of that in the white matter of the superior parietal fascicles, which are known to consist of both and superior frontal lobes, subcomponent II) short and long-range axonal fibers. The long courses from the caudal part of the inferior association fibers form compact white matter parietal lobule to the distal premotor and bundles establishing distant interlobar prefrontal cortex, and subcomponent III) is connections. Understanding the long identified in the opercular white matter of the association pathways that convey cortical parietal and frontal lobes extending from the connections is a critical step in exploring the inferior parietal lobule to the ventral anatomic substrates of cognition in health premotor and prefrontal cortex (Fig 12). and disease. The following long association The SLF by connecting the superior parietal fiber systems can be routinely reconstructed lobule (important for limb and trunk location using DTI methodology. in body-centered coordinate space) with Superior longitudinal fascicle (SLF) and premotor areas (engaged in higher aspects of arcuate fascicle (AF): the SLF and AF have motor behaviour) is relevant to higher order historically been regarded by Burdach and control of body-center action and the Dejerine as a single fiber bundle in the initiation of motor activity. By connecting human brain probably due to the inability of the inferior parietal lobule (concerned with gross neuropathology to differentiate the two visual spatial information) with the posterior tracts. They used both names prefrontal cortex (important for perception

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and awareness) is relevant in spatial attention. By connecting the supramarginal gyrus (concerned with higher order somatosensory information) with the ventral premotor area (containing mirror for action imitation) is relevant to gestural components of language and orofacial working memory. The AF originates in the cortex of the posterior ventrolatelar frontal lobe, passing backward to the inferior parietal lobe, where it arches around the lateral fissure to terminate in the posterior part of the superior Figure 12: DTI reconstruction of the SLF. The and middle temporal gyrus (Fig 13). The three subcomponents (I: yellow, II: violet, ventral portion of the frontoparietal segment III:cyan) composing this major association fiber runs dorsal to the external capsule and the system connect the frontal lobe with postrolandic insular cortex. Wernike postulated the parietotemporal association areas. existence of a direct connection between the fronto-opercular, speech production, area Superior fronto-occipital fascicle (SFO): (Broca„s) and the posterior temporal, the existence and location of the SFO were auditory word processing, area (Wernike„s) subject of continuous debate in the historical and that a lesion of this theoretical pathway literature however, this fiber bundle is would cause an aphasia characterized by readily identifiable in DTI tractography. It is normal language comprehension and fluent seen in the coronal plane as a triangular speech but inability to repeat what had just been heard. The AF fasciculus was first described by Burdach and later confirmed by Dejerine who referred to the pathway as Burdach„s arcuate fasciculus. Through this pathway the lateral prefrontal cortex receives auditory spatial information. Therefore the AF provides the means by which the prefrontal cortex can receive and modulate audiospatial information. Using DTI, Catani et al. showed that beyond the classical arcuate pathway connecting Broca‟s and Wernicke‟s areas directly, there is also an Figure 13: 3D, DTI reconstruction of the arcuate fascicle connecting the posterior ventrolatelar indirect pathway passing through the inferior frontal lobe with the posterior part of the superior parietal cortex. The indirect pathway runs and middle temporal gyrus after arching around parallel and lateral to the classical arcuate the lateral fissure. fasciculus and is composed of an anterior segment connecting Broca‟s territory with fasciculus running above the caudate the inferior parietal lobe and a posterior nucleus, medial to the coronal radiation and segment connecting the inferior parietal lobe lateral to the fibers of the corpus callosum. It to Wernicke‟s territory. This model of two extends from the parieto-occipital junction to parallel pathways may explain the diverse the dorsal prefrontal cortex connecting the clinical phenotypes of conduction aphasia. superior parietal gyrus (parastriate areas

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important for peripheral vision and visual crucial for a wide range of motivational and motion) with the dorsolateral prefrontal emotional aspects of behaviour and for cortex of the middle and inferior frontal gyri spatial working memory. Moreover, the (necessary for attention). These cortical limbic system plays a very important role in connections make this tract relevant for high-level mental processes relevant to visual spatial processing. (Fig 14) memory and emotion. It is part of the Papez circuit that links the hippocampus, parahippocampal gyrus, mammilary bodies, thalamus, and cingulated gyrus. Other structures have subsequently been integrated into the limbic system including the amygdala, septal region and the olfactory bulb. The function of these structures has been implicated in dementia, epilepsy and schizophrenia.

Figure 14: 3D, DTI reconstruction of the SOF fascicle (yellow). It is seem running medial to the coronal radiation (blue) and lateral to the fibers of the corpus callosum (red), extending from the parieto-occipital junction to the dorsal prefrontal cortex.

Cingulate fascicle (CF): lies within the white matter of the cingulated gyrus and extends from the frontal lobe, around the rostrum and genu of the CC, above the body Figure 15: 3D, DTI reconstruction of the of the CC, before curving ventrally around cingulated fascicle interconnecting multiple areas the spenium to lie within the white matter of around the CC that are part of the dorsal limbic pathway. the parahippocampal gyrus. It interconnects multiple areas around the CC including the Fornix: is also a limbic structure connecting orbital surface of the frontal lobe, the the hippocampus with the hypothalamus. It is endorhinal and perirhinal cortex, the an association fiber tract however, it also has supplementary motor areas (SMA), the a small commissural component. Fibers arise dorsolateral prefrontal cortex, the caudal from the hippocampus and parahippocampal inferior parietal lobule, the retrosplenial gyrus of each side and run through the cortex, the parahippocampal cortex and the fimbria to join beneath the splenium of the presubiculum (Fig 15). It forms the major CC to form the body of the fornix. Beneath component of the dorsal limbic pathway. By the splenium, some fibrial fibers cross the connecting the hippocampus and midline to project to the contralateral parahippocampal gyrus (critical for memory) parahippocampal gyrus and hippocampus with prefrontal areas (important for forming the hippocampal commissure. Most manipulating information, monitoring of the fibers within the body run anteriorly, behaviour and for working memory) and the below the body of the CC, towards the rostral cingulated gyrus (involved in anterior commissure. Above the motivation and drive), this fiber system is interventricular foramen the body of the NJR I VOL 1 I No. 1 I ISSUE 1 I JULY-DEC, 2011

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fornix divides into right and left columns. As and the tapetum, projecting to lateral each column approaches the AC it diverges (superior, middle and inferior temporal gyri) again forming an anterior bundle, which and medial (uncus, parahippocampal gyrus curves posterior to the AC to enter the and amygdale) anterior temporal regions (Fig mammillary body of the hypothalamus as the 17). No fibers are identified in the calcarine postcommissural fornix, and an anterior region. The ILF has a role in the ventral bundle, which curves anterior to the AC and visual stream that is in object recognition, enters the hypothalamus as the discrimination and memory. It appears to precommissural anterior fornix (Fig. 16). mediate the fast transfer of visual signals to Similar to the cingulum, the fornix is part of anterior temporal regions and the dorsal limbic system and the Papez neuromodulatory back-projections from the circuit having a very important role in high- amygdala to early visual areas. Face level mental processes relevant to memory recognition is likely dependent upon the ILF. and emotion. Disruption has been implicated in associative visual agnosia, prosopagnosia, visual amnesia, and visual hypoemotionality.

Figure 16: 3D, DTI reconstruction of the fornix connecting the hippocampus with the hypothalamus showing its course below. Figure 17: 3D, DTI reconstructions of the ILF, which is an important component of the ventral visual stream by connecting extrastriate visual Inferior longitudinal fascicle (ILF): first association areas with medial and lateral temporal described by Burdach in 1822 and later by areas. Dejerine represents a major occipitotemporal associative tract. Its presence has been Inferior fronto-occipital fascicle (IFO): the challenged by evidence in non-human existence of this fascicle in the primate brain primates that connections between the two has been debated in the recent literature regions are entirely indirect, conveyed by the although is often demonstrated in DTI so called “occipito-temporal connection tractography reconstructions. It runs system”- a chain of U-shaped association posteriorly from mainly prefrontal cortical fibers however, later evidence showed that areas immediately superior to the uncinate the ILF is a major associative pathway fasciculus in the frontal lobe. At the junction distinct from fibers of the optic radiation and of the frontal and temporal lobes, it narrows from U-shaped fibers connecting adjacent as it passes through the anterior floor of the gyri. It arises in extrastriate visual external capsule and then continues association areas (cuneus medially,and posteriorly terminating in the middle and fusiform and lingual gyri laterally), then it inferior gyri of the posterior temporal lobe runs forward, parallel to the optic radiations and in the lingual and fusiform gyri of the NJR I VOL 1 I No. 1 I ISSUE 1 I JULY-DEC, 2011

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inferior occipital lobe (Fig 18). This fascicle may also be a main component of the ventral subcortical pathway having an important role in object recognition, discrimination and semantic processing.

Figure 19: 3D, DTI reconstruction of the UF (red) showing its course between the orbital and polar frontal cortex and the anterior part of the temporal lobe and its anatomical relation with the IFO (blue). In its frontal portion the UF runs directly below the IOF and then separates from it as it hooks anteriomedially, at the level of the Figure 18: 3D, DTI reconstructions of the IFO, limen insulae, to enter the temporal lobe. connecting prefrontal cortical areas with posterior temporal and inferior occipital cortical areas. between emotion and cognition. It may also be critical in visual learning. Uncinate fascicle: connects the anterior part of the temporal lobe with the orbital and polar frontal cortex. Dorsolateral fibers from the frontal pole run posteriorly to join with more ventral and medial fibers from the orbital cortex to form the uncinate fascicle, which runs for a short length inferior to the IFO before entering the temporal lobe as a single compact bundle. The uncinate then hooks anteromedially (through the limen insulae) to terminate in the temporal pole, uncus, hippocampal gyrus, and amygdale Figure 20: 3D. DTI (Fig 19). The UF is a ventral limbic pathway. reconstruction of the EmC situated between the It links the rostral superior temporal gyrus claustrum and the insula, and interconnecting the (important for sound recognition), the rostral mid-portion of the superior temporal region with inferior temporal gyrus (important for object ventral and lateral parts of the prefrontal cortex. recognition) the medial temporal area (important for recognition memory) and the Extreme capsule (EmC): is situated between orbital, medial and prefrontal the claustrum and the insula, interconnecting cortices(involved in emotion, inhibition and the mid-portion of the superior temporal self regulation). It is critical for processing region with the mid portion of the ventral novel information, understanding emotional and lateral parts of the prefrontal cortex (Fig. aspects of the nature of sounds and for self 20). It is distinguished from the external regulation, including the regulation of capsule that is strictly a corticostriatal emotional responses to auditory stimuli. In pathway. In the frontal lobe the EmC divides other words the UF enables the interaction into a superior ramus that lies within the white mater of the inferior frontal lobe and NJR I VOL 1 I No. 1 I ISSUE 1 I JULY-DEC, 2011

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an inferior ramus that lies beneath the density, integrity of axonal cell claustrum on the floor of the orbital cortex, membranes in a complex way, but fiber path laterally adjacent to the UF. On the saggital geometry and crossing fibers may also images the EmC is seen to occupy a position contribute. Several studies suggest that FA behind the uncinate fasciculus in the superior reflects valuable microstructural information temporal gyrus. By connecting the superior that can be linked to electrophysiological temporal cortex and insula with the orbital measures of functional connectivity in a and dorsolateral prefrontal cortex may have a meaningful way however, this still needs function in the connection between Broca‟s further validation. The DTI method presently and Wernicke‟s areas important in the applied in humans has a limited resolution linguistic (non-articulatory) aspects of (both angular and voxel size) in comparison language communication. By virtue of its with classical invasive methods traditionally connections with the temporal operculum used to study connectivity. High field (auditory association cortices) may also be magnets and specialized acquisition relevant to sound and language techniques may seem promising in comprehension. demonstrating intracortical terminations of axonal fibers (Fig. 21) however, still fall from being able to describe the complex Applications of DTI in the investigating cellular architecture of the human brain. Also connectivity of the human brain none of the imaging methods so far provides directional information. The combination of DTI has opened an entirely new window on DTI with MEG/EEG connectivity might the white matter anatomy with both clinical provide directionality and dynamic and scientific applications. It, has been information however, increasing effort must applied clinically in neurosurgery for the be made to merge the transdisciplinary presurgical mapping of WM tracts before competences required for such combinations. intracranial mass resections, and already Therefore, clarification of the following advanced the scientific understanding of questions is essential for transdisciplinary many neurologic and psychiatric disorders. communication: Its utility is found in both the localization and the quantitative assessment of specific Can we study connectivity of the brain neuronal pathways. The potential of this using DTI? technique to address connectivity in the human brain has created a lot of excitement DTI provides information on the large scale in the neuroscience communities. Studying structural substrate that supports coherent diseased connectomes and their related physiological activity and therefore, is dynamics is certainly going to significantly probably the only non-invasive method increase our understanding of the related available to provide in-vivo information on pathophysiologies and potential therapeutic the anatomical networks (structural effects. However, there are certain connectivity) connecting functional areas in methodological limitations that someone the human brain. However, DTI does not needs to be aware when considering the provide information on large scale brain structural and dynamic complexity of dynamics as it is recorded by mammalian brain. For example, despite electrophysiological and other functional recent progress, the biological basis of FA is neuroimaging techniques (functional not entirely clear. This measure is influenced connectivity) and also does not provide by the degree of myelination, axon size, and directional informational (effective

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connectivity). This distinction between the parcellated into anatomically distinct areas different types of connectivity is important in that maintain specific patterns of order to understand the limitations and interconnectivity or anatomically segregated contributions of the available brain mapping brain regions connected by inter-regional techniques in the investigation of the brain pathways. Traditionally, connectivity at large and its functions. Although the definition of scale has been mapped by destructive a structural network helps us to understand methods such as, histological dissection and the fundamental architecture of interregional staining, degeneration methods and by connections, we must also consider axonal tracing. A wide spectrum of diffusion functional networks and their directional imaging paradigms and computational links directly to understand information tractography algorithms has been explored in processing in the brain and mental recent years, which established DTI as representations. promising new avenue for the non-invasive in vivo mapping of structural connectivity at At which scale operates DTI to define the macroscale level. Further improvements structural connectivity? in the spatial resolution of DTI may allow this technique to be applied in the near future Brain networks are defined at different levels for mapping connectivity also at the of scale that range from cells, to populations, mesoscale level however, maps acquired to systems. They corresponde to levels of through the use of diffusion imaging should spatial resolution, which can be roughly allow for cross-validation with anatomical categorized as microscale (micrometer data collected by more classical histologic resolution), mesoscale (corresponds to the techniques. (Fig. 21) spatial resolution of hundreds of micrometers), and macroscale (millimeter resolution). Connectivity at the microscale level comprises neural systems that are composed of interconnected neurons and mapping the human network composed by 1010 neurons and 1014 synaptic connections at this cellular resolution poses unique challenges that are beyond the resolution of DTI methods. Mesoscale connectivity is defined by anatomically and/or functionally distinct neuronal populations linking hundreds or thousands of individual neurons. Figure 21: 3D, DTI high-resolution reconstruction Many anatomical structures in the brain of thalamocortical fibers acquired on a 3T MR contain similar local circuits (e.g., cortical system using specilized surface coils. The fibers are columns). Methods for studying structural reconstructed up to the corticomedullary junction and eventually can be followed to the intracortical connectivity at the mesoscale level include level. cell staining and light microscopy, tract Suggested reading: tracing using labelling agents, and electronomicroscopy reconstructions of 1. M. Guye, et al. Curr Opin Neurol sectioned tissue blocks. Studying structural 2008; 21:393-403 connectivity at this level is also beyond the actual resolution of DTI methodology. At the 2. N. Makris, et al. Cerebral Cortex macroscale level, large brain systems are 2005; 15:854-869

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