REVIEW Advanced Applications of MRI in Human Brain Science

Verne S. Caviness, Jr.,1 Nikos Makris,1 Nicholas T. Lange,2 Martha Herbert1 and David N. Kennedy1,3

Departments of 1Neurology, Massachusetts General Hospital, 2Department of Psychiatry, McLean Hospital, and 3 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

(Received for publication on December 14, 1999)

Abstract. Magnetic resonance imaging of the brain is now generally indispensable to state of art clinical medicine. Robust, high resolution imaging systems are currently available worldwide. The availability of MRI has, in little more than a decade, revolutionized the certainty and efficiency of clinical diagnosis and management. As a dividend of this revolution, clinicians and radiologists who are expert in the many and varied applications of MRI methods are able to relate this expertise to a con fident mastery of the topographic anatomy of the brain as revealed in magnetic resonance images. Whereas the yield to clinical objectives has been massive, the clinician as yet draws upon a relatively limited sampling of the potential informational harvest from this technology which in theory could further enrich both clinical concerns and those of fundamental neuroscience. Here we will review early explorations into these other offerings with the expectation that the coming decade will see them established comfortably with current uses. We will also consider potential offerings of the extended applications of brain MRI to the characterization and insights into biological origins of certain obscure developmental disorders. (Keio J Med 49 (2): 66-73, June 2000)

Key words: MRI, brain morphometry, neural systems, developmental disorders

Three Stages of Application shape of the principal cerebral, brain stem and cere bellar regions and the gray scale compartments of MR represents the brain as a range of gray scale these regions match or do not match those of the images which may be formatted in any or all three of standard of normal brain. This level of application is the cardinal coronal, axial or sagittal planes. Planes may ufficient to those requirements needed to judge many be sampled only selectively from the brain with variable developmental malformations as abnormal.1 It is suffi plane thickness and interplane gaps or the image set cient for the recognition of stroke or tumor. may be fully 3 dimensional. The imaged set is an alge braic transform of the imaged brain. Respecting these Knowledge-based electively obtained properties of an image data set, we consider three potential stages of analytic operation. Here the observer, drawing upon a base of knowl These stages build, one upon the other, a systematic edge of the structure, organization and development of interpretation and view of the human brain as imaged the normal brain, looks beyond the raw gray scale and by the MRI system. shape presentation of the brain and makes inferences in these domains from the image presentation of pattern Pattern recognition (Fig. 1b). The interpretations of image pattern provided by the skilled radiologist and clinician will be richly By pattern recognition we intend judgements made reinforced by such knowledge. Conceptual frameworks practically with reference only to the gray-white pat and technologies only now beginning to mature will terns as viewed in the images (Fig. 1a). That is, the soon contribute much more at this level of analysis. judgement is made as to whether the gray scale and The critical issue here is the relationship of neural

Presented at the 1140th Meeting of The Keio Medical Society in Tokyo, November 9, 1999. Reprint requests to: Dr. V. S. Caviness, Jr., Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston , MA 02114, USA, e-mail: [email protected]

66 Keio J Med 2000; 49 (2): 66-73 67

Fig. 1 MRI image of the brain. a) A coronal Tl-weighted MRI image at the level of the head of the caudate. b) Results of anatomic segmentation of this image are demonstrated. Unique anatomic regions are color coded and labeled. Abbreviations: Fl, first frontal gyrus; F2, second frontal gyrus; Cga, anterior cingulate gyrus; PAC, paracingulate gyrus; PRG, precentral gyrus; TP, temporal pole; INS, insula; CO, central operculum; FOC, frontoorbital cortex; Aput, anterior putamen; CauH, head of caudate; NA, nuculeus accumbens; V, ventricle.

structure and of neural systems organization to what is gyri, the nuclear masses according to approximate actually visible in the gray scale MR images. For ex nuclear groups and the white matter into strata which ample the continuous cortical gray compartment at the distinguish the principal fascicular groupings.9-12 For surface of the cerebral hemisphere includes neocortex, each gray and white matter parcellation unit, generally archicortex and paleocortex.2 The extent of each of each only a few percent or less of the total volume of these structures is revealed by reliable topographic the hemisphere, we have formulated an atlas of systems landmarks, principally with reference to hemispheric related structural components. For each gray matter location and the local course and intersections of fis parcellation unit, whether cortical or subcortical, we sures. The neocortex is thrown into convolutions which have developed a reasoned atlas of principal con in the normal brain conform to a canonical pattern, nectivity, based upon dissection and, by extrapolation, though with substantial variations in the details of this upon hodologic experiment in primates. For each par pattern among individuals.3 The neocortex internally is cellation unit of white matter there is a companion atlas composed of several dozen architectonic fields, each of traversing principal fascicles given both in terms of with its specific role in the systems operation of the provenance and destination (Fig. 2). Standard anatomic forebrain. To a substantial extent there is good corre images may be complemented to this end by explicit 3 lation between specific gyrus and the location of archi dimensional demonstration of specific fiber tracts by tectonic field.4-6 Central gray masses, similarly, are di diffusion tensor imaging (Fig. 3).13 Finally, this presen visible into nuclei by local topographic landmarks.7 tation may be complemented by spectroscopy, EEG or Finally, the white matter is subcompartmentalized re MEG where the overlays from these additional tech specting the course and quality of principal associative, nologies may be registered computationally with those projection and commissural axon fascicles, and the of the basic 3 dimensional anatomic image sets (Fig . course of specific fascicles is systematically and reliably 4)14.15 positioned with respect to the three dimensional con Applications in general will apply to any analysis formation of the white matter stratification.8 where the objective is to deduce inferences about sys The extensive knowledge base which correlates top tems organization from the pattern data set. In the case ographic anatomy of the human brain with gray scale of lesion analysis in cognitive neuroscience , for exam MR images may be tapped only after extensive proc ple, the method first characterizes the lesion itself in essing of the topographic anatomy. We illustrate here in terms of the underlying gray and white matter struc outline an approach that has usefully allowed such cor tures destroyed where characterization extends to the relations. In brief, we work from a computer assisted domains of localization and size.16,17 In the domain of system of analysis that allows us first of all to segment connectivity, an estimate of interrupted connectivity apart, the gray, white and CSF compartments and to may be inferred from the mapping of destroyed gray partition the neocortex according to the principal set of and white matter parcellation units with reference to 68 Caviness VS, et al: MRI and the Human Brain

Fig. 2 Maps of anatomic connectivity. a) The cortical connections of the commissural systems, including the corpus callosum, anterior commissure (ac) and dorsal hippocampal commissure (dhc) are shown. The color coding of the cortical regions corresponds to the color coding of the commissural regions. b) This figure shows the map of cortical anatomic connectivity (MAC) for the cingulum bundle (CB). Abbrevia tions: AG: angular gyrus; CALC: intracalcarine cortex; CGa: cingulate gyrus, anterior; CGp: cingulate gyrus, posterior; CN: cuneal cortex; CO: central operculum; F1: superior frontal gyrus; F2: middle frontal gyrus; F3o: inferior frontal gyrus, pars opercularis; F3t: inferior frontal gyrus, pars triangularis; FMC: frontal medial cortex; FO: frontal operculum; FOC: frontal orbital cortex; FP: frontal pole; Hl: Heschl's gyrus; INS: insula; JPL: juxtaparacentral cortex; LG: lingual gyrus; OP: occipital pole; OF: occipital fusi form gyrus; OLi: lateral occipital cortex, inferior; OLs: lateral occipital cortex, superior; PAC: para cingulate cortex; PCN: precuneus; PHa: parahippocampal gyrus, anterior; PHp: parahippocampal gyrus, posterior; PO: parietal operculum; POG: postcentral gyrus; PP: planum polare; PRG: precentral gyrus; PT: planum temporale; SC: subcallosal cortex; SCLC: supracalcarine cortex; SGa: supramarginal gyrus, ante rior; SGp: supramarginal gyrus, posterior; SPL: superior parietal lobule; T1a: superior temporal gyrus, anterior; Tip: superior temporal gyrus, posterior; T2a: middle temporal gyrus, anterior; T2p: middle temporal gyrus, posterior; T3a: inferior temporal gyrus, anterior; T3p: inferior temporal gyrus, posterior; TFa: temporal fusiform, anterior; TFp: temporal fusiform, posterior; TO2: middle temporal gyrus, tem porooccipital; TO3: inferior temporal gyrus, temporooccipital; TOF: temporooccipital fusiform gyrus; TP: temporal pole.10 Keio J Med 2000; 49 (2): 66-73 69

Fig. 3 Diffusion tensor imaging using MRI.13.11 a) Diagram shows a coronal section taken from Dejerine8 at the level of the red nucleus (6 nun anterior to the posterior commissure). The anatomic regions containing major white matter fiber path ways are "blocked" using a geometrical region of interest outline. Abbreviations: SLF: superior longitudinal fasiculus; CB: cingulum bundle; OF: occipitofrontal fasciculus; EC: extreme capsule; ILF/OR: complex of inferior longitudinal fasciculus and optic radiations, Fo: fornix; CC: corpus callosum; IC: internal capsule; P: cerebral peduncles; BS: brainstem. b) A color coded tensor orientation map (TOM) which corresponds to the level demonstrated in a). Each pixel in the image is assigned a color based upon the direction of the largest eigenvalue of the diffusion tensor. Blue color-coding corresponds to superior inferior, green to anterior-posterior, and red to medio-lateral.

the hodologic atlas.15 Closely related applications will quently, more efficient methods sample a large set of follow from the needs of surgical planning for tumor strategically placed topographic landmarks and compu resection and epilepsy surgery. tationally "warp" an image data set to that of a stan dard brain which has already been volumetrically ana Quantitative volumetry lyzed by methods of high precision.19,20 The resulting mathematical "deformation" relating the imaged to the Because the magnetic resonance image is an alge standard brain provides a basis for volumetric esti braic transformation of the imaged brain the method is mates. The trade offs are that the warping based meth inherently a quantitative one.18 Methodological chal ods are applicable only to flawless image data sets , are lenges for the present allow volumetric measurements, less flexible in terms of the anatomic definitions they although in the present state of development of these allow and inherently work at a lower level of precision methods there is a trade off between those methods of anatomic definition. Future developments will see which provide for "real time" efficient computation and advances in both modes so that one foresees over 5 those which provide for high levels of precision in the to 10 years time a homogenization of methodology definition of anatomic boundaries. Methods of highest which progressively optimizes efficiency , flexibility and anatomic precision undertake volumetric analysis at the precision.18 cost of substantial investigator time and require sub One reasonably asks whether the advantages inher stantial investigator knowledge of brain topographic ent to volumetric treatment of the brain justify the anatomy. More completely automated and, conse obviously substantial costs that have already been and 70 Caviness VS, et al.: MRI and the Human Brain

Fig. 4 a) and b) show three-dimensional renderings of voxels color-coded using the primary diffusion direction. These figures include representations of the cingulum bundle, internal capsule, corpus callosum, pallido-thalamic and ponto-cerebellar fibers and the cerebral peduncle. Fiber orientations are indicated by the color-coded sphere where S/I represent superior/inferior (blue), L/M represents lateral/medial (red) and A/P represents anterior/posterior (green).

will be committed to their development. As in all areas relating to the structural nature and the developmental of science and in particular in medical science this origins of obscure developmental disorders, in particu question must be answered on an application by appli lar autism and schizophrenia. cation and an investigator by investigator basis. The affirmative answer implicit in the dedication of our own Volumetric determinations in the clinic: There are and other laboratories to this project, arises from two myriad situations, encountered daily, where the volu fundamental considerations. The first, a profoundly metric question is "satisfied" by "seat of the pants" practical consideration, is that judgements critical to the estimates. They relate to the recognition of disorder, most central objectives of clinical science require volu for example, the question of whether a structure or a metric determinations and, in particular, volumetric brain is of normal size, in the case of an unending comparisons. The second, a more theoretical yet prom parade of children with developmental handicaps of ising consideration, is the argument that enquiry into diverse nature. They relate to the issues of whether a the volumetric properties of brain as tissue, carries us tumor, the pattern of multiple sclerosis plaques or brain into a richly promising domain of fundamental brain volume loss in degenerative disease has stabilized or science with implications for evolution, ontogeny and advanced. They relate to the needs of high precision principles of neural systems operation. We will say quantitative longitudinal volumetric determinations as more about these possibilities in our conclusion where the principal independent variable in clinical trials of we introduce a set of possible dividends of such funda the efficacy of drugs that might impede degenerative mental inquiry which, rather like orienting "north process or tumor growth and the option to express such stars," may coax and enable elucidation of some of the processes as rate functions. They relate to clinical trials most vexing problems in all of developmental clinical of drugs that might salvage viable brain within a stroke neuroscience. These are the yet unsolved mysteries penumbra. Before giving the knee jerk response that Keio J Med 2000; 49 (2): 66-73 71

"the way we do it is already good enough" and cer sponding areas in the general population. From the tainly preferable to the very large undertaking which is perspective of these observations we see in action a the challenge of current high precision volumetric non-linear interactive individual gyrus times individual methods, one should reflect upon the following. First of experience determination of relative enlargement of a all a highly skilled neuroradiologist will not recognize a component of the relevant neural system.28 The larger change in tumor volume if this is less than about 60%.21 implications of this perspective are arresting. They are Secondly, and this from the realms of basic neural that powerful evolutionarily conserved constraints act science, current estimates of the cortical surface area of to set the total volume of neocortex to a narrow species the normal brain have varied as much as an order specific value but that mechanisms operating through of magnitude.22 The bottom line is that our "seat of individual experience have substantial freedom to mod pants" estimates are a flimsy basis for the serious needs ulate the volumes of restricted brain regions adaptively. that clinical exigencies daily present to us. We need The structure by structure view of the brain, and levels of precision that are at least in the 10-20% range indeed, the gyrus by gyrus view of the neocortex is in order to meet these exigencies. obviously a perspective that ignores the larger context of neural systems organization. Thus, it takes much Volumetric determinations and fundamental brain more, structure-wise, than primary motor cortex or pri science: The central thesis here is that volume is a fun mary acoustic cortex to provide the neural systems damental property of brain tissue.18 By this we mean, support for excellence in keyboard or otherwise musical on the evolutionary scale, that there is a regular stoi skills. These aptitudes reflect the coordinate operation chiometry that relates the volume of brain within spe of a neural system distributed to all levels of the central cies to the body plan and mean size of animals of that nervous system. More than this they require the coor species.23.24 By this we also mean that within species, dinate operation of this system with other systems and the implementing and constraining oppositions of the linking of associative mechanisms which so domi ontogenetic processes work to minimize the variation in nate the landscape of forebrain structure.31 One volume of the brain or certain of its principal major reasonably inquires "what about the other processing structures. Yet, more elementary components of certain outposts of the primary system" or "what about the structures may be greatly variable from individual to intervening and linking associative processors." It is at individual.25.26 By illustration, the coefficient of varia this point that much more observation is needed in tion of the mean volume (CV) of neocortex of a set of order to support and develop theory further. What is normal young adults with equal male and female rep already in hand is the observation that morphometry resentation was found to be less than 10%.27,28 By (volumes or areas as the case may be) of the primary contrast the mean CV of neocortex surmounting the main line structures of the human visual system in canonical gyral set of the normal brain was well over cluding optic tract, lateral geniculate and primary vis 20% and greatly variable across the full set of gyri.28 ual cortex, co-vary strongly with Pearson coefficients We have from this analysis developed a computational approaching 0.8.32 Again the variance is minimally if at model that identifies a non-linear factor, interactive all scaled to total brain volume. Although raw volumes between individual and specific gyrus, as the determi of larger brain structures do vary more on average nant of approximately 70% of this variance.28 Uniform than smaller structures, this size-variance dependency scaling to species (mean neocortical volume of the total is removed in large part by simple re-expression of population) or even individual (deviation of individual volumes of the natural logarithmic scale. Within the neocortical volume from the population mean) together cerebrum itself we have found through principal com satisfy less than 20% of the variance. Whereas there is a ponent analysis and also through simple pair-wise cor pervasive sexual dimorphic effect, this is of low order, relations, a lower order but still significant force of estimated in this study as the source of less than 1% of co-variance (some positively, some negatively in sign) gyral volume variance. of systems and associatively linked structures at both The implications of this set of findings are fully con cortical and subcortical (striatal and thalamic) levels.33 cordant with, perhaps even predictable from other types The thesis arising from these observations, plausible yet of investigations which suggest that neocortex directly requiring substantially more inquiry , is that the strength serving highly overlearned motor skilled or acoustic of volumetric covariance of linked structures will vary capacities are significantly larger than the volumes of (perhaps either positively or negatively in sign) both as corresponding gyri in individuals without such experi a function of the intervening "synaptic distance" and ence or skills. Specifically, the primary motor cortex of also as a function of the degree of the exclusiveness of keyboard artist29 and the acoustic cortex of the tempo the association (convergence-divergence considerations) ral plane of musicians with pure pitch,30 both trained of the structures.18 To the extent that such volumetric from early childhood, are large relative to the corre covariance does occur, it becomes a parameter by which 72 Caviness VS, et al.: MRI and the Human Brain to explore the previously uncharted systems relation turbations may be expected to be large in effect in the ships of diverse and widely distributed brain regions. neural systems functional domain. Such speculations Such explorations are a natural companion to those are offered in a search for directions and possibilities proceeding through the methodology of functional MRI. within the larger potential offerings of MRI-based brain morphometry. Developmental Disorders of Obscure Nature Acknowledgments: The graphic reconstructions in figures 3 and 4 The observations and speculations reviewed here were contributed by Andre Worth. These investigations were sup have arisen in the course of work undertaken in a fun ported in part by NIH grants NS27950, DA09467 and NS37483; NIH grants NS34189 and MH57180 as part of the Human Brain Project; damental investigative laboratory but which is based in grants from the Fairway Trust, the Giovanni Armenise-Harvard a large general hospital. Clinicians who are directly Foundation for Advanced Scientific Research and Cure Autism Now concerned with developmental disorders have partici Foundation. pated as equal partners with computer scientists, statis ticians and physicists in this program. Inevitably appli References catttion of this methodology to obscure developmental disorders has been close to the surface of thought in this 1. 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