Anterior and Middle Cranial Fossa in Traumatic Brain Injury:Relevant Neuroanatomy and Neuropathology in the Study of

Neuropsychological Outcome

Erin D. BiglerBrigham Young University and University of Utah

The frontal and temporal lobe regions of the brain have a high vulnerability to injury as a consequenceof cerebral trauma. One reason for this selective vulnerability is how the frontal and temporal regions aresituated in the anterior and cranial fossa of the skull. These concavities of the skull base cup the frontaland temporal lobes which create surface areas of contact between the dura, brain, and skull wheremechanical deformation injures the brain. In particular, the sphenoid ridge and the free-edge of thetentorium cerebelli are uniquely situated to facilitate injury to the posterior base of the frontal lobe andthe anterior pole and medial surface area of the temporal lobe. Three-dimensional image reconstructionwith computerized tomography and magnetic resonance imaging are used to demonstrate the vulnera-bility of these regions. How neuropsychological deficits result from damage to these areas is reviewedand discussed.

Keywords: traumatic brain injury, skull, cranial fossa, frontotemporal damage

Since the first systematic studies of cerebral trauma, it has beenwell known that the frontal and temporal lobes are more suscep-tible to injury. For example, in autopsy-based research as early as50 years ago both Courville (1950) and Gurdjian (1975) used aline-drawing approach at autopsy to record where visible contu-sions had occurred in those who succumbed to trauma. Figure 1,from Gurdjian (1975), demonstrates the typical appearance offrontal and temporal contusions at post mortem, where visiblecontusions are shown on the ventral surface of the brain. Inspect-ing the brain in such a manner, both Courville and Gurdjian useda general brain schematic to draw the boundaries of contusionsoutlining their visible borders, plotting them on a standard braintemplate, as shown in Figure 2. This illustration distinctly dem-onstrates the preponderance of frontotemporal contusions in casesof traumatic brain injury (TBI).

From the neuropsychological standpoint the frontotemporal sus-ceptibility to injury has long been assumed to be the basis for thecore cognitive and neurobehavioral symptoms of TBI, namelyimpairments in attention, concentration, memory, executive func-tion, and emotional regulation (Bigler, 2005, 2007). The intent ofthis neuroanatomic and neuropathological review is to use con-temporary neuroimaging techniques to demonstrate how the finestructure of the frontal and temporal lobes is affected by injury andhow damage to these regions can be systematically studied inneuropsychological and neurobehavioral investigations. In thepast, because of limitations in imaging technology and image

analysis methods, the ability of such techniques to fully identifymacroscopic pathology was restricted. With this review, variousmethods and procedures for advancing structural neuroimaginganalyses in the study of the neuropsychology of TBI are offered.Much of the pathology in frontal and temporal brain regions can beattributed to how these brain areas interface within the anterior andmiddle cranial fossae and the mechanical deformation of the brainagainst these boney structures and, therefore, the review will beginwith a basic neuroanatomy primer of these skull and brain regions.

Basic Neuroanatomic Assumptions That Relate toSusceptibility of Frontal and Temporal Lobe Regions to

Cerebral Trauma

The cranial fossae encapsulate much of the brain, holding it inplace during normal movement. Likewise, the uneven surfaces ofthe inner table of the skull represent an evolutionary design featurethat cups the brain in position, providing a rough interior to thebase of the skull that holds in place the smooth dural surface thatcoats the brain. If the inner table of the skull were completelysmooth, with the similarly smooth outer surface of the dura matter,the brain would glide, even with slight head movement. Accord-ingly, the rough, irregular contours of the inner skull act asmoorings, in conjunction with the three cranial fossae along withthe falx cerebri and the tentorium cerebelli, all literally holding thebrain in place. However, what evolutionary advantages this designaffords for brain development and integrity in normal circum-stances actually become vulnerability factors with high-speed im-pact injuries of modern societies.

At birth, brain and intracranial volume (ICV) are but about 25%of their adult size (Courchesne et al., 2000). However, both brainand ICV rapidly expand in concert, such that by age 5 years, bothhave reached approximately 90% of their adult volume (Caviness,Kennedy, Richelme, Rademacher, & Filipek, 1996; Courchesne etal., 2000), with cranial vault size reaching maximal volume aroundage 7 (Wolf et al., 2003). Dynamic brain changes occur throughout

Erin D. Bigler, Departments of Psychology and Neuroscience, BrighamYoung University, and Department of Psychiatry, University of Utah.

The assistance of Tracy J. Abildskov, JoAnn Petrie, and Craig Vickersis gratefully acknowledged, as is the support from the Ira Fulton Founda-tion.

Correspondence concerning this article should be addressed to Erin D.Bigler, Departments of Psychology and Neuroscience, 1190D SWKT,Brigham Young University, Provo, UT 84602. E-mail: erin_bigler@byu.edu

Neuropsychology Copyright 2007 by the American Psychological Association2007, Vol. 21, No. 5, 515–531 0894-4105/07/$12.00 DOI: 10.1037/0894-4105.21.5.515

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childhood and adolescence (Caviness et al., 1996; Toga, Thomp-son, & Sowell, 2006), but by mid to late adolescence overall adultbrain volume has been achieved, and ICV becomes a proxy forbrain volume (Wolf et al., 2003). As such, in the youthful brain,particularly the adolescent and young adult brain when the fitbetween brain volume and ICV is at its tightest, the brain isliterally hugged within the cranial vault. In normal circumstances,the intracranial fault is stimulated by the brain growth. The twoessentially develop as a unit, and because of the irregular internalsurfaces of the skull as mentioned above, the brain is readily heldin position for most kinds of natural movement, including jumpingand running, even at high speed. This is also true for generalminor-impact types of blows to the head, including that resultingfrom fisticuffs (Gurdjian, 1975). The tight conforming fit of thebrain to the inner skull represents a protective anatomical feature,where the meninges-encapsulated brain is enfolded by the skulland buoyant in the surrounding cerebral spinal fluid (CSF). Suchintegrated morphological connections between the brain and skullprobably afforded evolutionary advantages for survival, enablingrapid movement without injury to the brain. Being held tightlywithin the cranial vault was (and still is) protective for mostday-to-day activities where the head may be bumped or a simplefall may occur with no ill effect. Also, a tightly held brain isprotective for most ordinary blows or jarring to the head that

occurred in routine fighting or simple hand-to-hand combat ofearlier times or any hunter–gatherer activities that would put thehead at risk for injury. However, there was never a time inevolutionary history where any advantage would have been af-forded to recovery of function from high-velocity impact thatoccurs in modern injuries, such as from motor vehicle accidents(MVA). The importance of this point is that the skull–braininterface that affords protection during everyday movement, andeven minor trauma, quickly becomes a vulnerability factor inhigh-speed impact injuries. For example, the sphenoid ridge thatreadily holds the temporal lobe in place during ordinary headmovement acts as a fulcrum in high-speed collisions, where theanterior aspect of the temporal lobe and posterior and inferioraspects of the frontal lobe deform against the sphenoid (see Sumeret al., 2003).

Brain injury relates to several continuums from severity ofinjury to resiliency to injury and different rates and types ofoutcome. In fact, the degree of trauma-induced cerebral atrophyappears to be directly related to trauma severity (see Bigler, Ryser,Gandhi, Kimball, & Wilde, 2006). Accordingly, by understandingwhat happens on the extreme of one continuum (i.e., studying theTBI that leads to death) helps in understanding what may beoccurring on the other end of the spectrum (i.e., mild TBI [mTBI]).For example, Kampfl et al. (1998), using qualitative and quantita-

Figure 1. Frontal and temporal pole contusions in two cases as reported by Gurdjian (1975). Note theextensiveness of the ventral surface contusions. From Impact head injury: Mechanistic, clinical and preventivecorrelation (pp. 242, 243), by E. S. Gurdjian, 1975, Springfield, IL: Charles C. Thomas. Copyright 1975 byCharles C. Thomas. Reprinted with permission.

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tive magnetic resonance imaging (MRI) measures, examined 42TBI patients clinically assessed to be in a persistent vegetativestate. All had imaging abnormalities, and 100% had detectablelesions in the corpus callosum (CC). The next highest location ofdetectable abnormality was in the brainstem (74%), followed by65% having frontal and/or temporal lobe lesions. The Kampfl et al.study clearly demonstrates the selective vulnerability of frontaland temporal lesions in TBI in severe brain injury and CC involve-ment, the structure that interconnects these frontal and temporalregions. In fact recent studies have shown that volume loss infrontal and temporal areas is associated with reduced CC size,likely secondary to transneuronal-type degeneration coming fromneuronal death at the site of the frontotemporal lesions (Wilde,Chu, et al., 2006).

Skull Anatomy

Figures 3–5 provide various views of the skull base and thethree cranial fossae. In Figure 3, adapted from McMinn, Hutch-ings, Pegington, and Abrahams (1993), a posterior oblique view ispresented with visualization of the right cranium where the falxcerebri, tentorium cerebelli, and dural base are left in situ. Thisfigure provides a straightforward visualization of the three maincranial compartments and how encapsulated the frontal and tem-poral lobes are in their respective fossa. Figure 4 is a dorsal viewof the skull base with the midbrain left in situ, along with the dura,also adapted from McMinn et al. Essentially all brain parenchymais encapsulated by the dura, except a small band right at the levelof the entorhinal cortex, and when one is sitting or standing erect,the brain “sits” or “rests” on the skull inner surface, as shown inFigure 4, only separated by the thin CSF collection housed within

the subarachnoid space. When the dura is removed, as shown inFigure 5, the uneven surface of the base of the skull is revealed. InFigure 5, in the anterior cranial fossa, the boney protuberances ofthe base of the frontal and temporal bones and the crista galli allcreate surfaces where, following impact or a rapid acceleration/deceleration, the undersurface of the frontal and temporal lobesgrates and/or deforms against these regions. Neuropathologistshave also described this as a “slapping” action (see Gurdjian,1975), where as a result of the dynamic forces of movement, thebrain is momentarily lifted away from the bone and then slappedback as momentum shifts in other directions. The posterior cranialfossa and the union of the brainstem to the spinal cord likely holdthe posterior fossa structures more rigidly, whereas the frontal andtemporal regions are more likely to move. These momentum shiftsoccur because the head is, of course, tethered to the body via theneck and can only move so far before a rebound or pulling-backaction results. Additionally, in any high-speed (e.g., MVA) orhigh-force impact (e.g., fall, assault) injury, a variety of forcevectors apply simultaneously or in rapid succession, includingrotational forces, which place a specific strain on neural tissue(Bayly et al., 2005; Goldsmith & Monson, 2005; LaPlaca, Cullen,McLoughlin, & Cargill, 2005). All of these forces create concur-rent regional differences in brain movement resulting in shear-strain actions throughout brain parenchyma, including deep struc-tures. Forces sufficient to damage brain tissue are also sufficient todamage blood vessels (McKinney, Willoughby, Liang, & Ellis,1996; Shreiber et al., 1999), and accordingly, vascular injury isoften seen concomitantly with diffuse axonal injury (Besenski,2002; Messori, Polonara, Mabiglia, & Salvolini, 2003; Rodriguez-Baeza, Reina-de la Torre, Poca, Marti, & Garnacho, 2003; Tong etal., 2004), again with the highest preponderance of injury in thefrontotemporal regions of the brain (Scheid, Preul, Gruber, Wig-gins, & von Cramon, 2003). Likewise, by definition a componentof vascular injury (i.e., bruising) has occurred when contusionsresult from trauma in these boney edges of the cranial fossae.

One look at the middle cranial fossae, as shown in Figures 3–5,and straightforwardly it becomes apparent why the temporal lobeis so vulnerable to injury (see also Giannetti, Prandini, SantosAraujo, & de Araujo Herval, 2005). The sphenoid ridge is createdby the sphenoid bone plate that sharply folds back on itself,positioning a boney ridge that encapsulates the temporal pole, asdemonstrated in Figure 6. The view of the temporal lobe in thesagittal cut shown in Figure 6 also demonstrates the close prox-imity of the head of the hippocampus to the point of the sphenoidridge (note that the difference between the innermost point of thesphenoid to the head of the hippocampus in Figure 6 is less than 2cm). As the sphenoid bends medially it connects to the clinoidprocess, and connected to the clinoid is the free edge of thetentorium cerebelli (see Figure 3). Returning to Figure 3, the freeedge of the tentorium can be seen to run along the full length of themedial temporal lobe (MTL). The role of the free edge of thetentorium has long been known as the source of contusion and isthe region of herniation when significant localized temporal lobeedema is present (Maramattom & Wijdicks, 2005; Van Hoesen,Augustinack, & Redman, 1999). The surface of the MTL butts upagainst these boney structures created by the medial surface wallof the middle cranial fossa. Indeed, as the fusiform and parahip-pocampal gyri curve upward in the middle cranial fossa, aspects oftheir cortical surface are in contact with the medial wall of the

Figure 2. At post-mortem, both Courville (1950) and Gurdjian (1975)visually examined the location of surface contusions as depicted in Fig-ure 1 and outlined the boundaries by hand of the contusions on a schematicof the brain to illustrate the preponderance of contusions to the frontotem-poral region. From Impact Head Injury: Mechanistic, Clinical and Pre-ventive Correlation (p. 244), by E. S. Gurdjian, 1975, Springfield, IL:Charles C. Thomas. Copyright 1975 by Charles C. Thomas. Reprinted withpermission.

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middle cranial fossa and the free edge of the tentorium. It isimportant to note, as discussed by Van Hoesen et al. (1999), thatthe free edge of the tentorium attaching to the petrous apex andanterior and posterior clinoid processes (see Figures 3–5) results ina part of the parahippocampal gyrus being unprotected by duramatter. This has been referred to as the “tentorial notch” (seeJefferson, 1938), and the region of the parahippocampal gyrus thatsits at the level of the tentorial notch is entorhinal cortex, whichhas direct input to the hippocampus (Van Hoesen et al., 1999). Atthe base of the middle cranial fossa, boney protuberances may alsobe present, just as in the anterior cranial fossa. Again, the purposeof these boney protuberances is to function as moorings holdingthe dura encapsulated brain in place, where only the dura comes indirect contact to bone.

Although not a point of discussion in this article, there is a thirdor posterior cranial fossa (see Figure 6) which houses the cerebel-lum, which can also be a site for brain contusion (Graham &

Lantos, 2002). The pterous bone that forms, in part, the posterioraspect of the middle cranial fossa and the anterior aspect of theposterior cranial fossa also acts as a source of contusion for themore posterior aspect of the temporal lobe.

TBI and Frontotemporal Neuroanatomy

Figure 7 provides a medial surface schematic showing thelocation of the basal forebrain and medial surface of the temporallobe and an enhanced view showing some of the cytoarchitectonicdivisions of the hippocampus in coronal plane. What is not appre-ciated in this figure is the interface between frontal and temporalareas and bone. Bone is often hard to fully visualize with MRI, asthe signal associated with bone is often ill-defined because of itslow water content. CT imaging is far more suitable for visualizingbone, as shown in Figure 8. Also shown in Figure 8 is the tentorialnotch, in the cross hairs in G, H, and I. Returning to Figure 7, it is

Figure 3. Posterior oblique sagittal view of the falx cerebri and tentorium cerebelli in situ looking into thecranial contents of the right side cranial fossae, with the brain removed. The sturdy appearance of the dura isreadily captured by this post-mortem preparation. Note the position of the free margin of the tentorium (22) andthe attached margin of the tentorium cerebelli (24) to where the medial temporal lobe would be located (seeFigure 8). From McMinn’s Color Atlas of Human Anatomy (p. 61), by R. M. H. McMinn, R. T. Hutchings, J.Pegington, and P. H. Abrahams, 1993, St. Louis, MO: Mosby-Year Book. Copyright 1993 by Elsevier. Reprintedwith permission.

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readily clear why the MTL, particularly the region of the entorhi-nal cortex, is so susceptible to injury because of its location in themedial cranial fossa. The point of the tentorial notch as shown inFigure 8 is precisely the same area telescoped in Figure 7. Becausethis is a rich area of input to the hippocampus, damage to this MTLsurface would disrupt hippocampal function.

As shown in Figure 7, the region of the basal forebrain sits justabove boney surfaces of the posterior base of the anterior cranialfossa immediately in front of where the sphenoid joins the clinoidprocess and above the adjacent middle cranial fossa where theMTL functionally connects to the frontal lobe regions via uncinateand arcuate fasciculi (Catani & ffytche, 2005; Gaffan, Easton, &Parker, 2002). As can be visualized in these illustrations, the undersurface of the basal forebrain is in proximity to bone, and the entirelength of the medial surface of the temporal lobe interfaces witheither bone or tentorium, creating a circumstance in which defor-mation of these surfaces can readily occur with any movement orrotation of the frontal or temporal lobes. Thus, both the criticalregions of the basal forebrain and MTL are situated in a mannerthat make them highly vulnerable to impact deformation againstbone or sturdy dural structures that enhance the likelihood of

injury to these regions. Furthermore, because these two regionsinterconnect via the arcuate and uncinate fasciculi and other path-ways (Peuskens et al., 2004), a solitary lesion in either of thesefrontal or temporal lobe regions or in one of the fasciculi has thepotential to disrupt function in both.

Frontotemporal Focus of Pathology Demonstrated byVoxel-Based Morphometry (VBM)

In conventional MRI, the distinction between white matter, graymatter, and CSF is expressed by differences in gray scale intensity.If one capitalizes on these differences, the entire brain can beclassified or segmented into pixels that are most likely whitematter, gray matter, or CSF. If the segmented images from anindividual subject are now uniformly placed into a standardizedspace (typically a Talairach or Montreal Neurological Institutespace; Chau & McIntosh, 2005), so that each x, y, and z coordinatecan be lined up, then a comparison can be made between contrast-ing groups with regard to pixel density of white matter, graymatter, or CSF within a given voxel (as shown in Figure 9, a 2 �2 � 2 pixel three-dimensional space) anywhere in the brain. VBM,

Figure 4. Dorsal view of the tentorium cerebelli in situ. Once again, note the location of the free margin of thetentorium cerebelli (18) in relationship to the location of the medial temporal lobe. From McMinn’s Color Atlasof Human Anatomy (p. 60), by R. M. H. McMinn, R. T. Hutchings, J. Pegington, and P. H. Abrahams, 1993, St.Louis, MO: Mosby-Year Book. Copyright 1993 by Elsevier. Reprinted with permission.

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Figure 5. Skull base. The skull cap has been removed, exposing the inner surface of the ventral base of theskull, with the various anatomic structures with the three cranial fossa clearly defined. The uneven surface ofeach fossa is clearly observable. The general location of the hippocampus (medial wall of the middle cranialfossa) and where the base of the frontal lobe is located (anterior cranial fossa) are depicted. A � frontal crest;B � anterior cranial fossa; C � crista galli with cribiform plate beneath; D � sphenoid bone; E � petroustemporal bone; F � clinoid bone and area of the sella turcica; G � clivus; H � foramen magnum; I � middlecranial fossa; J � posterior cranial fossa.

Figure 6. Parasagittal plane through the long axis of the hippocampus at post-mortem. Note how the temporalpole is “cradled” and “hugged” by the middle cranial fossa as well as the sharp edge of the sphenoid ridge, asit juts into the Sylvian fissure. The head of hippocampus is approximately 2 cm from the sphenoid ridge and,when brain compression occurs, can deform over the ridge. See Figures 11 and 12. From Atlas of the HumanBrain (2nd ed., p. 83), by J. K. Mai, G. Paxinos, and J. K. Assheuer, 2004, Amsterdam: Elsevier. Copyright 2004by Elsevier. Adapted with permission.

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as this method of analysis is called, has demonstrated frontotem-poral pathology in TBI (Gale, Baxter, Roundy, & Johnson, 2005;Salmond, Chatfield, Menon, Pickard, & Sahakian, 2005), as shownin Figure 9, taken from Yeates et al. (2007). In fact what is mostinteresting to note about Figure 9 is its similarity to Figure 2,generated 30 years earlier as a simple line drawing in which

cortical contusions could actually be visualized post-mortem. Theconvergence of these two methods again specifies the vulnerabilityof frontotemporal areas to damage in TBI. Caution does need to beused in interpreting VBM findings because such analyses are basedon density coefficients of white, gray, or CSF pixels in asegmented image and therefore are not directly comparable to

Figure 7. (A) Lateral view of the left hemisphere showing the plane for cutting the coronal section depictedin Panel C. (B) Mid-sagittal view of the right hemisphere showing the location of the basal forebrain andhippocampus. (D) Zoomed-in view of the medial temporal lobe shown in Panel C. This view shows the generallocation of the component parts of the parahippocampal gyrus and its contiguity with the hippocampus.Hippocampal nomenclature is a bit complicated. Because of its C-shaped appearance reminiscent of a horn (e.g.,ram’s horn) when viewed from several orientations, some early neuroanatomists labeled this structure “Am-mon’s horn” or “cornu ammonis” after a mythical Egyptian god, whose symbol was a ram. The wordhippocampus is also Greek for seahorse, because its appearance can be construed in the form of that sea creature.The Latin term, then, for the hippocampus is Cornu (Latin for horn) Ammon, referring back to its appearanceof a horn, but the terms hippocampal fields or Cornu Ammonis (CA) fields also refer to the histological layersof the hippocampus. In this illustration, the lighter blue represents, in part, the subiculum, and the worm-like darkblue structures represent the different cytoarchitectonic divisions of the hippocampus. The flow is fromsubiculum to CA1 through CA4. Seen in this schematic is CA1 bending into CA2, with the reverse curl,representing the CA3 region, extending into CA4, which is less well defined than the other layers. The cross hairpoint in Figures 8G–8I is at this same level, depicting the vulnerability of this region of the parahippocampalgyrus to injury from middle cranial fossa structures. From Neuroscience: Exploring the Brain (p. 531), by M. F.Bear, B. W. Connors, and M. A. Paradiso, 1996, Baltimore, MD: Williams & Wilkins. Copyright 1996 byLippincott. Adapted with permission.

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region of interest volumetric studies, and VBM results arepotentially influenced by developmental and demographic fac-tors between the patient and control groups (Allen, Bruss,Brown, & Damasio, 2005). Nonetheless, VBM represents anexcellent method for the study of structural changes in the brainin response to injury.

Frontal Lobe

As shown in Figure 10, by virtue of how the frontal bone curvesback over the anterior frontal lobe, the frontal bone literally cups

the lobe, such that except for the medial surface of the frontal lobe,all other cortical surface regions are in contact with the inner tableof the skull in the anterior cranial fossa. As can be seen inFigures 10, 3, and 4, the clinoid process juts up right at the levelof the basal forebrain region of the frontal lobe, and the anterioraspect of the middle cranial fossa is defined by the sphenoid bone,which provides a rigid structure where the inferior and posterioraspect of the frontal lobe may strike. As shown in Figure 2, this isa common area of contusion, which can also be seen in CTimaging. This is depicted in Figure 11, which is from a patient whosustained a head injury from a fall, where the focal impact was tothe back of the patient’s head, with the resulting contra coup injuryto frontotemporal regions.

Temporal Lobe

Just as with the anterior cranial fossa cupping the frontal lobe,the middle cranial fossa cups the temporal lobe, but unlike the

Figure 9. Voxel-based morphometry (VBM) of traumatic brain injury(TBI) showing the greater likelihood of gray matter pixel density reductionin frontal and temporal areas. The top gray scale “glass image” is from theinitial statistical parametric mapping analyses, where darker shading indi-cates less dense area. Note that in this series of TBI patients, the darkestregion is in the basal forebrain area (red arrow). This analysis is based ona group of adolescent TBI subjects who on initial scanning had sustaineda frontal or temporal lobe contusion. VBM analyses were based on chronicmagnetic resonance imaging done at least a year post injury, compared toage matched controls. From “Social Outcomes in Childhood Brain Disor-der: A Heuristic Integration of Social Neuroscience and DevelopmentalPsychology” by K. O. Yeates, E. D. Bigler, M. Dennis, C. A. Gerhardt,K. H. Rubin, et al., 2007, Psychological Bulletin, 133, p. 546.

Figure 8. The CT images are based on spiral imaging technology, wherethe top row depicts the bone window, highlighting the intracranial cavityand the three cranial fossae, specifically the anterior cranial fossa, themiddle cranial fossa, and the posterior cranial fossa. Note that with theimage threshold set at the bone window, only bone is highlighted in the toprow. The second and third rows are at identical levels and planes as theimages at the top of each column but were made with a brain parenchymathreshold, to highlight brain tissue. Note that at this threshold, bone undulythickens as a slight distortion of actual bone width. The images in the toprow show true skull thickness, but at bone window intensity brain paren-chyma is ill defined. Brain parenchyma depicted in the middle and bottomrows are in sagittal (D, G), coronal (E, H) and axial planes (F, I). The crosshairs in the bottom row are the intersection point in the different planeswhere the free margin of the tentorium evolves (see arrows) into theattached margin that connects with the boney surface of the skull (regionof the sphenoid and clinoid processes). For anatomical identification of thevarious structures, see Figures 3–5. Note that the free margin connects inthe exact location where the parahippocampal gyrus is positioned, which inthis patient is adjacent to entorhinal cortex. This is best viewed in Panel H,where the arrow points to the temporal horn, the hippocampus sits in thefloor of the temporal horn, and the parahippocampal gyrus surrounds thehippocampus. This patient had sustained a temporal lobe contusion 2 yearsprior to this CT scan, with some temporal lobe atrophy evidenced byprominent gyri and dilated temporal horn. See also Figure 12, which is theMRI from this patient taken on the same day.

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frontal lobe, even the medial surface of the temporal lobe comesinto contact with bone or dura. In fact, the interface of the medialsurface of the temporal lobe with the sphenoid, clinoid, and ten-torial notch is one explanation for the vulnerability of this brainregion in trauma and the resulting memory problems associatedwith TBI. This was previously shown with CT imaging in Fig-ure 8. As shown in Figure 12, MRI from the same patient, but witha coregistered bone window CT of this patient integrated with theMRI so as to better visualize the bone–brain interface, the middlecranial fossa cups the temporal lobe. The patient depicted inFigures 8, 10, and 12 is a middle-aged individual who sustained asignificant temporal lobe contusion as a consequence of a high-speed, side-impact MVA. Because in MRI bone has an indistinctsignal compared to brain parenchyma and in some imaging se-quences is associated with a signal void, it is often difficult to viewthe precise location and configuration of bone in relationship to thesurface of the brain in MRI. By superimposing the bone fromcoregistered CT scan with that from the MR scan performed thesame day, the vulnerability of these regions to injury becomesreadily apparent in terms of how mechanical deformation and/orcontusion of these brain regions occur, as shown in Figure 12.Although the neuropathology associated with contusion is morestraightforwardly understood (Povlishock & Katz, 2005; Zafonte,Ricker, Yonas, & Wagner, 2005), mechanical deformation may

directly injure cell body metabolic function, initiating an adversemetabolic cascade (Fei, Zhang, Jiang, Huang, & Bai, 2005; Floyd,Gorin, & Lyeth, 2005; Hovda et al., 1995; Huang et al., 2002;Shreiber et al., 1999; Wu et al., 2004) that ultimately leads toneuronal injury or death, which from an imaging perspective maybe expressed as gray matter volume loss without the appearance ofovert cortical contusion (Bigler, 2005, 2007). Also, the shear-stretch-strain effects of mechanical deformation of the axon dis-rupt its cytoarchitecture (LaPlaca et al., 2005), which from amacroscopic and imaging perspective may be expressed as re-duced white matter integrity (Goetz et al., 2004). Additionally, anyform of cellular and transneuronal degeneration ultimately leads toboth white and gray matter loss, thereby contributing to the overallvolume loss associated with brain injury (Bramlett & Dietrich,2002; Rodriguez-Paez, Brunschwig, & Bramlett, 2005).

Wallerian Degeneration

Downstream or so-called Wallerian degeneration (Rodriguez-Paez et al., 2005; Thomalla, Glauche, Weiller, & Rother, 2005)results when a target structure, like the hippocampus, is damagedbut more than just local damage or atrophy of the hippocampusresults; rather a more widespread degeneration of distal or “down-stream” structures occurs because of the loss of sustainable trophicinput. Thus, although the MTL vulnerability as discussed above isstraightforward, the effects of MTL damage may be much morediverse than just focal. An excellent example of this is the fornix,as shown in Figure 13, and its connection to the mammillary body.In the patient in Figure 13, there were no identifiable lesions in thefornix either acutely or in the chronic imaging studies performed(there were multiple CC hemorrhagic shear lesions, however), yet

Figure 11. Axial CT toward the base of the skull depicting acute inferiorfrontal and anterior temporal lobe contusions, with associated edema. Notethe close proximity of the contusions to the sphenoid.

Figure 10. For the same case as shown in Figures 8 and 12, the midsag-ittal MRI view is superimposed on the identical coregistered midsagittalbone window cut from the CT on this patient, to highlight bone. The yellowarrow points to the top of the anterior clinoid process where it joins withthe lesser wing of the sphenoid and the white arrow points to the tuber-culum sellae, also referred to as the sella turcica that houses the pituitarygland. This creates another distinct surface where bone may interface withbrain, increasing the likelihood of injury in this area.

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the follow-up imaging more than a year post-injury clearly dem-onstrates fornix atrophy. The MTL in this patient, in particular thehippocampus, shows marked atrophy (see Figure 13). Accord-ingly, the fornix atrophy likely represents Wallerian degenerationfrom the nonspecific atrophic changes of the MTL, which in turndisrupts input to the mammillary body, resulting in atrophy of themammillary bodies and absence of an identifiable mammillotha-lamic tract, all shown in Figure 13. Figure 14, from a teenager whosustained a severe TBI but with only a single small focal lesion inthe thalamus, shows another view of the fornix atrophy amidst thebackdrop of generalized atrophy. Clearly the fornix atrophy issymmetric.

The coronal view in Figure 14 also shows the susceptibility ofthe temporal stem, a region that houses much of the afferent–efferent connections of the temporal lobe (Kier, Staib, Davis, &Bronen, 2004) and a region very susceptible to Wallerian degen-eration. Likewise, the anterior commissure that interconnects thetwo MTLs is affected in TBI, likely from multiple sources, includ-ing Wallerian degeneration (Wilde, Bigler, et al., 2006). Reductionin the size of the anterior commissure is evident in Figure 13. Thuswhen there is general volume loss of the temporal lobe, atrophy ofthe temporal stem, and reduction in size of the anterior commis-sure, there is typically atrophy of the fornix. With regard to thefunctional significance of these proximal, as well as distal atrophicchanges that occur as a result of TBI, not just of the fornix but forany structure found to be atrophic, the concept of diaschisis isimportant to keep in mind (Flint, Naley, & Wright, 2006; Kim,Lee, Lee, Kim, & Kim, 2005). Accordingly, although focal andWallerian degeneration may appear impressive in a particularbrain region, it may be the disruption of more distal areas thatbecome expressed neuropsychologically—the concept of diaschi-sis (Finger, Koehler, & Jagella, 2004). This underscores the po-tential explanation of why a single anatomical measurement maynot relate robustly with neuropsychological outcome, whereastaking multiple measures representative of the multiple integral

links of a neural system may yield much more meaningful rela-tionships (see Lewine et al., 2007; Moscovitch et al., 2005; Rosen-baum et al., 2004).

Methods of Image Analysis

Table 1 summarizes a variety of studies that provide details oneither anatomic identification of key frontotemporolimbic regionsor actual neuroimaging quantification methods. The majority of theneuroimaging quantification studies also detail interrater reliabili-ties and other aspects of validation for using these techniques.With higher field strength and better image resolution techniques(Naganawa et al., 2004), identification of these subtle structuralabnormalities will only improve. On the basis of the studiesreviewed in this table, detailed quantification of frontal and tem-poral lobe structures can now be accomplished in the study ofdamage to these regions and their effects on neuropsychologicalfunction.

Neuropsychological Relationships

The discussion that follows could select any of the frontal ortemporal lobe structures discussed so far, but without exception,the hippocampus has been the most studied in TBI where neuro-psychological outcome, in particular memory function, has beeninvestigated. What is particularly interesting about such studies isthat they universally demonstrate only modest relationships ofmemory function with overall hippocampal volume, while show-ing robust hippocampal volume loss associated with severity ofinjury (Bigler, Anderson, & Blatter, 2002; Himanen et al., 2005;Serra-Grabulosa et al., 2005; Tomaiuolo et al., 2004). Because ofthe critical nature of the hippocampus in memory (Moscovitch etal., 2005), its selective vulnerability in TBI (Wilde et al., 2007),and the commonness of memory impairment associated with TBI(Vakil, 2005), one would expect a more robust relationship be-

Figure 12. These illustrations are taken from the same patient as in Figures 8 and 10. In this case, the 3-D spiralCT bone window is coregistered with the 3-D thin-slice MRI done on the same day. CT is superior to MRI invisualization of skull anatomy, and therefore, what is shown in this illustration is bone colorized pink from thecoregistered CT superimposed upon the MRI. This helps in visualizing the location of bone–brain interface, aswell as the compartmentalization of the cranial fossae. This patient did sustain a significant left temporal lobecontusion, where the follow-up MRI approximately 2 years post-injury demonstrates significant temporal horndilation, hippocampal atrophy (compare left and right hippocampal size), and general volume loss of thetemporal lobe. Temporal lobe volume loss is best visualized in A, a T2 weighted image showing increased levelsof cerebral spinal fluid in the temporal pole and region of the Sylvian fissure. B is coronal T1 and C is sagittalT1 view through the long axis of the hippocampus (compare this view with that in Figure 6).

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tween the degree of hippocampal volume loss and memory per-formance (Himanen et al., 2005). Squire and colleagues (Squire,2004; Rempel-Clower, Zola, Squire, & Amaral, 1996), using an-oxic brain injury as the model to study hippocampal damage andmemory, showed variable levels of association between degree ofhippocampal atrophy on memory until there was over 40% volumereduction. Once a 40% volume reduction was surpassed, patientsbegan “to display dense declarative memory impairments, somewith complete amnesia” (Rempel-Clower et al., 1996, p. 5233).Although anoxic brain injury represents an obviously differentetiology than TBI, it does share several similar neuropathologicaleffects (e.g., excitotoxicity) on the hippocampus (see Hopkins,Tate, & Bigler, 2005), such that memory impairment and hip-pocampal atrophy from anoxia cannot necessarily be distinguished

from that seen in TBI. Gold and Squire (2005) showed the differ-ential and selective effects of cytoarchitectonic injury to the hip-pocampus, where “bilateral damage limited primarily to the CA1region of the hippocampal formation is sufficient to produce amoderately severe anterograde memory impairment” (p. 83; seealso Bayley, Gold, Hopkins, & Squire, 2005). In anoxia, becauseof differences in the vascular distribution to the MTL (DeReuck,Van Kerckvoorde, De Coster, & vander Eecken, 1979), CA1 hasbeen considered the “vulnerable sector” (Sommer sector; seeHogan et al., 2004), whereas CA2 and CA3 may be part of a more“resistant sector” (Spielmeyer sector; see DeReuck et al., 1979;Hogan et al., 2004), with the CA4 being a sector of mediumvulnerability (Bratz sector; Mark, Daniels, Naidich, Yetkin, &Borne, 1993). In TBI, selective hippocampal damage, especially inthe CA1 and CA3 areas, has been demonstrated in post-mortemstudies (Maxwell et al., 2003), and the head of the hippocampusmay be more vulnerable to injury, possibly because of its proxim-ity to the sphenoid bone (Ariza et al., 2006). Contemporary MRImethods now permit general identification and quantification ofthese subfields of the hippocampus (see Table 1) as well as otherMTL, basal frontal, and limbic regions. Because more has beendone with hypoxic injury to this region, more work with TBIsubjects is warranted to determine CA subfield contributions tomemory impairment in TBI. As shown in the Figure 7 schematic,an aspect of the anterior medial wall of the parahippocampal gyrusgives rise to entorhinal cortex that folds into the subiculum, whichis contiguous with CA1, and then to the other hippocampal sub-fields. Additional anatomic details of this region can be found inDuvernoy (1997). Figure 15, from Saitoh, Karns, and Courchesne(2001), provides a convenient outline of these regions for imagequantification, a procedure that can be readily replicated (seeBigler et al., 2003). Higher field strength MRI may provide evenmore detailed quantitative approaches to hippocampal quantifica-tion (Hogan et al., 2004; Posener et al., 2003), but as shown inFigures 12–15, trauma-induced atrophy of the hippocampus makesit difficult to identify specific subfields with clarity. Therefore, amethod like that of Saitoh et al. (2001) is adequate at this time,even though this method does not include all of the subiculum. Asshown in Figure 16, distinctly visible hippocampal atrophy ispresent in this single coronal slice, with clearly reduced size of thesubiculum and all hippocampal fields (refer to Figure 15) in this11-year-old child who sustained a severe TBI (Glasgow ComaScore � 5). Parceling the hippocampus and fornix from the rest ofbrain parenchyma and placing the image into three-dimensional(3-D) space nicely demonstrates the generalized nature of hip-pocampal and fornix atrophy, as shown in Figure 16. Thus, in TBIthe loss of memory function probably has multifaceted origins thatcannot be specifically attributed to just hippocampal pathology,because both input as well as output from the hippocampus isaffected. Indeed, as shown in Figure 16, positron emission tomog-raphy shows extensive reduction in activity throughout the entiretyof the MTL, likely indicating widespread neural pathology. Un-doubtedly TBI-induced hippocampal pathology is a major reasonfor neuropsychological impairment in TBI, but it must be viewedas just one part of the overall pathological changes in the MTL andits connections with the rest of the brain (see Van Petten, 2004;Van Petten et al., 2004).

Accordingly, the structural imaging TBI study has not beendone in such a way that a more comprehensive assessment is

Figure 13. This patient sustained a severe traumatic brain injury (TBI;Glasgow Coma Score � 3) in a motor vehicle accident, with imagingstudies done more than 2 years post-injury demonstrating the principle ofWallerian degeneration of the fornix. Significant trauma-induced hip-pocampal atrophy is clearly identified in the coronal section shown at thebottom in D compared to the control in H. Clearly these sagittal imagesshow a withered fornix in A, with reduction in the size of the mammillarybody (MB) and anterior commissure (AC) in B and C and less than clearidentification of the mammillothalamic track. The age-matched controlcase in E–H clearly shows how these regions can be identified in thesagittal plane. Note in the control how distinctly each pathway can beidentified and isolated and that at every level the TBI patient has atrophicchanges making the pathways impossible to identify or barely perceptible.Figure 14, from a different patient, shows how fornix atrophy can beidentified in the coronal plane and is simply a different perspective on thesame problem of Wallerian degeneration of the fornix.

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Figure 14. Coronal views are presented on top from an older teenage patient who sustained a severe traumaticbrain injury (TBI). As visualized, the fornix has withered in comparison to the age-matched control. This isthought to represent downstream degeneration of this structure as a result of the hippocampal and medialtemporal lobe damage, including temporal horn dilation, that can be seen on the right in comparison with thecontrol subject, where the true inversion recovery sequence MRI scan provides exquisite anatomical detail of thebrain. There is also nonspecific white matter loss as reflected by reduction of corpus callosum surface area. Whenviewed in coronal perspective at the level of the crus fornix, the symmetric loss of the size of the fornix can bereadily appreciated. Also, note the marked reduction in the size of the temporal stem and overall reduction in theamount and integrity of the temporal lobe white matter in comparison to the control.

Table 1Quantitative Methods for Volumetric Analysis of Frontal and Temporal Lobe Structures

Frontal lobe Peuskens et al., 2004; Wilde et al., 2005Temporal lobe Bigler et al., 2003; Bonilha et al., 2004; Peuskens et al., 2004; Wilde et al., 2005Basal ganglia structures Abernethy et al., 2002; Peterson et al., 2000, 2003Limbic structures

Hippocampus Bigler et al., 1997; Connor et al., 2004; Duvernoy, 1988, 1997; Gardner & Hogan, 2005;Hogan et al., 2004; Jack et al., 1995; Korf et al., 2004; Posener et al., 2003; Thom etal., 2005; Watson et al., 1992; Wilde et al., 2005; Xu et al., 2000

Cytoarchitectonic regions Bigler et al., 2003; Gold & Squire, 2005; Kiefer et al., 2004; Saitoh et al., 2001Subiculum Gold & Squire, 2005; Varho et al., 2005Fimbria D. C. Davies et al., 2001; Zahajszky et al., 2001

Entorhinal and perirhinal cortex R. R. Davies et al., 2004; DeToledo-Morrell et al., 2004; Insausti et al., 1998; Jutila et al.,2001; Pruessner et al., 2002; Raz et al., 2004; Rodrigue & Raz, 2004; Xu et al., 2000

Fornix D. C. Davies et al., 2001; Gale et al., 1993; Nakamizo et al., 2002; Zahajszky et al., 2001Amygdala Bonilha et al., 2004; Jernigan et al., 2005; Brierley et al., 2002; Watson et al., 1992Mammillary bodies Kesler et al., 2001Basal forebrain Teipel et al., 2005Substantia innominata (nucleus basalis of Meynert) Hanyu et al., 2002Nucleus accumbens Jernigan et al., 2005

Note. This table contains but an example of studies that have demonstrated reliability in quantifying various frontal and temporal lobe as well as limbicstructures. The table should not be considered exhaustive review of this area, as many other studies could have been cited.

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conducted, simultaneously analyzing the neural systems involvedin memory function. For example, the patients presented in Figures12–15, have distinct hippocampal atrophy and memory impair-ment, where clearly the CA1 region is either indefinable or atro-phic, suggesting generalized loss of neurons that project via thisarea. However, generalized limbic system atrophy is also presentin each case, so clearly any memory impairment is not just hip-pocampal atrophy. The entire limbic projection system from en-torhinal cortex to fornix, mammillary body, anterior thalamus, andcingulate are atrophic. Therefore, what is needed in the study ofmemory or cognitive correlates of TBI, from a structural imagingperspective, is an integrative approach simultaneously examiningall of these structures and their relative contribution to memory orother cognitive functions. Van Petten (2004) showed in a meta-analysis the variability and weak relationships between just simplehippocampal volume and memory. This is further evidence thatTBI memory and MTL research needs a far more detailed analysisof the various structures that make up the MTL as well as asso-ciated structures critical for memory function. Additionally, com-bining quantitative structural image analysis with functional MRI

may be particularly beneficial (Chen et al., 2004; Rosenbaum etal., 2005). Finally, complex developmental and life-span issuesobviously contribute to the cognitive and neurobehavioral outcomefollowing traumatic injury to the MTL.

Conclusions and Implications for Future NeuropsychologicalResearch: Experimental Design Recommendations

The current review provides the rationale for in-depth analysesof the gross and fine structure of MTL as well as frontal loberegions in investigating neurobehavioral outcome from TBI. PastTBI research that explored neuropathological changes in brainimaging with neuropsychological outcome, first used qualitativemethods (i.e., a lesion in the region of the hippocampal formation)followed by quantitative methods that tended to focus on a singlemeasurement of a specific anatomical structure (i.e., hippocampalvolume). As demonstrated in the current review, neuroimagingtechnology has rapidly improved such that straightforward analy-ses of any given brain structure can be performed, includingexamination and quantification of a given structure’s afferent and

Figure 15. The hippocampal formation in the coronal plane used for image quantification of hippocampalsubfields. (A) Representative T1-weighted coronal image. The left hippocampal formation is indicated with abox. The image is from a 6-year-old autistic boy. (B) Magnified coronal image of left hippocampal formation.AB � angular bundle; AL � alveus; CA � cornu ammonis; CO � collateral sulcus; DG � dentate gyrus; FM �fimbria; FD � fimbriodentate sulcus; HF � hippocampal fissure; PHG � parahippocampal gyrus; PP � perforantpath; S � subiculum; TH � temporal horn of the lateral ventricle. (C) Drawing of the hippocampal formation adaptedfrom Duvernoy (1988). The cross-sectional areas of the area dentata (AD; dentate gyrus � CA4) and combinedsubiculum and CA1–CA3 (CAS) were measured as shown in Panel D. (D) Magnified coronal image of lefthippocampal formation with lines depicting anatomical boundaries of AD and CAS. Line thickness was increased forillustrative purposes. From “Development of the Hippocampal Formation From 2 to 42 Years: MRI Evidence ofSmaller Area Dentata in Autism,” by O. Saitoh, C. M. Karns, and E. Courchesne, 2001, Brain, 124, p. 1320.

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efferent pathways and, in some cases, cellular layers of a structure(i.e., hippocampal subfields). More unified methods of analysis areoccurring in such a way that large normative databases will beavailable for comparison to any patient group (Gogtay et al., 2006;Joshi, Davis, Jomier, & Gerig, 2004; Luders et al., 2005; VanHorn, Grafton, Rockmore, & Gazzaniga, 2004; Van Horn et al.,2005). Understanding these macroscopic neural systems or net-works subserving particular functions will likely advance the un-derstanding of how neuropsychological function(s) relate to anygiven brain structure, region, or system. On the basis of theseadvances, neuropsychological research designs that examine post-TBI memory and related function can no longer focus only on asimple volumetric analysis of a specific structure. Rather, anintegrative approach to studying frontal and temporal lobe brainstructure, as well as other critical structures (i.e., thalamus and itsdivisions, corpus callosum, etc.) and function in TBI should nowbecome the standard.

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Received January 17, 2006Revision received August 16, 2006

Accepted October 30, 2006 �

531TRAUMATIC BRAIN INJURY AND CRANIAL FOSSA