Diffusion MRI || Tractography for Surgical Targeting

415Diffusion MRI Copyright © 2009 Elsevier Inc. All rights reserved

AbstrAct

Diffusion tractography forms a natural extension of presurgical FMRI to exert impacts on surgical decisions. Delineating fiber pathways improves preoperative evaluation, planning and surgical targeting by neuronavigation. This chapter discusses tractography indications for surgical targeting, methods available to it, and intrinsic limitations.

Tractography indications cover surgical tract preservation, selective tract dissection, and preimplantation tracking. For surgical preservation the pyramidal tract, arcuate fascicle, and optic radiation are of primary relevance. In surgical dissections, tractography may improve targeting for pain, spasm, or seizure control. Prior to surgical implantation, e.g. of auditory prostheses or deep brain electrodes, tractography can supplement preoperative assessments.

Surgical applications are most concerned about false-negative tractographies. In addition to displacing, infiltrating, or destructing tracts, lesions can alter diffusion signals and lead to false negatives. Compared to streamlining false negatives are decreased by probabilistic tracking and modeling multiple fiber orientations. Prior clinical knowledge about (residual) tract integrity can, within Bayesian frameworks, facilitate conversion of tractography outputs into proper probability values and constrained probabilistic tracking. Therewith, adverse clinical conditions (such as low fractional anisotropy due to perifocal edema) must no longer reduce the probability to assign a voxel to a given tract. Probabilistic tractography further increases both sensitivity and specificity under aversive clinical conditions. Surgical targeting ought to take advantage of these benefits and should not trade speed for accuracy.

In general, tractographies are not indicated in medical emergencies and will not substitute intraoperative monitoring. Nevertheless, they constitute a valuable tool for preoperative diagnostics and surgical targeting.

Keywords: Diffusion tractography, clinical applications, tract preservation, functional neurosurgery, probabilistic tracking

I. Introduction 416

II. surgical target and Intent 417A. Lesion Stereotaxy and Resection 419B. Epilepsy Surgery 424C. Functional Neurosurgery (Selective

Ablations, Auditory Implants, DBS) 424

III. tractography strategies for surgical Purposes 425A. Pyramidal Tract 427

B. Arcuate Fascicle 429C. Sensory, Brainstem, and Spinal Tracts 431D. The Specter of False Negatives 432

IV. conclusions 438

Acknowledgments 439

references 439

o u t l I n E

C H A P t E R

tractography for Surgical targetingAndreas J. Bartsch, Armin Biller and György A. Homola

19

III. dIffuSIon mRI foR In vIvo nEuRoAnAtomy

19. tRACtogRAPHy foR SuRgICAl tARgEtIng416

I. IntroductIon

The unique ability of diffusion MRI to non-invasively reveal anatomical connections within the central nerv-ous system (CNS) in vivo has attracted steadily increas-ing neurosurgical attention (Clark et al., 2003; Dellani et al., 2007; Inoue et al., 1999; Krings et al., 2001a, b; Mikuni et al., 2007a, b; Nimsky et al., 2005a, b; Yu et al., 2005). By delineating functionally relevant fiber path-ways, diffusion tractography has sought to improve preoperative patient evaluation, intervention plan-ning, and surgical targeting through intraoperative neuronavigation and outcome prediction. In this way, diffusion tractography forms a natural extension to presurgical functional MRI (FMRI) to exert an impact on surgical decisions. Unlike the vast majority of FMRI tests, diffusion imaging does not require task compli-ance and can even be performed in patients with con-sciousness impairments due to sedation or narcosis.

Fiber trackings are increasingly requested by neuro-surgeons. This is especially so for interventions in the motor system, whose primary cortical strip is in most cases readily identified by anatomical landmarks, and for which tractography may already be more popular than preoperative FMRI exams. However, the mere fact that CNS pathways can be tracked in principle, and that conducting tractography investigations is consid-ered to be in the vanguard of progress, does not nec-essarily translate into tangible and proven advantages for a given patient. As with FMRI, patients undergo-ing tractographic mappings should be well selected. According to our experience, only a fraction of the trac-tography requests to a neuroradiological department are in fact sensible for concrete clinical (as opposed to research) purposes and actual neurosurgical decision-making.

In many cases, lesion topography and its relation to relevant fiber systems becomes evident by simple phys-ical examination. Involvement of the pyramidal tract, the somatosensory or the optic radiation, in particular, is often deductible based upon the signs and symptoms clinically exhibited by the patient possibly prior to any imaging. In other cases, tract involvement is obvious by pure anatomic criteria applied to structural CT, MR (Figure 19.1) or to native, unprocessed diffusion- weighted images. (In this chapter image slices are always displayed in a left-handed coordinate system, i.e. ‘‘radiological convention’’ with the left side of the image corresponding to the right side of the patient.)

In one way or another, most lesions adversely affect conventional diffusion-weighted imaging (DWI). Some lesions do so to an extent that effectively precludes them from any expedient tractography (Figure 19.1d).

Even when fiber tracking is feasible, its proprietary pre-dictive value often remains elusive – primarily due to the increased cost of false negatives encountered under clinical conditions. Therefore, validation of tractogra-phy is crucial for surgical targeting, and we explicitly refer the reader to Chapter 16.

Most of the data published on tractography for sur-gical targeting so far essentially represent feasibility studies supporting a proof of principle. The majority of these have focused on the pyramidal tract, the subject of about 85% of the investigations (out of 50 surgically relevant reports reviewed in detail for this chapter). Less than one third have – additionally or exclusively – investigated other bundles, especially the arcuate fasci-cle and optic radiation (about 25% of the studies).

Unfortunately, precisely establishing tractographic sensitivity and specificity for clinical purposes is impractical. For one, this is due to the wide variety of different lesions encountered in practice and their vari-able effect on fibers themselves as well as on fiber trace-ability by DWI. The issue is further complicated by the fact that there is no real gold standard or even alterna-tive with which to establish ground truth in vivo and to compare with DWI results. Depending on the method, tractography at times either fails or yields unexpected results in clinical cases. Anatomical a priori knowledge is always required to reasonably reconstruct any fiber system (Mori et al., 2005). Electrical stimulation map-ping (ESM) and monitoring techniques are certainly valuable and essential to achieve some validation level in the operating room (OR) itself during the neurosur-gical procedure (Bello et al., 2008; Berman et al., 2004; Henry et al., 2004; Kamada et al., 2005a, b; Mikuni et al., 2007a, b). However, these are not imaging techniques in the sense that they do not visualize the tracts or their integrity. They do not definitely differentiate imminent structural damage to fiber pathways from functional irritation phenomena in their proximity or along their course. Electrical stimulation causes seizures in up to every fourth patient (Bello et al., 2008) and elicited responses strongly depend on the individual current applied (Kinoshita et al., 2005). Obviously, chemical axon tracing, neurodegenerative lesioning or post-mortem preparations are not available to directly and systemati-cally validate presurgical tractography results. At least, axonal degeneration can be demonstrated by non- diffusion-weighted MR sequences (Goodin et al., 1988; Orita et al., 1991; Sawlani et al., 1997) and is later accom-panied by atrophic changes. Nevertheless, tractography stands largely on its own and effectively depends on prior knowledge to obtain some level of face validity.

Furthermore, preoperative tractography results are transferable into the operating room only within certain limits, especially when brain shifts and the


417

ensuing co-registration difficulties set in. Although intraoperative DWI has become technically possible and has even been proposed to solve the brain shift problem (Coenen et al., 2005; Nimsky et al., 2005a, b), it is conducted under quite a hostile OR environment and is affected by the procedure itself (e.g. associated bleeding and operative edema). It also faces firm time constraints for data acquisition and analysis.

On the other hand, crude and macroscopically com-plete resections of highly malignant brain tumors such as glioblastomas primarily increase the risk of severe postoperative disabilities but do not prevent recur-rences due to extensive glial invasion (Burger et al., 1989; Giese et al., 2003; Jänisch, 1989; Kelly et al., 1987) or substantially extend survival. Notably, the level of evidence demonstrating benefits for gross total brain tumor removal by radical resections remains rather lim-ited (Proescholdt et al., 2005). Thus, surgical resections should be performed to the extent that is safely possi-ble, regardless of the tumor grading. Often resections are not limited by the actual proximity to vital tracts

but by other factors, such as immuration of crucial vessels by a tumor and the difficulty of skeletonizing the tumor by a safe and tolerable surgical procedure. Nonetheless, improving tractographic accuracy and minimizing false-negative results are crucial for surgi-cal targeting.

In this chapter, we will discuss presurgical indi-cations and perspectives for tractographic patient examination, methods available, and their intrinsic limitations. Minimal requirements for the diffusion data acquisition and analysis are proposed, and surgi-cally relevant tractography results are illustrated by a variety of relevant showcases.

II. surgIcAl tArget And Intent

Prior to diagnostic tractography, the surgical tar-get and intent must be clarified (Boxes 19.1 and 19.2). Most commonly, the surgical target is a lesion and

SuRgICAl tARgEt And IntEnt

* *^ ^

(c)(b)(a)

**

^ ^

^ ^

(f)(e)(d)

FIgure 19.1 (a–c) T1-weighted Gadolinium-enhanced MRI of a bronchial carcinoma metastasis to the right paracentral lobule with hypointense perifocal edema. The patient exhibited monoparesis of the contralateral leg, and lesion location is obvious by pure anatomic cri-teria (* handknob, ^ cingulate sulcus). There is hardly any point in conducting either pyramidal tractography or motor FMRI in this case. (d–f) T2*-susceptibility- (d) and T1-weighted native (e) and Gadolinium-enhanced (f) MRI of a cavernoma (cavernous (hem-) angioma or ‘‘occult cerebrovascular malformation’’) in the junction of the middle frontal with the precentral gyrus between the superior and intermediate precen-tral sulcus. The patient had experienced a seizure and transient contralateral facial paresis. Note the profound T2* black-out that extends far beyond the enhancing core and hypointense rim of iron-storage products (ferritin/hemosiderin) on T1 weighting. Aside from its definite loca-tion (* handknob, ^ cingulate sulcus), the lesion effectively prevents expedient pyramidal tractography or motor FMRI: lesion-induced signal changes will almost inevitably cause false-negative results the lesser the distance to it.



the intent is to obtain a specimen from it (stereotac-tic biopsy), to reduce its mass effect or to remove it (resective surgery). So far, essentially all clinical data derived for presurgical or intraoperative tractography pertain to this scenario. Here, the common goal is to preserve functionally important tracts from surgical damage. Treatment planning for gamma-knife sur-gery represents a somewhat special case but mostly falls into the same category (stereotactic radiosur-gery). If the patient already suffers from preopera-tive deficits, these must not be further changed for the worse through surgery (‘‘nil nocere’’ principle). Optimizing the surgical approach and targeting by tractographic navigation can further guide stereotactic tissue probing and lesion resectioning. Promising data indicate that tractography potentially reduces dura-tion of resective surgery, incidence of ESM-induced

seizures, and postoperative morbidity while it may also improve extent of tumor resection, postopera-tive assessment of the surgery, and outcome in gen-eral (Bello et al., 2008; Berman et al., 2004; Yu et al., 2005). Selective tractotomies for ablative or epilepsy surgery differ from targeting for path preservation in that removal of a particular tract is not feared but specifically desired for treatment. Functional naviga-tion at the cortical level is substantially aided by the anatomy of the sulci and major vessels, and FMRI results can often be related to given sulcal, gyral, and vascular landmarks. Commonly used landmarks are the Rolandic or central sulcus, the pre- and postcen-tral gyrus, the sylvian or lateral fissure including the horizontal and ascending ramus, the inferior frontal gyrus, the calcarine sulcus, Heschl’s gyri, and supe-rior (Trolard) or inferior (Labbé) anastomotic veins

surgical Intentl stereotactic biopsy (tissue probing) → pyramidal

tract1 (primarily)l resection/evacuation, stereotactic radiosurgery →

pyramidal tract, arcuate fascicle, somatosensory and/or optic radiation1

l seizure control → corpus callosum2 (callosotomy), optic radiation1 (uncinate2/arcuate1 fascicle?) (temporal lobectomy TLE*)

l functional ablation (for pain and/or spasm control) → spinal: dorsal/ventral root2 of spinal nerves (rhizotomy), commissura alba2 (midline or commissural longitudinal myelotomy), anterolateral fascicle2 (anterolateral cordotomy), spinal tract of trigeminal nerve2 (Sjöqvist’s tractotomy)

l intracranial♣: spinal lemniscus2 (lemniscotomy or ‘‘mesencephalotomy’’/medial thalamotomy), cingulum2 (bilateral cingulotomy)

l functional implantation → acoustic radiation/lateral lemniscus3 (prior to auditory cochlear, brainstem or midbrain implants), deep brain pathways4 (prior to insertion of electrodes for deep brain stimulation DBS)

target/lesion localization1

l sub-/peri-Rolandic → pyramidal tract, possibly arcuate fascicle and/or somatosensory radiation

l peri-sylvian (including frontal, fronto-parietal and temporal operculum) → arcuate fascicle and/or pyramidal tract

l temporoparietal lobes → arcuate fascicle, somatosensory and optic radiation, rarely pyramidal tract

l pre-Rolandic frontal lobes (F1/2, in particular) →arcuate fascicle (possibly)

l deep brain (brain stem and basal ganglia) →pyramidal tract

l occipital lobes → optic radiation

box 19.1

n e u r o s u r g I c A l I n t e rV e n t I o n s ( c l A s s I F I e d A c c o r d I n g t o I n t e n t V s l e s I o n l o c A l I z At I o n ) A n d F I b e r P At h -

wAy s o F P o t e n t I A l I n t e r e s t

The goals are: 1 . . . preservation, 2 . . . partial or total transection, 3 . . . presurgical assessment of integrity or 4. . . of connectivity patterns for surgical targeting. 3/4 are plausible to predict or improve success of the procedures but no hard data are available yet to support that notion.* Homonymous superior quadranthemianopsia of the contra-lateral visual field is a common deficit after TLE (due to injury to Flechsig–Meyer’s loop, i.e. temporal genu of the optic radiation). ♣ Currently less often performed.


419

(see Figures 19.1, 19.6, and 19.8 for example). White matter, on the other hand, presents itself as rather unstructured to the surgeon. Landmarks are either una-vailable or only available to a limited extent for in vivo navigation through its substance and the embedded fiber trajectories. This very fact further emphasizes the appeal tractography exerts on surgical targeting.

A. lesion stereotaxy and resection

A particular problem with tractography in the pres-ence of brain lesions is that they can affect not only the fibers but also the diffusion signal itself (Boxes 19.3 and 19.4). For the peripheral nervous system (PNS), structural correlates of nerve damage of different severity (i.e. neuro-, axonotmesis, and neurapraxia) and subsequent regeneration are well established. For CNS, classification of tract damage has remained more descriptive – probably because it is less accessible to other means of examination. Little to nothing is known about white matter recovery from structural damage but there is ample evidence for such capacities in the adult human brain (Bartsch et al., 2007). Essentially, fibers may be displaced, compressed, disaggregated

in their environment, swollen, infiltrated and/or destroyed by a given lesion (Figure 19.2). DWI and tractography have raised expectations to depict these processes (Bello et al., 2008; Bennett et al., 2004; Chen et al., 2007a, b; Clark et al., 2003; Ducreux et al., 2005a; Fujiyoshi et al., 2007; Gossl et al., 2002; Holodny et al., 2001; Niizuma et al., 2006; Okada et al., 2007; Ozanne et al., 2007; Schluter et al., 2005; Schonberg et al., 2006; Stieltjes et al., 2006; Wei et al., 2007; Yu et al., 2005) but it has been acknowledged that perifocal edema, for example, can induce tracking failures or terminations that are indistinguishable from the effects of tract destruction (Berman et al., 2004; Ducreux et al., 2006). Clearly, the failures to connect two ROIs due to fac-tors such as edema must not be confused with fiber destructions.

Displacement and compression are due to the mass effect of a space-occupying lesion. Both represent less severe changes of the fiber architecture and less of an obstacle to successful and accurate tractography than edema, for example. It has been shown, for exam-ple, that even though diffusivity parallel to the larg-est diffusion tensor eigenvalue (i.e. along the main fiber orientation) may increase upon displacement and compression, radial diffusivity (i.e. perpendicular


tracts to Preserve from surgical damagel pyramidal tract1 (somatotopically predictable motor

functions)l arcuate fascicle2 (less predictable language

functions: conduction/repetition aphasia?)l somatosensory radiation1 (somatotopically

predictable epicritic functions ascending from the posterior funiculus/medial lemniscus)

l optic radiation1 (retinotopically predictable visual functions)

The pyramidal tract is of primary concern since dam-age to it inevitably results in hemiparetic/-plegic loss of motor functions.

tracts constituting Potential surgical targetsl corpus callosum3

l uncinate fascicle2

l spinal and trigeminal lemniscus, spinal tractus of trigeminal nerve1

These tracts may be targeted by epilepsy surgery, ablative pain or spasm therapy; others might become relevant for stimulation devices.

tracts whose Integrity Matters for surgical Implantsl acoustic radiation and lateral lemniscus1

(tonotopically predictable auditory functions ascending from the cochlea)Here, (residual) integrity or maturation capacity is

essential for ultimate implant functioning.

1 . . . projection, 2 . . . association, 3 . . . commissural fiber systems

box 19.2

M A I n F I b e r P At h wAy s o F s u r g I c A l I n t e r e s t



lesion Impact on cns Fibersl displacement (dislocation): shifting of fiber bundles,

virtually always accompanied by other phenomena such as compression

l compression (compaction): densification of fiber bundles due to increased pressure and displacement, for example

l rarefaction (‘‘dilution’’): fiber loosening due to perifocal (vasogenic) edema, for example

l swelling (turgor): temporary tumescence of fibers due to cytotoxic edema, for example

l intermingling (‘‘benign mixing’’): normal fibers and pathological tissue are nested closely

l infiltration (‘‘malignant penetration’’): invasion of fiber bundles by underlying pathology

l destruction (disruption): transection of fiber bundles after infiltration, for example

l disentangling (detachment): disassembling of fiber tracts due to displacement and traction, for example

l splitting (separation): deflecting more or less parallel running fiber bundles away from each other, e.g. by displacement through the intervening pathology

Destruction and infiltration may be considered as more or less severe forms of (irreversible) disintegra-tion; disentangling, splitting, and edematous rarefaction as particular forms of (at least potentially reversible) disaggregation.

box 19.3

P o t e n t I A l I M P A c t o F l e s I o n s o n F I b e r P At h wAy s

hyperintense diffusion signal changesl restricted diffusion: cytotoxic edema (e.g. by

ischemic stroke), high-cellular malignancies (e.g. lymphomas), inflammatory lesions (esp. with abscess formation), epidermoids, . . .

l T2 shine-through: vasogenic (perifocal) edema, extracellular methemoglobin (late subacute/chronic hemorrhages), moderately increased macromolecule content (e.g. proteinaceous cysts in hemangioblastomas), other bright T2 lesions (e.g. FCD, gangliogliomas, DNET), . . .

hypointense diffusion signal changesl T2 darkening/black-out: paramagnetic effects

from drilling abrasions, deoxyhemoglobin (acute

hemorrhage), intracellular methemoglobin (early subacute hemorrhages), or hemosiderin/ferritin (e.g. residuals from prior bleedings), etc.; normal intravascular deoxyhemoglobin (e.g. in venous angiomas*), flow void (e.g. in AVMs), very high macromolecule concentration (e.g. fibrocollagen), low spin density (e.g. calcifications, scant cytoplasm), melanin (in melanotic melanomas) and free radicals, . . .

Mixed diffusion signal changesl hyper-, hypo-, or intermediate intensities: cellular

debris/necrosis/hemorrhages of different ages, etc. (e.g. in high-grade brain tumors such as glioblastomas or PNETs), fat-containing lesions (e.g. lipomas or teratomas), and chemical shift on fat-water boundaries (e.g in ruptured dermoids), enhanced ghosting (by pulsation or motion of intralesional fluid), colloid cysts, . . .

* Venous angiomas are ‘‘no-touch’’ lesions, i.e. they should not be removed.

box 19.4

e x A M P l e s o F l e s I o n - I n d u c e d d I F F u s I o n s I g n A l c h A n g e s w I t h P o t e n t I A l ly A d V e r s e

t r A c t o g r A P h y I M P A c t


421

to the main fiber orientation) may actually counter-act and outweigh this by a more substantial decrease (Schonberg et al., 2006). Thus, fractional anisotropy can effectively increase and tracts may turn out easier to trace (or ‘‘de-masked’’) under the influence of a space-occupying lesion.

However, pure compression is rare and, unless the displacement leads to herniation, effects of compres-sion are more likely to remain subclinical. More often, lesions are accompanied by perifocal edema. Perifocal edema increases radial diffusivity and decreases the fractional anisotropy of a given tract (Bastin et al., 2002; Lu et al., 2003), which may be further pronounced by tumor infiltration (Lu et al., 2004; Provenzale et al., 2004). This makes it harder to trace fibers by diffusion MRI (Roberts et al., 2005; Stadlbauer et al., 2007b) and can eventually mask them despite the fact that their structural integrity may be quite well maintained and not irreversibly disrupted. Note that none of the cases shown by Schonberg et al. (2006) exhibited profound perifocal edema such as in Figure 19.3.

Similarly to such T2 shine-through effects, more or less isotropically restricted diffusion (within cytotoxic edema or dense accumulations of certain neoplastic

cells; Figure 19.4) and various T2 darkening or black-out phenomena (Figures 19.1d and 19.6c) may conceal tracts of interest from detection (Box 19.4). Lowering the fractional anisotropy constitutes the common final effect of various hyper-, hypointense, or mixed dif-fusion signal changes induced by lesions in vivo (see also Table 19.1). By escalating the associated false-negative risk, it imposes the real clinical challenge to tractography for surgical targeting. T2 black-out lesions such as cavernomas or arteriovenous mal-formations (AVMs) deserve particular mention and have recently gained tractography attention (Chen et al., 2007b; Coenen et al., 2003; Moller-Hartmann et al., 2002; Niizuma et al., 2006; Okada et al., 2007; Ozanne et al., 2007). Originating from vascular spaces, they are not destructive to adjacent fibers and do not infil-trate tracts as gliomas may do, but intraparenchymal hemorrhage is a common complication. Such presen-tation may be occult, i.e. asymptomatic, or sympto-matic and can cause tract disruption as well as local distortions on diffusion-weighted echo-planar imag-ing (EPI). However, surgical removal may be rather straightforward and quite atraumatic depending on location and extension. For example, surgery of dural


H2O

Lesion

Node of Ranvier

Myelinated axons

Myelinating arms(of oligodendrocytes)

Oligodendrocyte(with Soma)

(a)

(b) (c) (d) (e)

FIgure 19.2 Schematic representation of axonal myelination in the central CNS and some effects lesions can exert on fibers (see also Box 19.3). In the CNS, axons are myelinated by oligodendrocytes. In contrast to Schwann cells of the PNS, these extend to multiple axons (a). Lesions can be accompanied by perifocal edema (b) which increases diffusivity, reduces fractional anisotropy and may cause false- negative tractography results (see also Table 19.1). Space-occupying lesions can displace, compress, and possibly split fibers (c). By decreasing the extracellular space between fibers (see left two axons), compression is able to reduce radial diffusivity and to increase fractional anisotropy. Cytotoxic edema causes cellular (including glial and axonal) swelling (d) which reduces diffusivity as well as fractional anisotropy and may also cause false-negative tractographies. Additionally, intra-axial lesions can destruct fibers and their myelin sheaths (e).



or sulcal AVMs may not require dissection of CNS parenchyma, and uncomplicated embolization itself does not typically cause axonal injury. Both can ade-quately relieve functional symptoms resulting from circulatory changes such as congestion or stealing phenomena and are usually performed in a combined treatment approach.

Thus, the most important factor which determines the effect of a lesion on adjacent fibers and the diffusion signal is the lesion type or entity (Box 19.5). For further details, we refer the reader to standard neuroradiologi-cal textbooks (Atlas, 1996; Orrison, 2000; Osborn, 1994). To some extent, diffusion MRI reflects the histopatho-logical and clinical features of a lesion (Kim and Kim, 2007; Lemort et al., 2007; Lui et al., 2007; Tropine et al., 2004; Vijayakumar et al., 2007), with tumor infiltration of white matter tracts being just one of these features (Bennett et al., 2004; Schluter et al., 2005). Aside from fiber tracking applications, there has been, for exam-ple, a considerable interest in relating diffusion MRI to the cellularity, malignant infiltration, growth kinetics, and grading of brain tumors and in aiding the defini-tion of optimal biopsy sides (Gauvain et al., 2001; Guo et al., 2002; Inoue et al., 2005; Jbabdi et al., 2005; Kono et al., 2001; Lu et al., 2004; Sugahara et al., 1999). In extra-axial tumors, i.e. meningeomas in particular, fractional anisotropy values may indicate their mechanical con-sistency (Kashimura et al., 2007; Tropine et al., 2007). As indicated above, high-cellularity malignancies such as primary CNS lymphomas typically result in isotropic diffusion restrictions which can impair successful fiber

(a)

(e)

(b)

(f)

(c)

(g)

(d)

(h)

FIgure 19.3 Diffusion- (a), T2- (b), and T1-weighted Gadolinium-enhanced (c, d) MRI of an extra-axial meningeoma with extensive perifocal edema. Because the tumor is located outside of the brain parenchyma, the vasogenic edema is pure and not accompanied by tumor infiltration. It substantially lowers the fractional anisotropy (e) and increases radial (f), parallel (g), and mean (h) diffusivity. There is no point in performing pre-surgical tractography in this case as the surgery is not supposed to enter brain tissue. Note the Gadolinium-enhancing dural meningeoma tails in (c, d).

* ^^

^

*

°°

°

°

°

^^^*

(a) (b)

(c) (d)

FIgure 19.4 Diffusion-weighted EPI (a), ADC map (b), T2- (c), and T1-weighted Gadolinium-enhanced (d) MRI of a primary CNS lymphoma in right periventricular location with callosal and basal ganglia involvement. The intra-axial malignancy reveals isotropic diffusion restriction within the large, dense accumulation of lym-phoma cells (*), multiple contrast-enhancing areas (°), and perifocal edema with T2 shine-through (^). Lesion-induced signal changes increase the false-negatives’ risk for tractography but fiber tracking is dispensable anyway because the lesion can be safely approached from right frontal for stereotactic biopsy. (Case by courtesy of Marius Hartmann, Heidelberg)


423SuRgICAl tARgEt And IntEnt

lesion typel intra-axial (within the CNS parenchyma):

primary glial (e.g. astrocytoma, glioblastoma, oligodendroglioma), mixed (e.g. ganglioglioma, dysembryoplastic neuro-epithelial tumor DNET), or non-glial (e.g. primitive neuroectodermal tumors PNET, primary CNS lymphoma) neoplasms of the neuraxis, metastases, focal cortical dysplasias (FCD), vascular malformations (especially parenchymal/gyral arteriovenous malformations (AVMs), cavernomas), intracerebral hemorrhages (e.g. hypertensive mass bleeding), . . .

l extra-axial (outside the CNS parenchyma, i.e. extra-encephal/-medullar): meningeomas, developmental mass lesions (e.g. arachnoidal cysts), vascular malformations (i.e. dural/“sulcal” AVMs, dural

fistulas), extracerebral hemorrhage (e.g. epi- or subdural hematoma), . . .

Tractography is generally superfluous for purely extra-axial lesions but often dispensable even for vari-ous intra-axial processes (such as the evacuation of hypertensive mass bleedings).

lesion levell supratentorial: cerebral hemispheresl infratentorial: brain stem and cerebelluml spinal: intramedullar

Due to artifacts and resolution limits, current trac-tography techniques are increasingly compromised at lower (i.e. infratentorial and spinal) lesion levels.

box 19.5

t y P e s A n d l o c At I o n s o F b r A I n s u r g I c A l ly tA r g e t e d c n s l e s I o n s

tAble 19.1 Pyramidal tractographies (n 27) conducted for surgical targeting in 20 patients with different intra-axial lesions.

Tractography algorithm Deterministic Probabilistic

RESULTS 100 [%] Simple streamlining#

Interpolated streamlining°

Without crossing fibers

Modeling 2 fibers per voxel (incl. ARD)

Constrained Bayesian model^

FNR 0.33 0.30 0.00 0.00 0.00(9/27) (8/27) (0/27) (0/27) (0/27)

*VOL LL/CS 0.84 0.54 0.85 0.57 0.98 1.27 1.19 1.99 1.01 0.08(0.10–1.72) (0.10–2.37) (0.02–6.65) (0.02–10.43) (0.85–1.18)

*FA LL/CS 0.88 0.19 0.91 0.19 0.92 0.15 0.94 0.14 0.90 0.16(0.48–1.10) (0.52–1.24) (0.57–1.11) (0.62–1.14) (0.55 –1.14)

*MD LL/CS 1.07 0.14 1.05 0.15 1.09 0.20 1.07 0.17 1.07 0.20(0.92–1.36) (0.90–1.52) (0.85–1.77) (0.86–1.64) (0.69–1.46)

*Dr LL/CS 1.14 0.23 1.13 0.28 1.13 0.31 1.11 0.24 1.17 0.37(0.90–1.59) (0.74–1.97) (0.78–2.11) (0.82–1.85) (0.66–2.11)

*DII LL/CS 1.00 0.09 1.00 0.11 1.04 0.12 1.04 0.12 1.00 0.13(0.80–1.13) (0.79–1.17) (0.85–1.46) (0.82–1.44) (0.71–1.35)

#with probabilistic sampling, °with a fixed step-length (as implemented in the DTI Task Card v. 1.71); ^modeling a single fiber per voxelFNR – false-negative rate on the lesion side (given that no contralateral upper limb mono- or hemiplegia was present, i.e. pyramidal tract fibers descending from the handknob were known to be not completely destructed, at least);*volume (VOL), fractional anisotropy (FA), mean diffusivity (MD), radial (Dr) and parallel (DII) diffusivity of the pyramidal tract ipsilateral to the lesion are all expressed as fractions compared to the contralateral side (CS) at lesion level (LL, in native diffusion space and for the successful trackings only).



tracking. However, inflammatory lesions, especially with abscess cavity formation, may exhibit similar diffusion features (Schroeder et al., 2006). In general, dif-fusion MRI per se is not sufficiently diagnostic, i.e. typi-cally, additional studies (such as proton-density- and T2-weighted/FLAIR, native and Gadolinium-enhanced T1-weighted MRI, etc.) are needed to establish the pre-cise diagnosis for a given lesion. The lesion entity is also crucial for the particular treatment of choice and its potential side effects.

Surgical resection of space-occupying lesions can be accompanied by substantial brain shifts of more than 2 centimeters. In part, shifting is determined by relief from the space occupancy of the underlying mass but its consistency, intraoperative swelling, and other fac-tors turn it into a phenomenon whose size, and even direction, cannot easily be predicted. Pre-, intra- and postoperative diffusion tensor imaging (DTI) and streamline tractography have been used to estimate the resulting displacement (Nimsky et al., 2006a, b, 2005a, b). As yet, such studies have simply illustrated feasibility. Acquisition time, processing requirements, performance, and accuracy have not been strin-gently evaluated against registration to fast structural non-diffusion-weighted images. Such intraoperatively acquired scans are certainly superior for referencing brain shift to any edge or intra-axial point of reference and possibly entirely sufficient to integrate preopera-tive tractography analyses into the neuronavigation.

b. epilepsy surgery

On the other hand, tracts may also constitute the surgical target in the presence or absence of an addi-tional lesion (Box 19.2).

Callosotomy, i.e. splitting the corpus callosum par-tially or totally, is an established form of epilepsy sur-gery to control intractable seizures (e.g. in patients with generalized seizures without an identifiable focus to resect or in Lennox–Gastaut syndrome). However, the surgical approach to the corpus callosum is rather easy and does not require tractography. In theory, it might be useful to establish patient-specific cal-losal somatotopy (see, for example, Huang et al., 2005) for optimal outcome but this remains specula-tive given that no prospective studies seem to have yet addressed the subject.

In temporal lobe epilepsy, the uncinate fascicle can conduct epileptic discharges from the temporal to the frontal lobe and peri-sylvian cortex. So-called uncinate seizures typically produce olfactory hallu-cinations. Since temporal lobe epilepsy and uncal fits are thought to originate from gray matter, the hippo-campus in particular, ‘‘uncinate fasciculotomy’’ is not

performed selectively but rather accompanies anterior temporal lobectomies (TLE) and possibly, at least to some extent, selective amygdalohippocampectomies. Uncinate tractography is feasible (Jbabdi et al., 2007; Rodrigo et al., 2007b) but a surgical advantage has not yet been demonstrated.

Note that TLE for seizure control or resection of other (not necessarily epileptogenic) lesions can easily injure Flechsig–Meyer’s loop leading to homonymous superior quadranthemianopsia of the contralateral visual field. Tractography of the optic radiation, which is in part somewhat challenging but possible (Conturo et al., 1999; Heiervang et al., 2006; Staempfli et al., 2007; Xie et al., 2007), may be valuable to the neuro-surgeon (Coenen et al., 2005, 2003; Kamada et al., 2005; Reinges et al., 2004; Yu et al., 2005). Additionally, TLE of the speech-dominant hemisphere can cause postop-erative decline of verbal cognitive functioning (Martin et al., 2002; Stroup et al., 2003), which is primarily related to the removal of the dominant hippocampus (Powell et al., 2008; Rabin et al., 2004; Richardson et al., 2004). However, TLE that extends far posteriorly may also compromise the arcuate fascicle, and fiber con-nections of Mills’ basotemporal language area (BTLA; Mills and Martin, 1912) but these effects have – to the best of our knowledge – not yet been examined.

c. Functional neurosurgery (selective Ablations, Auditory Implants, dbs)

Another appealing application of tractography for surgical targeting pertains to ‘‘functional neurosurgery’’ (see, for example, Romanelli et al., 2004; Slavin, 2000). Here, selective ablations are performed for pain and spasm control or electrodes are implanted for deep brain stimulation (DBS; Boxes 19.1 and 19.2). Tractography has the potential to aid identification of relevant targets but has rarely yet been utilized in this context.

Rhizotomy, midline myelotomy, and probably cin-gulotomy are not likely to benefit from tractographies, mainly because their targets are readily identified without it. The precision of anterolateral cordotomies, Sjöqvist’s tractotomies, lemniscotomies, or ‘‘mesen-cephalotomies’’, and even medial thalamotomies could be conceivably enhanced. The medial lemniscus, for example, constitutes a prominent brainstem trajectory visible even on color-coded DTI maps of the principle diffusion direction (Mori et al., 2005), with the spinal tract of the trigeminal nerve, the trigeminal and spinal lemniscus of the anterolateral fasciculus flanking it.

A minimal integrity of auditory pathways consti-tutes the prerequisite to successful cochlear, brain-stem, or midbrain implantation of auditory prostheses. Establishing the integrity of the lateral lemniscus and


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acoustic radiation, in particular, may be useful in the evaluation of deaf patients suffering from bilateral severe sensorineural hearing loss (SNHL), especially when proper hearing tests (including FMRI-promontory testing and ‘‘FMRI audiometry’’; Bartsch, 2007; Bartsch et al., 2007a, b, 2006c; Biller et al., 2007) remain incon-clusive or negative. Here, the precise tract course is not relevant because it is not targeted but its presence may predict favorable outcomes and influence the decision as to what side and level to place the implant (Figure 19.5). For the visual system, it has been shown that amblyopia may ‘‘detract’’ the optic radiation from normal development (Xie et al., 2007). Due to multiple crossing fibers, auditory projections are quite chal-lenging to trace but probabilistic tractography, espe-cially when accounting for multiple fiber orientations, has recently overcome this limitation (Behrens et al., 2007; Devlin et al., 2006).

DBS for treatment of movement disorders is targeted at deep brain nuclei, i.e. the globus pallidus, specific subdivisions of the thalamus, the subthalamic, or the pedunculopontine nucleus. Diffusion-based connectiv-ity analyses are likely to promote further understand-ing of their role in the underlying disease process and may eventually facilitate optimal DBS placement in advanced Parkinson’s disease (Aravamuthan et al., 2007; Muthusamy et al., 2007), other movement disorders

or even treatment-resistant psychiatric illnesses such as depression or obsessive–compulsive disorder (Johansen- Berg et al., 2008). Currently, identification of the pyrami-dal tract may be valuable to minimize side effects of motor activation upon DBS placement at the level of the internal capsule (Coenen et al., 2006).

III. trActogrAPhy strAtegIes For surgIcAl PurPoses

Fiber tracking relies on different algorithms for dif-fusion parameter estimation and tract reconstruction. Available methods vary considerably with regards to their complexity in post-processing of the diffusion data. To a certain degree, this is reflected by compu-tational intensity and the associated requirements in terms of time as well as hardware.

In order to reduce such requirements, some of the ear-lier studies have suggested just using diffusion-weighted images as delivered by the scanner without any fur-ther post-processing except structural co-registration and intensity-based thresholding (Coenen et al., 2005, 2003; Krings et al., 2001a, b). Here, prior anatomical knowledge about the descending projection of the pyramidal tract, for example, is used in interpreting

tRACtogRAPHy StRAtEgIES foR SuRgICAl PuRPoSES

(e)

(f)

(c)

(d)

(a)

(b)

^^

FIgure 19.5 Tractography for targeting auditory neural prostheses. Probabilistic tracking (with multiple fiber orientations, 64 diffu-sion directions at 3 T, 1.5 1.5 2.1 mm3) of auditory pathways (red-to-yellow) in a 28-year-old female suffering from diffuse axonal injury with bilateral deafness and tetraspastic paresis after a motor vehicle accident. Temporal bones were not fractured. Brainstem evoked response audiometry (BERA) was positive but with delayed and attenuated late responses suggesting retrocochlear deafness. (a) Heavily T2-weighted (CISS3D) MRI revealed regular vestibulocochlear nerves and fluid signals in both inner ears. Auditory fibers crossed in the trapezoid body and acoustic striae of the pons. (b–f) Heavily T2*-weighted (SWI) MRI depicted multiple intra-axial ‘‘shearing’’ hemorrhages. One of them (^) had destroyed the left lateral lemniscus (b d). Above the inferior colliculus (c) and the medial geniculate body (d), used as waypoints from the primary auditory cortex, the acoustic radiation was traced on both sides. Thus, auditory midbrain (AMI) or left cochlear implantation (CI) was considered. Upon left extratympanic promontory electrostimulation, which had to be performed under shallow propofol sedation, contralat-eral auditory FMRI activations were detected (blue-to-light blue). Therefore, the patient was admitted for left CI: when successful, subsequent restoration of hearing abilities is usually better than for AMI. Tractography was appropriate in this case (contrary to the case illustrated in Figure 19.1d–f) to demonstrate integrity of auditory pathways ascending from the left ear.



anisotropic diffusion restrictions along selected diffu-sion encodings (i.e. in the antero-posterior or left–right direction) and possibly to differentiate the tract from T2 shine-through effects of perifocal edema. Although such an approach may be appealing to clinicians due to mini-mal requirements of time and expertise, inference about the tract course will strongly depend on the precise dif-fusion encoding scheme, slice angulation, other acquisi-tion parameters, the space-occupying and other effects of the lesion. Such an approach is not adequate to achieve a best-possible 3D representation of the tract under investi-gation. Similarly, it seems dubious to segment tracts man-ually based on color-coded principal eigenvector maps to estimate brain shift, for example (Nimsky et al., 2005a).

For proper tract reconstructions, several strategies can be applied. First of all, tractography can be seeded from a single voxel, from several voxels independ-ently, or from all voxels within a number of regions-of-interest (ROIs). Single voxel seeding corresponds to the special case of an ROI containing just one voxel and is in general not sufficient for presurgical tractography evaluations. Second, tractography can be initiated from one ROI only (so-called ‘‘from-ROI-approach’’). Alternatively, more and possibly all vox-els (so-called ‘‘brute-force-approach’’) can be visited to delineate the tracts penetrating a given ROI more comprehensively (Conturo et al., 1999; Mori et al., 2002, 2005; Stieltjes et al., 2006).

Unfortunately, similar methods are often described by different terms but similar terminologies may also refer to different methods. For example, single voxel or single mask seeding usually corresponds to a ‘‘from-ROI-approach’’ whereas the ‘‘brute-force-approach’’ effectively recovers all tracts which pass through a tar-get ROI under the constraints of the given criteria set (e.g. the tract curvature threshold, etc.). If tracts are gen-erated from every brain voxel and are all retained and not edited with regards to specified targets or exclusion criteria, results are usually too confusing and hardly interpretable for surgical purposes.

Trackings through multiple voxels or ROIs can be edited by different Boolean operators. These are applied to the tracts with respect to their course through, between, or after the predefined voxels or ROIs. For multiple ROIs, the AND operation is most important and commonly used. In addition, further optional masks can be applied to guide the tractography, i.e. ‘‘inclusion’’ or ‘‘waypoint’’ masks (retaining only tracts that pass through all these masks), ‘‘termination’’ masks (to ter-minate tracts as soon as they enter the mask), or ‘‘exclu-sion’’ masks (to discard tracts entering the space of these masks). For example, tractography can be terminated as soon as pathways reach the brain surface (using a bihemispheric brain termination mask) and, for projec-

tion and association fibers such as the pyramidal tract and the arcuate fascicle, tractography can be limited to fibers within one hemisphere only (using a hemispheric exclusion mask). Terminology varies between packages; termination masking according to one terminology may correspond to a CUT operation in another, for example.

Notably, employing two or more ROIs for tractog-raphy imposes strong constraints which make the results more precise and reproducible (Heiervang et al., 2006; Huang et al., 2004). Shape and even size of the ROIs have a rather subordinate influence (see Figure 19.6, for example). Beyond the ROIs, i.e. when pathways are not terminated after having reached the target, tractography results are more susceptible to noise and partial voluming effects. At the same time, pathways that are constrained to travel between two stringently placed ROIs are less likely to depict the branching-off or divergence of relay connections (e.g. of fronto-ponto-cerebellar pathways; see Figure 19.10). For decussations of fiber bundles, tracking algorithms cannot sufficiently resolve ‘‘kissing’’ and ‘‘crossing’’ solutions but may tend to prefer the former since voxels containing tracts of different orientations lose anisotropy.

For DBS targeting and somatotopic mappings (i.e. to guide and restrict callosotomies, for instance), connectivity-based segmentations of seed ROIs based on connections to pre-specified targets would be used. For the other purposes mentioned above, presurgi-cal tractography greatly benefits from prior knowl-edge supplied to the tracking by sensible seed, target, waypoint, exclusion, and possibly termination masks. For example, a simple two-ROI approach can reduce intersession coefficients of variation to less than 10% for mean volume and less than 2% for mean FA of the pyramidal tract in healthy subjects (Heiervang et al., 2006).

Definition of ROIs or masks constraining the trac-tography can be based on prior anatomical and/or functional knowledge. In some instances, FMRI-based ROI/mask selection may allow for more specific and comprehensive fiber trackings (Schonberg et al., 2006; Staempfli et al., 2008). In our experience, this is prima-rily true for guiding arcuate tractographies by prior speech mapping (see Figure 19.8). It will, however, heavily depend on the paradigm, data analysis, and thresholding applied for inference. In general, sym-metric tracking – i.e. back and forth between two ROIs by exchanging seed and target – should be performed, assuming that the results computed by the algorithm can in fact be somewhat different when seed and tar-get masks are reversed. If so, the results can be com-bined by suitable operations (e.g. simple adding or binary AND).


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The following sections describe how the use of spe-cific ROIs/masks has been shown to be very useful and convenient for identification of five pathways of surgical interest: the pyramidal tract, the arcuate fasci-cle, the optic and acoustic radiation as well as the lem-niscal system.

A. Pyramidal tract

Pyramidal tractography at the supratentorial level proceeds best from the primary motor cortex to the inter-nal capsule or the cerebral peduncle (see Figure 19.6). By the use of the latter, fibers of the thalamic radia-tion are mostly excluded so that the tracking becomes more specific. On the other hand, EPI distortions are usually more profound at the level of the peduncles due to the B0 inhomogeneities at the base of the skull. Therefore, EPI preprocessing results by motion, eddy current, and distortion correction possibly using field-maps or non-linear registration (Merhof et al., 2007) must be carefully checked.

To properly delineate the origin of the pyramidal tract, it is important to appreciate that its fibers origi-nate not only from the outer surface of the precentral gyrus but also from the cortex turned towards the sulcus. Whereas the primary motor cortex of the pre-central gyrus with its handknob is often easily identi-fied (see Iwasaki et al., 1991; Kido et al., 1980; Naidich et al., 1995, 2001; Steinmetz et al., 1990; Yousry et al., 1997 for useful anatomic criteria), the deeper intrasul-cal motor cortex is much harder to discriminate in native diffusion space even when recorded at a reason-able resolution. Thus, drawing ROIs on high-resolution anatomical scans and co-registering these with dif-fusion space may be helpful for this purpose and for other tracts as well. Furthermore, part of the pyrami-dal tract (i.e. 20 to 40%) is of retrorolandic origin (Lang et al., 1985; Nieuwenhuys et al., 2008) (see Figure 19.10) even though its postcentral branching is in general not considered surgically relevant. Segmentation of the precentral gyrus can be guided by registration to avail-able atlases such as the Harvard–Oxford cortical atlas (www.fmrib.ox.ac.uk/fsl/fslview/atlas-descriptions.


* *

*

^

^

(a) (b) (c)

(d) (e) (f) (g)

FIgure 19.6 Anatomical versus functional seed definition for pyramidal tractography: (a–c) Left thalamic cavernoma with late subacute hemorrhage, i.e. hyperintense extracellular methemoglobin on T1- (b) and T2*-weighted (c) MRI. Landmarks such as the handknob (*) and cingulate sulcus (^) are well preserved on both sides (a) and allow for anatomical seed mask definition (transparent red). Compared to func-tional seeding (mask in transparent blue, tract in blue-to-light blue), derived by a finger tapping experiment with conservative voxel-based family-wise error corrected thresholding at false-positive probabilities p(FP) 0.05, probabilistic tractography from the anatomical seed recov-ered a larger pyramidal tract (red-to-yellow) that extended much closer to the lesion and even into the marginal T2* black-out of the chronic hemorrhage, i.e. the hypointense ferritin/hemosiderin ring on T2*-weighted MRI (c). (d–g) Left retro-Rolandic glioblastoma with profound mass effect, hyperintense perifocal edema on T2-weighted MRI (d, f, g), a large cystic component and pathological Gadolinium enhancement on T1-weighted MRI (e). Handknob (*) and cingulate sulcus (^) were reliably identified only on the contralesional side. On the lesion side, the handknob had to be determined functionally (mask in transparent blue) based on a finger tapping experiment with conservative voxel-based family-wise error corrected thresholding at false-positive probabilities p(FP) 0.05. Functionally informed anatomical seeding was then extended to the adjacent precentral motor cortex (transparent red). Probabilistic tractography from the functional (blue-to-light blue) and ana-tomically extended (red-to-yellow) seeds did not substantially differ. Streamlining was false negative on the lesion side.

www.fmrib.ox.ac.uk/fsl/fslview/atlas-descriptions.html#ho







html#ho). Using the ipsilateral cerebral peduncle as an ROI in conjunction with the entire precentral gyrus (preferably slightly dilated to cover adjacent white matter of higher FA, with exclusion of the contralateral hemisphere and brain surface termination) is somewhat laborious but leads to a quite comprehensive identifica-tion of the pyramidal tract in most cases.

The course of the pyramidal tract is not simple, i.e. it often does not simply descend straight down. From the primary motor cortex, where the tongue and face areas are located ventral and lateral to the hand area (all usually supplied by blood from the middle cere-bral artery), and where the leg and foot representation extends mesially to the paracentral lobule (usually supplied by the anterior cerebral artery), the pyrami-dal tract may tend to curve slightly backwards, espe-cially from its lower lateral and intrasulcal origins, and then to bend forwards again to enter the internal capsule. Along this way, the somatotopic trajectories twist so that tongue and face fibers descend in front of arm and leg fibers in the posterior limb of the internal capsule (Jbabdi et al., 2007; Kretschmann et al., 1996; Lang et al., 1985; Monakow, 1905; Mori et al., 2005), i.e. its dorsal third quarter (Holodny et al., 2005; Jbabdi et al., 2007; Nieuwenhuys et al., 2008) (see Figures 19.6 and 19.10). At the level of the mesencephalon, the fib-ers to the leg are located further outward and those to the arm are inward rotated. Fibers to the cranial nerve nuclei descend even more medially, intertwined with arm fibers. The corticospinal and corticonuclear fibers are flanked by non-pyramidal frontopontine as well as superficial lemniscal (medially) and parieto-temporopontine (laterally) pathways in the cerebral peduncle. The cerebral peduncle measures around 11 to 17 mm (Lang et al., 1985) in its longest diameter on axial slices in adults and is therefore readily discerned even in native diffusion space. For the sake of simplic-ity, the entire cerebral peduncle can be defined as an ROI to trace the pyramidal tract.

The typical course and fiber arrangement of the pyramidal tract are important to know, especially in the presence of the mass effect of space-occupy-ing lesions. If the lesion does not cause a substantial mass effect, the pyramidal tract follows a relatively predictable course that can be estimated using ana-tomical landmarks without any tractography (Yamada et al., 2007a). For first-pass orientation, reconstructing the pyramidal tract from the commonly well-defined handknob to the cerebral peduncle may be suffi-cient. In particular, this approach may be adequate when both course and fiber arrangement are consid-ered together with the symptoms (i.e. presence or absence of mono-/hemiparesis or -plegia). The prob-lem is that pyramidal tractography can fail from the

tongue, face, and even hand area due to the presence of crossing association and commissural fibers such as the superior longitudinal or fronto-occipital fascic-ulus and the corpus callosum (Yamada et al., 2007c). Such failures are reduced by modeling more than a single fiber orientation and by probabilistic tractog-raphy in particular (see below) but inclusion of the adjacent face, leg, and trunk areas in addition to the handknob is certainly a much safer choice (see Okada et al., 2006a, b, 2007; Yamada et al., 2007c for exem-plary mask placements). Somatotopic mapping of spe-cific motor functions involving the hand or other areas can be performed using arterial spin labeling (ASL) or blood oxygenation level dependent (BOLD) FMRI to inform pyramidal tractography (Bartsch et al., 2006c; Holodny et al., 2001; Schonberg et al., 2006; Smits et al., 2007). However, as long as anatomic localiza-tion is well preserved and not concealed by a lesion’s mass effect or abnormalities of gyration, for example, precentral ROI placement according to pure structural criteria remains straightforward and entirely sufficient (Figure 19.6a–c).

In these cases, benefits of functional ROI definitions cannot be expected. The study of Smits et al. (2007), which suggested a benefit of functional over ana-tomical guided tractography, was biased in that their FMRI-informed pyramidal tractography took advan-tage of a two-ROI approach whereas the anatomically guided counterpart employed just a single ROI in the peduncle. The single case illustrating anatomical landmark vs FMRI-based pyramidal tractography in Schonberg et al. (2006) is not convincing because the anatomically defined ROI is only shown for the poste-rior limb of the internal capsule. Probably, it was also used in a single-ROI approach – otherwise the fibers rostral to the lesion should not have been extracted. Also, the particular lesion could well be of extra-axial origin, meaning that neither presurgical tractogra-phy nor FMRI would have been necessary (Box 19.5). Notably, the lesion type was not specified for any of their patients which is a profound shortcoming and limitation. Selecting ROIs based on the largest eigen-vector maps from diffusion tensor fitting can impose unnecessary restrictions on tractography and is in danger of leading to somewhat circular conclusions. Therefore, true anatomical criteria ought to be pre-ferred for structural ROI definition. Nevertheless, FMRI-based seeding/targeting may occasionally be helpful for pyramidal tractography (Figure 19.6d–g).

Guidelines to optimal FMRI thresholding for FMRI-based seeding/targeting have not yet been established. Thresholding should certainly be rather liberal but should also account for anatomical landmarks when these are residually available for interpretation. In





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general, spatial correspondence of anatomical versus functional seeding seems to be good for the pyrami-dal tract (Figure 19.6). It must be pointed out though that somatotopy-specific seeding/targeting can only recover the respective parts of the pyramidal tract and not the entire tract. On the other hand, tongue and frontal face are innervated from both hemispheres so that tracking from the motor hand, arm, trunk, and leg area is usually sufficient and pyramidal tract fib-ers from the lower third of the precentral gyrus are surgically somewhat less relevant. According to Kleist (1934), however, damage to the base of the dominant precentral gyrus can cause pure motor aphasia reflect-ing either cortical phonemic apraxia or subcortical dysarthria, and this proposition is supported by at least one case of our own observation.

Pyramidal tractography at the supratentorial level is particularly important for sub-Rolandic lesions accompanied by contralateral motor and sensory hemisymptoms. Here, it can establish pre-, intra-, or retropyramidal location of the lesion and thereby influ-ence the decision on the surgical approach (Figure 19.7). At the brainstem level, the cerebral peduncle and the ventral third of the upper medulla oblongata at the level of the pyramids or the lower pons (Stieltjes et al., 2001) constitute good reference ROIs. At the spinal level, cord fibers are usually extracted as a whole and selective tracking of the larger lateral and smaller ven-tral corticospinal tract have not yet been documented for clinical cases. Monitoring of motor evoked poten-tials (MEPs) elicited by cortical or subcortical electri-cal stimulation remains essential when the surgery is performed in close proximity to the pyramidal tract (Kinoshita et al., 2005).

b. Arcuate Fascicle

Within the classical language model according to Wernicke and Lichtheim, interruption of the arcuate

fascicle leads to conduction aphasia which is charac-terized by poor repetition performance, in particular. Although the traditional scheme is a largely outdated, heuristically driven oversimplification and the entity of conduction aphasia has been controversial from the very beginning (Kleist, 1934), the arcuate fascicle has remained the primary fiber pathway of potential surgical concern linking temporoparietal and frontal language areas. Other disconnection aphasias, such as postcommissurotomy mutism and disconnection agraphia following callosotomies, may be either tran-sient or easier to cope with and have overall attracted less attention than disruptions of the arcuate fascicle.

Contrary to the motor representations in the pyramidal motor system, there is no absolute repre-sentation of speech and language in the brain. That is, damage to certain brain areas does not invariably lead to aphasic symptoms (Exner, 1881): anatomical location does not absolutely predict specific apha-sia syndromes possibly resulting from focal lesions. Therefore, careful localization of speech and language functions must be considered in evaluating patients prior to elective peri-sylvian resections, especially of the language dominant hemisphere. Mapping func-tions by FMRI does not predict if and which areas are dispensable for task performance. Consequently, it cannot replace ‘‘reversible lesioning’’ by electrical stimulation mapping (ESM; Bello et al., 2008; Henry et al., 2004) during awake craniotomies or (super-) selective barbiturate injections (original report by Wada, 1949) with preoperative neuropsychological testing. Unlike the pyramidal tract, anatomical vari-ability of morphological substrates for speech and language predisposes arcuate tractography to FMRI-based ROI selection (Figure 19.8).

There is some confusion with regards to the nomen-clature and course of the arcuate fascicle. Based upon some earlier terminological collapse (Kappers et al., 1967; Talairach et al., 1993), the term is often used as a synonym for the superior longitudinal fasciculus (SLF;


(a) (b) (c) (d)

FIgure 19.7 Impact of tractography on the surgical approach: (a–d) T2-weighted MRI of a left sub-Rolandic cystic lesion with perifocal edema scheduled for biopsy. Stereotaxy was initially planned from the front. Probabilistic tracking reveals largely retropyramidal location which was, even in comparison with the contralateral pyramidal tract, hardly predictable (b). Therefore, the lesion was approached from the back. Postoperatively, right hemiparesis did not worsen. Histological examination established inflammatory parasitosis. Streamlining was false negative on the lesion side.



Catani et al., 2002), its fourth subdivision (Makris et al., 2005), or brachium anterius (Nieuwenhuys et al., 2008). Originally, the arcuate fascicle was deliberately distin-guished from the SLF which was itself introduced as a synonym for the (superior) fronto-occipital fasciculus (Monakow, 1905) that – contrary to its name – primarily projects to the parietal lobe (Mori et al., 2005).

The anatomical region that ties the bundles of the arcuate fascicle is the subcortical white matter around the circular sulcus of the insula. This is best appre-ciated and assessed on coronal sections. However, arcuate tractography by a single ROI is easily con-taminated: if the ROI is drawn too far inferiorly and anteriorly, the uncinate and the inferior fronto-occipi-tal fasciculus may be tracked. Both of these pathways may subserve semantic language processing such as naming (Bello et al., 2008). If the ROI is drawn too far posteriorly and laterally, the inferior fronto-occipital and inferior longitudinal fasciculus (ILF) may be tracked. The latter is considered dispensable for lan-guage functioning (Mandonnet et al., 2007). Thus, pure anatomical ROI definition for arcuate tractography is difficult and of questionable reliability. It has been proposed to use the principal eigenvector map from the diffusion tensor fit (Mori et al., 2002; Mori and Van Zijl, 2002) but that can bias the results and add to con-fusion with the SLF.

It is therefore advisable to constrain arcuate trac-tography by FMRI results (Kamada et al., 2007) but the usefulness of simple word generation tasks is limited

(Blank et al., 2002). Paradigms of complex syntactic and semantic processing can reliably elicit activations of an extended language network, and we have good experience of using synonym judgments or reading non-final embedded clause sentences for that purpose (Bartsch et al., 2006c). Inference should be liberal, i.e. aim to minimize false negatives (FN) by threshold-free cluster enhancement (TFCE; Smith and Nichols, 2007) or mixture modeling (Beckmann et al., 2003; Woolrich et al., 2005), for example. Then, frontal and temporoparietal activations can be used as separate masks to guide the tracking, possibly with a waypoint mask adjacent to the upper sulcus circularis insulae. Notably, using the latter alone or slightly misplaced may generate considerable variation in the fibers reconstructed (Figure 19.8). Again, ground truth can-not be established in such cases.

Recent tractography-driven investigations have indicated structural and functional subdivisions within the arcuate fascicle (see also Chapter 18 for greater discussion of language pathways described using tractography): In addition to a direct medially running pathway, there seems to be a lateral portion where the inferior parietal cortex or Geschwind’s ter-ritory is interposed between Broca’s and Wernicke’s area. Damage to its anterior portion has been specu-lated to account for more Broca-like aphasias and damage to its posterior segment to account for more Wernicke-like conduction aphasias (Catani et al., 2005; Yamada et al., 2007b). The direct pathway in particular

(a) (e)(b)

(c) (d)

FIgure 19.8 Anatomical versus functional ROI definition for arcuate tractography: (a–c) T2-weighted MRI of a left temporo-insular low-grade astrocytoma with functional activations of the language system (blue-to-light blue; arbitrarily thresholded TFCE image) evoked by read-ing non-final embedded clause sentences as opposed to consonant strings and the arcuate fascicle (red-to-yellow, overlaps with functional activations in green) reconstructed by probabilistic tractography with crossing fibers modeling between posterior temporoparietal and anterior frontal activation masks. (d) 3D rendering of T1-weighted MRI comparing probabilistic arcuate tractography between functional and anatomi-cal ROIs (masks in green). Anatomical masks placed into the white matter around the sulcus circularis insulae revealed another tract segment (in grass green) below the one (in red) extracted between the functional masks. Despite that discrepancy, functional relevance of the lower seg-ment was considered and both were preserved by the surgery. Note the small inferior anastomotic vein descending to the transverse sinus and that some arcuate fibers seem to terminate in Exner’s area in F2.


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is strongly left lateralized and measures of its later-ality correlate with verbal recall (Catani et al., 2007; Rodrigo et al., 2007a). Furthermore, superior temporal terminations of the arcuate fascicle may subserve pho-nological functions and medial temporal terminations lexical–semantic functions (Glasser and Rilling, 2008).

According to this model, damage to the latter would lead to transcortical motor aphasia (which can also evolve after transient mutism from left or bilat-eral damage to the supplementary motor area or the anterior cingulate) whereas damage to the former may cause conduction aphasia. Alternatively, repetition aphasia could also be caused by damage to a straight ventral running pathway in the extreme capsule which is, however, more prominent in the non-dominant hemisphere and non-human primates (Rilling et al., 2008). Additional arcuate fibers seem to connect to the posterior medial frontal gyrus (F2) which has been implicated in pure motor agraphia (Exner, 1881) (see also Figure 19.8) even though grammatical speech production may not depend on it (Blank et al., 2002). According to intraoperative ESM and fiber track-ing, there are other connections to the putamen via the external capsule which may lead to speech arrest upon stimulation (Henry et al., 2004). Clinical signifi-cance of these findings is not yet established but they emphasize that arcuate tractography is not a trivial task when fairly comprehensive results shall be com-municated with the neurosurgeon.

c. sensory, brainstem, and spinal tracts

As yet, other pathways are rarely tracked for sur-gical purposes. Nevertheless, general somatosensory and special sensory tracts may gain more attention in the near future and will be briefly discussed.

In the brainstem, ascending somatosensory fibers of the medial, trigeminal, and spinal leminisci constitute the medial lemniscal system in the broad sense of the term. As a whole, it is easily identified on multidirec-tional DWI and DTI. The spinal lemniscus is the brain-stem portion of the spinothalamic tract, the trigeminal lemniscus carries the fibers from the spinal nucleus of the trigeminal nerve (whose primary afferents are derived from the spinal tract of the trigeminal nerve). Both the spinal and trigeminal lemnisci are crossed and subserve protopathic, pain conducting systems which makes them potential targets of selective abla-tions. The medial lemniscus in the strict meaning of the term corresponds to the bulbothalamic tract and mediates epicritic sensations. It is usually not tar-geted by surgery. The medial lemniscal system can be tracked between two carefully chosen oval ROIs at the

level of the upper and lower pons (or lower midbrain/ caudal colliculi and upper medulla oblongata; Chen et al., 2007a, b; Stieltjes et al., 2001) but may need some further tract editing based upon anatomical knowledge. Its subsets cannot be readily discriminated from each other or from the lateral lemniscus which subserves the largely crossed auditory system (Figure 19.5). The somatosensory projections of the superior thalamic radiation are not commonly tracked for surgical plan-ning and navigation. Despite this, they can be traced quite easily between thalamic ROIs and the postcentral gyri. Spinal tractography is viable, becoming a more popular challenge, and will benefit from further techni-cal and analytical improvements (Ciccarelli et al., 2007; Ducreux, 2006, 2005b; Fujiyoshi et al., 2007; Kavec et al., 2007a, b; Ozanne et al., 2007; Renoux et al., 2006; Voss et al., 2006; Wheeler-Kingshott et al., 2002). So far, surgi-cal relevance has not been demonstrated but FA reduc-tions seem to be a sensitive marker for disturbances of the spinal cord as well (Ciccarelli et al., 2007; Facon et al., 2005) and the potential clinical utility has been alluded to (Vargas et al., 2008). For example, tractography can eventually extend to the nerve roots and MR neurogra-phy of the peripheral nervous system (Kavec et al., 2007b; Tsuchiya et al., 2008, 2007).

The acoustic radiation has recently become acces-sible for reconstruction by probabilistic tractography between the medial geniculate nucleus (MGN) or body and the primary auditory cortex. Due to the large number of crossing fibers, e.g. thalamocortical pro-jections from the lateral part of the dorsal thalamus, tractography of the acoustic radiation benefits from accounting for multiple fiber orientations (Behrens et al., 2007). Accompanied by the tectothalamic tract, its fibers can be traced from the MGN down to the inferior colliculus and even the cochlear nuclei (Devlin et al., 2006) (Figure 19.5). The optic radiation can be reconstructed between the lateral geniculate nucleus (LGN) and the primary visual cortex. MGN and LGN can be defined anatomically on high-resolution structural MR images (see, for example, Devlin et al., 2006). The primary auditory and visual cortices can be defined anatomically, functionally and/or by regis-tration to available cytoarchitectonic atlases. Presence of the acoustic radiation may increase the confidence for positive outcomes of auditory implant candidates (Figure 19.5) whereas the optic radiation and its tem-poral knee, in particular, may be spared by TLE sur-gery, for example. Note that the temporal knee turns sharply behind and lateral to the amygdala and is easily missed using inappropriate masks or curvature thresholds. Surgical inviolacy of the optic radiation can be probed intraoperatively by visually evoked potentials (VEPs; Kamada et al., 2005a, b).




In general, tractography of the somatosensory, optic and acoustic radiations are clinically less relevant. Patients tend to cope better with deficits (hemihypes-thesia, -anopsia, hypacusis) resulting from unilateral damage to the respective tract than with deficits in motor or language functions. Here, the bilateral cor-tical representation of the retina and organ of Corti must be also considered. However, tractography of the optic radiation has been successfully integrated into stereotactic radiosurgical treatment planning (Maruyama et al., 2007).

d. the specter of False negatives

As with FMRI, false negatives are a major concern in conducting presurgical tractographies. To minimize their occurrence, the choice of diffusion parameter estimation and tract reconstruction method is no less important than proper ROI placement. In principle, two fundamentally different tractography methods are available: deterministic tractography proceeds by making binary, dichotomic decisions about the pres-ence of fibers. In the case of a single tensor fit, the course of a tract is reconstructed from the principal diffusion direction (PDD) along the first eigenvector as fitted to the data. Hence, the method is also called streamlining in a broad sense of the term. Trajectories are recovered in an all-or-nothing fashion and end at arbitrarily chosen FA thresholds. Default thresholds may be too high to enable tracking into low-FA areas within or around lesions (Akai et al., 2005; Bello et al., 2008; Kunimatsu et al., 2004; Stadlbauer et al., 2007a), but ‘‘optimal’’ values remain elusive and certainly quite specific to the patient and particular lesion. By contrast, probabilistic tractography accounts for the uncertainty in the diffusion data and quantifies tract probabilities over the distribution of possible orienta-tions (Behrens et al., 2003). Here, probability density functions (PDFs) are constructed on local fiber trajec-tories by voxelwise diffusion modeling that accounts for noise and signal ambiguities. Thereby, fibers can be traced into areas of ambiguous or even undeter-mined PDDs with very low FA values such as the cer-ebral cortex (Behrens et al., 2003).

Fortunately, the advantageous properties of proba-bilistic tractography meet and match clinical require-ments (Bartsch et al., 2005, 2006a, b): The potentially adverse effect of a vast majority of intra-axial lesions on both the fibers and the diffusion signal (Boxes 19.3 and 19.4; see above) almost invariably increases the uncertainty in the diffusion data and lowers the FA values of a tract proximal to the pathology. This effectively masks the tracts by making it harder to

disambiguate their course. Only when compression by a space-occupying lesion prevails over its perifo-cal edema, for example, is decreasing diffusivity per-pendicular to the tracts dominant and thus tracking facilitated. Pure compression and displacement are primarily paradigmatic to extra-axial tumors such as meningiomas or developmental extra-axial mass lesions such as arachnoid cysts. Due to their extrapa-renchymal location, presurgical tractography is not necessary in these cases. Similarly, it is not surgically relevant for extradural compressions of the spinal cord. Irrespectively, tractography has been performed in extra-axial lesions of the head and spine (Facon et al., 2005; Inoue et al., 1999). Having said that, sur-gically targeted intra-axial lesions always face the risk of false-negative tractography results due to their intraparenchymal occurrence and the accompanying effects on fibers and diffusion signal (see Figures 19.2, 19.6, 19.7, and 19.9).

To evaluate the false-negative rate (FNR) of different methods, we prospectively compared 27 perilesional pyramidal tractographies conducted for surgical tar-geting in 20 patients with different intra-axial lesions (seven were follow-up exams, mostly after surgery to ascertain proper target hits). All cases were his-tologically confirmed and diagnoses consisted of 11 high-grade and three low-grade gliomas, two cer-ebral metastases, one gliomatosis, one inflammatory lesion, one cavernoma, and one AVM. The latter two were characterized by profound T2 black-outs (see Figures 19.1d and 19.6c) whereas the former exhibited hyperintense or mixed diffusion signal changes. All high-grade tumors (including the metastases) were sur-rounded by a variable degree of perifocal edema (see Figures 19.6d–g, 19.9, and 19.10). None of the patients suffered from mono- or hemiplegia, i.e. the pyrami-dal tract was certainly not completely destroyed. Deterministic tractography was performed by simple streamlining (with probabilistic sampling using FDT v. 2.0 www.fmrib.ox.ac.uk/fsl/fdt/, part of FSL, and Matlab) and a dedicated interpolated streamline algo-rithm (with a fixed step-length using the DTI Task Card v. 1.71 (Wang et al., 2006); both with the same FA thresh-old of 0.18). Here, the tensor is ‘‘smoothed’’ yielding more continuous, longer tracts. Interpolated streamlin-ing is somewhat less sensitive to noise than the stand-ard Fiber Assignment by Continuous Tracking (FACT) algorithm but its results do not differ much from second-order Runge–Kutta or a tensorline propagation algorithm. Probabilistic tractography was performed without (using bedpost/probtrack) and with crossing fibers modeling (using bedpostX/probtrackX includ-ing an Automatic Relevance Determination (ARD) of the second fiber fit; all carried out using FDT v. 2.0,

www.fmrib.ox.ac.uk/fsl/fdt/


433tRACtogRAPHy StRAtEgIES foR SuRgICAl PuRPoSES

(a) (b) (c)

(d) (e) (f)

FIgure 19.9 Showcase of a right retro-Rolandic glioblastoma surrounded by perifocal edema on non-diffusion T2-weighted EPI. (a) Exemplary section, areas through which the pyramidal tract passes circled in green. (b–f) Performance of the five different tracking algorithms: simple (b) and interpolated streamlining (c), probabilistic tractography without (d) and with crossing fibers modeling (e) and according to the constrained Bayesian framework (f). Note that overall spatial correspondence is quite good but streamlining was false negative on the lesion side.

part of FSL; Smith et al., 2004) and within a constrained Bayesian framework, first ensuring that a connection is found and then inferring on its exact location (Jbabdi et al., 2007). Curvature thresholds were set to 0.17, cor-responding to a minimum allowable angle between two steps of approximately 80 degrees. Pyramidal tract volumes and DTI parameters on the lesion side were compared to the not primarily affected contralateral side. The pyramidal tract was reconstructed between

handknob and peduncular masks which were equally sized on both sides but not necessarily symmetric in shape. In four cases, the drawing of the handknob ROI was informed by the FMRI results of a simple finger tapping task. None of the patients was mono- or hemi-plegic, proving (at least a residual) structural integrity of the pyramidal tract. Table 19.1 summarizes the results, and Figure 19.9 illustrates correspondence and discrep-ancies of the five different tracking methods evaluated.

min

max Normalized probabilityNumber of samples

FIgure 19.10 Connectivity output of probabilistic tractography before and after normalization to the total number of samples making it from the motor cortex seed to the peduncular target. The left four images display tract probabilities between the minimum number of visits per voxel and the maximum number of samples reaching the target from the seed. On the side of the lesion, a grade III astrocytoma surrounded by perifocal edema on non-diffusion T2-weighted EPI, voxels are visited by fewer samples than on the contralesional side. Normalization reveals that probabilities of assigning a voxel to the pyramidal tract are not necessarily reduced by the lesion if (and only if) prior clinical knowl-edge about (residual) tract integrity is incorporated. However, it does not alter the extension of the estimated tract. Also note the postcentral branches of the pyramidal tract on both sides and the fronto-ponto-cerebellar pathway depicted on the right parasagittal slice.



Lesions induced significantly more deterministic than probabilistic tracking failures: nine exams were false negative for simple and eight for interpolated streamlining whereas probabilistic tractography suc-ceeded in all of our cases on the lesion side (p 0.01, Fisher’s). Even when accounting for premature tract terminations or very sparse trackings (i.e. less than 5% of the ROIs are reached by the tracts; three of the streamlinings vs two of the probabilistic trackings), probabilistic tractography was less prone to insuffi-cient trackings than deterministic algorithms. Notably, success rates did not necessarily differ for the side con-tralateral to the lesion (seven simple and three interpo-lated streamlining failures vs one probabilistic without crossing fibers modeling). Modeling multiple fiber ori-entations recovered larger tracts ipsi- and contralateral to the lesion but occasionally these were implausibly asymmetric in favor of the lesional side (Table 19.1).

Our false-negative rate of roughly one third of deterministic pyramidal streamlinings in lesional hem-ispheres is within the range of 20 to 100% reported in the literature (Berman et al., 2004; Mikuni et al., 2007a; Yamada et al., 2007b). Unfortunately, few studies are devoted to the occurrence of tracking failures and we are not aware of any clinical studies evaluating the spatial correspondence of different tracking algo-rithms. Simply fitting two tensors instead of one and streamlining through both of them does not protect against false negatives: such dual-tensor streamlining still results in up to 20% false-negative trackings – as opposed to 70% for a single tensor fit – from the hand-knob to the peduncle in the contralesional hemisphere (Yamada et al., 2007b). Also, it does not prevent under- or overfitting as ARD does, at least to some extent (Behrens et al., 2007; Hosey et al., 2005).

On average, lesions reduced the FA of the ipsilateral pyramidal tract whereas radial diffusivity increased. In 70% of our exams FA of the ipsilateral pyramidal tract was reduced compared to the contralesional side. Radial diffusivity, on the other hand, was decreased in no more than 44% of the exams and parallel diffu-sivity was, on average, less altered compared to the contralateral side (Table 19.1). Thus, the white mat-ter displacement and tract compression described by Schonberg et al. (2006) (who considered cases without infiltration, perifocal edema, or other lesion-induced diffusion signal changes) are more an exception than the clinical rule.

Probabilistic tractography does not eliminate but does minimize false-negative results despite the above-mentioned adverse FA and diffusivity changes associated with intra-axial lesions. In addition, prior clinical knowledge about (residual) tract integ-rity, such as the presence of sub-Rolandic mono- or

hemiparesis without hemiplegia, can – within Bayesian frameworks – facilitate (i) conversion of trac-tography outputs into probability values and (ii) con-strained probabilistic tracking. The following section describes the process of converting probabilistic track-ing outputs into path probabilities in order to encode prior knowledge that a tract exists into tractographies that meet surgical requirements.

For the showcase of the corticospinal tract, say that we want to establish the probability that a voxel belongs to the pyramidal tract. Say, furthermore, that based on both prior anatomical knowledge and appropriate clinical evidence (such as physical examination) we definitely know that the pathway between the primary motor cortex (M1) and the cer-ebral peduncle exists and is, at least in part, intact in the particular patient. In this case, we do not want to consider the absolute number of samples/streamlines that pass through our voxel of interest, but rather we want to normalize this number by the total number of samples that pass between M1 and the peduncle. This normalization will help deal with problems that arise when tracking performs very differently across different brains, sessions, or hemispheres. Let’s take, for example, a voxel on the pyramidal tract that we know to exist but that is located within the perifocal edema of a brain tumor. Now assume that this voxel is visited by only three samples and that just 300 sam-ples in total make it between the seed and target in the hemisphere affected by the perifocal edema. In the contralesional hemisphere not affected by the peri-focal edema, another voxel is visited 500 times and 50 000 samples make it between the seed and target. According to the above normalization logic, probabil-ity values for these two voxels are equivalent – given the prior knowledge about tract existence and integ-rity. Using this approach, the size of seed and target masks can be ignored, an important advantage since tracts may pass through variable parts of the masks and mask placement becomes less of a bias source. The effect of incorporating prior anatomical and clini-cal knowledge through normalization is illustrated by Figure 19.10.

This normalization process does not aim to pro-duce ‘‘true’’ path probabilities for surgical target-ing. Specifically, probabilities will not represent the amount of a tract in each voxel relative to other tracts. It can be shown, however, that adverse lesion effects such as perifocal edema, etc. do not necessarily reduce the probability of assigning a voxel to a given tract when we account for the clinical evidence that the tract has not been totally destroyed by the lesion (Figure 19.10). Such evidence is easily obtained for the pyramidal tract or the optic radiation, for example,


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by simple physical examination. Given that the ‘‘method of negative cases’’ (i.e. to localize brain func-tions by mapping the extent of all lesions in which performance was not disturbed; Exner, 1881) has tra-ditionally not been applied to speech and language, such evidence may not be straightforward to obtain for the arcuate fascicle though. For the pyramidal tract our data confirm that the greater the number of seed voxels that connect to the target, the higher the total number of samples that make it to the target from the seed (Figure 19.11). Interestingly, the fewer the number of samples that reach the target from the seed relative to the contralateral side, the more pro-nounced the motor weakness in our sample (Figure 19.12). FA reductions at the lesion level compared to the contralesional side exhibited a similar but weaker relationship to motor deficits. Previously, Stadlbauer et al. (2007b) and Ozanne et al. (2007) have, for exam-ple, reported significantly lower pyramidal and spinal FA values in patients with sensorimotor deficits com-pared to those without, but at the brainstem level at least that may depend on the infiltration of surround-ing tissue by the lesion (Lui et al., 2007).

Normalization to the total number of samples reach-ing the target from the seed quantifies the confidence with which the pathway is located given clinical a priori evidence that it exists. It does not, however, further improve the probabilistic estimation having ensured that the connection is in fact found (i.e. the unweighted tract extension remains identical compared to the orig-inal tracking). This is necessary because unconstrained probabilistic tractography tends to inflate both the vol-ume and the within- and across-subject variance of the extracted pathway (Figure 19.13).

Within a Bayesian framework of parameterizing con-nectivity, first on a global level and then inferring on global and local parameters simultaneously, exact tract extension and location can be constrained after hav-ing ensured that the connection is detectable (Jbabdi et al., 2007). Such constrained Bayesian estimation reduces the sensitivity to noise and modeling errors and increases the robustness of the algorithm. Anatomical priors can then also enforce somewhat different trajectories especially in crossing fiber areas. Most importantly, inference about tract extent is cru-cial for surgical targeting. Commonly, tracking failures


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FIgure 19.11 Pyramidal tractography from the handknob to the cerebral peduncle in the presence of intra-axial lesions I: the more seed voxels are connected with the target (x-axis), the more samples will eventually reach it from the seed (y-axis; simple exponential fits, R 0.84, p 0.00). Lesions in proximity to the pyramidal tract significantly reduce the number of samples that make it to the target compared to the contralateral side, even if similar numbers of seed voxels connect to the targets. This reduction becomes more obvious the higher the con-nectivity is to start with (p 0.00, ANCOVA rejecting both equality and parallelism of the fits; n 27 probtrackX exams, each on lesional and contralesional side, two outliers excluded; both x- and y-values were extracted and added for tracking in both directions, from handknob to peduncle and vice versa, at identical individual mask sizes between lesional and contralesional seed and target, respectively).


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FIgure 19.12 Pyramidal tractography from the handknob to the cerebral peduncle in the presence of intra-axial lesions II: the fewer samples reach the target from the seed on the lesional relative to the contralesional side (x-axis), the more pronounced was the motor weakness according to a standard grading score (MRC, 1978)in our sample (y-axis; Kendall’s 0.88, p 0.00; n 27 prob-trackX exams, each on lesional and contralesional side, two outliers excluded; x-ratios are of the added samples counted both ways, from handknob to peduncle and vice versa). FA reductions at the lesion level compared to the contralesional side (Table 19.1) showed a similar but weaker association (Kendall’s 0.35, p 0.02).

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FIgure 19.13 Pyramidal tractography from the handknob to the cerebral peduncle in the presence of intra-axial lesions III: tract vol-umes as estimated by five different tractography methods, only exams in which the tracking was successful on both the lesional as well as contralesional side are plotted (simple streamlining 12, interpolated streamlining 19, bedpost/probtrack 26, bedpostX/probtrackX 27, and con-strained probabilistic tracking 27 out of n 27). Unconstrained probabilistic tracking significantly reduces false negatives but also inflates tract volumes and aggravates their reduction possibly induced by lesions (p 0.01). According to constrained probabilistic tracking, tract volumes were only insignificantly reduced on the lesional compared to the contralesional side (p 0.63, t-tests) and, on average, much less variable and disproportionate. Spatial cross-correlation of constrained binary tract distribution with interpolated streamlining was high (xcorr coef-ficient 0.67 0.11, 0.41 – 0.94, p 0.00).

and reduced path volumes are taken as explicit or implicit evidence for tract infiltration and destruc-tion. However, it is well known that tractography can underestimate fiber bundle size. Electrical stimulation sometimes evokes responses more than 0.5 to 1 cm away from the estimated tract (Berman et al., 2007; Kamada et al., 2007; Kinoshita et al., 2005; Mikuni et al., 2007a). A recent study reduced such mismatches to less than 5% of the cases by lowering the FA threshold for streamlining (Bello et al., 2008), but that simply expands the tracts within the same deterministic estimation. The FA value chosen remains entirely arbitrary with dis-crepant recommendations across studies (Akai et al., 2005; Bello et al., 2008; Stadlbauer et al., 2007a). It con-tinues to require patient specific adjustments to achieve correspondence with ESM, which then appears circular and unsatisfactory. Eventually, intraoperatively respon-sive stimulation sites are located not only at the margin of the tract but also within it (Bello et al., 2008). Then, however, surgical damage and corresponding deficits must be expected. In general, ESM distances should be evaluated against the border of the extracted fiber bun-dle. The tract center, as used by Okada et al. (2006b), is not very informative in that regard. By the same token, lowering the FA threshold reveals that fibers can penetrate a tumor (Akai et al., 2005; Bello et al., 2008; Stadlbauer et al., 2007a) and sharp tract terminations


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should always raise suspicions of tracking failures. Since direct histopathological validation is only feasible post hoc and rarely available, there is no gold standard to determine real tract volumes and ground truth can usually not be established. Although probabilistic track-ing is in general less susceptible to false negatives than deterministic tractography (Table 19.1), the increased sensitivity of unconstrained algorithms is achieved at the expense of specificity. This is expressed by a signifi-cant increase in bilateral tract volumes and by an exag-geration of paired tract volume differences between the lesional and contralesional side (Figure 19.13): Unconstrained pyramidal tractography suggested sig-nificant lesion-induced path volume reductions com-pared to the unaffected side whereas with constrained modeling such reductions were no longer apparent. This exemplifies the robustness of constrained probabi-listic tractography, maintained even under the adverse clinical conditions of intra-axial lesions, without the associated risk of increased tracking failures. In our opinion, this approach should be further evaluated against, for instance, geodesic tractography (Jbabdi et al., 2008; Parker et al., 2002). It may become the trac-tography method of choice for surgical targeting as it is capable of incorporating prior knowledge with a low risk of false negatives.

Taking advantage of probabilistic tractography for surgical targeting requires the diffusion data to be recorded with a minimum number of non-coplanar gradient directions. Disturbingly, some reports lack specifications of the scanner and pulse sequence used (Niizuma et al., 2006). Deterministic tractography can

be performed with as few as six sampling directions but with too few directions there is a strong depend-ence of orientational uncertainty on the principal vec-tor orientation. Additionally, crossing fiber modeling will benefit from more gradient directions. On the other hand, acquisition time should be minimized for patient compliance and comfort and to avoid contamination of the data by excessive head motion. We have good expe-rience of sampling 30 directions for clinical purposes (which were also used for pyramidal tractography at 1.5 T in the above patient sample) and would advise not to apply fewer than approximately 25. Single shot diffusion-weighted EPI data can be acquired in about 5 minutes on current scanners, which is acceptable.

Increased field strength can augment and refine tracking results (Okada et al., 2006b). High angular samplings and analyses such as q-ball and diffusion spectrum imaging may improve interpretation of com-plex diffusion behavior but are time-consuming even in hybrid diffusion encoding (Wu et al., 2007) or resid-ual bootstrap analysis strategies (Berman et al., 2008). As yet, they have not been systematically applied to clinical conditions. Box 19.6 summarizes the proposed minimal requirements in diffusion data acquisition and analysis for surgical targeting above the cerebral peduncles. For the lower brain stem and the spinal cord, pulse sequences and acquisition parameters may be modified to achieve optimal results (Stieltjes et al., 2001; Voss et al., 2006; Wheeler-Kingshott et al., 2002). In particular, the need for external triggering to reduce cardiac pulsation artifacts may increase with brainstem and spinal cord imaging.


data Acquisitionl 1.5–3 tesla, whole-head diffusion capability, FoV

usually 192 mm, Matrix 64 64, 30 slices (depending on tract of interest), preferred resolution 3 3 3 mm3 (roughly isotropic), fat saturation (to reduce ghosting/chemical shift artifacts), no upsampling or extensive zero padding

l single-shot EPI: diffusion weighting b-value 800 s/mm2, 25 gradient directions (isometrically distributed on a sphere), at least one b 0 image with no diffusion weighting (2 or 3 are usually better,

these can later be co-registered and averaged off-line), record all images in a single run (series)

l minimize TR/TE (preferably 100 ms) within acceptable settings for bandwidth (1–2 kHz/pixel) and echo spacing (0.5–1.5 ms; the lower the bandwidth the higher the fundamental frequency peak and noise level of EPI)

l use multi-channel phased array head coil, possibly with partial k-space and parallel imaging (both can be used to further minimize TE: the former at the expense of zero-filling, the latter at the expense of SNR)

box 19.6

d I F F u s I o n d AtA A c q u I s I t I o n A n d P r o c e s s I n g r e q u I r e M e n t s F o r s u r g I c A l tA r g e t I n g A b o V e

t h e c e r e b r A l P e d u n c l e s



IV. conclusIons

Tractography can be a valuable tool for preop-erative diagnostics and surgical targeting. However, lesions exert variable effects both on fibers and on the diffusion signal, and these are usually more profound the closer a lesion is located to a tract. Therefore, wher-ever possible, presurgical tractography must make use of the best data acquisition and analysis methods available. It should not trade sensitivity for speed and is rarely indicated in medical emergencies. Like FMRI, tractography is no substitute for but should be supple-mented by intraoperative electrophysiological moni-toring and ESM, preferably.

The growing popularity and flood of publications on the subject contain astonishingly few rigorous and criti-cal clinical investigations. Thus, the utility of tractog-raphy for surgical targeting is challenged by dubious interpretations of its results. The diagnostic aim and potential benefit of a tractography exam should be scru-tinized in advance for their relevance to clinical decision-making. Recognized as a potential source of illusory certainty or an excessive apprehension of surgeons and neuroradiologists involved, tractography can be a mixed blessing to the patient. When misused, it is prone to deliver self-fulfilling prophecies. For exam-ple, reduced fiber volumes or tracking failures are commonly taken as evidence of tract infiltration or destruction but largely depend on the sensitivity and robustness of the tractography algorithm. It is very

important to appreciate these differences. Currently, there is no way to reliably determine tract latitudes by diffusion MRI. The inability to establish ground truth, and the lack of a non-invasive gold standard to com-pare with, mean that we can characterize our data by different methods but are often left with uncertainties over interpretation. It seems, for instance, unequivo-cal that unconstrained probabilistic algorithms may distend tract volumes beyond anatomical plausibil-ity (Figure 19.13, Table 19.1). Yet, the information con-tained in their results can still be meaningful (Figures 19.11 and 19.12). The best we can do is to incorporate anatomical, functional, and clinical a priori knowl-edge into our tractographies and interpretations. Nonetheless, tract volumes and locations are not pre-cisely predictable. At first glance, this may appear to seriously limit tractography applications for tract preservation during surgery. The good news is that it is often sufficient to approximate the course of the tract, particularly when electrophysiological monitor-ing and ESM are available in the OR. Thus, minimiz-ing false-negative total tracking failures is what matters most in tractography for surgical targeting. Under adverse clinical conditions probabilistic tractography obviously outperforms deterministic tracking on that score (Table 19.1). As a first-pass screening, determinis-tic tractography often seems adequate and fast to con-duct. When it succeeds, spatial cross-correlation with constrained probabilistic tracking is high (Figure 19.9). However, when deterministic tracking fails, and for

l minimize distortions (which increase the higher the bandwidth and the lower the echo spacing), e.g. by parallel imaging (with sufficient reference lines); distortion correction by fieldmapping or alternating phase encode directions (‘‘blip-up/down’’) is possible but not trivial and requires additional acquisitions

l preserve brain symmetry by phase-encoding (i.e. A ↔ P for axial slices)

l check magnet cooling status prior to data acquisition (increased magnet temperature due to low helium levels, for example, may introduce eddy currents and impede their compensation)

data Processing/handling of tractography resultsl experienced image analysis expert, adequate

computing equipment (multiple cores 1 GHz,

preferably parallelized, 2 GB RAM; software such as FSL, freely available for non-commercial use at http://www.fmrib.ox.ac.uk/fsl/), sufficient processing time (1 day per data set)

l team discussion with operating neurosurgeon and experienced neuroradiologist who should be available for answering questions during the procedure and – if possible – ready to visit the OR

l data transfer into neuronavigation, possibly updating the registration of preoperative tractography results with intraoperative structural recordings

l careful state-of-the-art intraoperative patient monitoring, possibly in conjunction with ESM

http://www.fmrib.ox.ac.uk/fsl/


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connectivity analyses in DBS, probabilistic tractography becomes indispensable.

The most important pathway to preserve from sur-gical injury is the pyramidal tract. Damage to its face or limb portions inevitably results in mono- or hemi-paresis (i.e. weakness) or -plegia (i.e. total paralysis). Effects of damage to the dominant arcuate fascicle are less predictable but may include impaired eloquence and may lead to aphasia. Pyramidal tractography is essential for sub-Rolandic lesions, in particular, as the corticospinal and corticobulbar tract can pass in front and/or behind a given lesion. Arcuate tractography may be informative for peri-sylvian and peri-insular lesions. Here, concurrent mapping of speech and lan-guage function by FMRI is almost invariably required and may be used to generate appropriate seeds/targets for the tractography. Presurgical tractogra-phy to avoid collateral damage is only indicated for intra-axial lesions. In particular, it can influence the decision on how to approach the lesion. During the procedure, surgical manipulation further increases the false-negative risk and decreases the interpretability of tractographic exams. Therefore, intraoperative diffusion tractography is – aside from demanding critical acquisition time within a hostile environment – of very questionable value and must be stringently evaluated against appropriate registration of preoper-ative results with intraoperative structural recordings. Instead, efforts to translate presurgical tractography results into the operating room (Chen et al., 2007a, b; Coenen et al., 2003a, b; Coenen et al., 2001; Dellani et al., 2007; Kamada et al., 2003; Mikuni et al., 2007a, b; Nimsky et al., 2006b; Talos et al., 2003) should be encouraged and are becoming increasingly available.

AcknowledgMents

We are extremely grateful to Matthias Rüber who has supplied lots of data from the current work on his thesis for the chapter. Tim Behrens and Saad Jbabdi deserve our special thanks in many regards: for sup-port, discussions, assisting and performing parts of the data analysis (Tim for implementing the simple stream-line algorithm and for picking up on the idea to account for prior knowledge that a tract exists to encode tract probabilities; Saad for constrained probabilistic modeling, in particular). We also thank Stefan Thesen and Heiko Meyer (Siemens Medical), Stefan Popp (Aycan Digitalsysteme GmBH) and Hubert Noras (Noras Medizintechnik) for indispensable furtherance of hard- and software solutions and Carol Di Perri for most valuable advice. Last but not least we are deeply

beholden to Klaus Roosen, Professor and Chair of the Neurosurgical Department at the University of Wuerzburg, for many fruitful collaborations and trans-mission of pre-eminent clinical insights. The work was generously supported by the Volker and Vera Doppelfeld-Foundation.

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