**Impact of White Matter Damage After Stroke**

Robert Lindenberg1,2 and Rüdiger J. Seitz3,4

*1Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, 2Department of Neurology, Charité – Universitaetsmedizin Berlin, Berlin, 3Department of Neurology, University Hospital Düsseldorf and Biomedical Research Centre, Heinrich-Heine-University Düsseldorf 4Florey Neuroscience Institutes, Melbourne, Victoria, 1USA 2,3Germany 4Australia*

**1. Introduction** 

232 Neuroimaging – Methods

Lowe LH, Bulas DI. Transcranial Doppler imaging in children: sickle cell screening and

Makhoul IR, Eisenstein I, Sujov P, et al. Neonatal lenticulostriate vasculopathy: further characterisation. *Arch Dis Child Fetal Neonatal Ed* 2003; 88:F410–F414 Middleton WD, Kurtz AB, Hertzbert BS. *Ultrasound: the requisites*. St. Louis, MO: Mosby-

Needelman H, Schroeder B, Sweeney M, Schmidt J, Bodensteiner JB, Schaefer GB. Postterm

Nelson MD Jr, Maher K, Gilles FH. A different approach to cysts of the posterior fossa.

North K, Lowe L. Modern head ultrasound: normal anatomy, variants, and pitfalls that may

Ostlere SJ, Irving HC, Lilford RJ. Fetal choroid plexus cysts: a report of 100 cases. *Radiology*

Pal BR, Preston PR, Morgan ME, Rushton DI, Durbin GM. Frontal horn thin walled cysts in preterm neonates are benign. *Arch Dis Child Fetal Neonatal Ed* 2001; 85:F187–F193 Rosenfeld DL, Schonfeld SM, Underberg-Davis S. Coarctation of the lateral ventricles: an

Schafer RJ, Lacadie C, Vohr B, et al. Alterations in functional connectivity for language in

Seigel M, ed. *Pediatric sonography*, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins,

Slovis TL, Kuhns LR. Real-time sonography of the brain through the anterior fontanel. *AJR* 

Soetaert AM, Lowe LH, Formen C. Pediatric cranial Doppler sonography in children: non-

Sudakoff GS, Montazemi M, Rifkin MD. The foramen magnum: the underutilized acoustic

Te Pas AB, van Wezel-Meijler G, Bokenkamp-Gramann R, Walther FJ. Preoperative cranial

Teele RL, Hernanz-Schulman M, Sotrel A. Echogenic vasculature in the basal ganglia of neonates:a sonographic sign of vasculopathy. *Radiology* 1988; 169:423–427 van Baalen A, Versmold H. Choroid plexus cyst: comparison of new ultrasound technique

Winchester P, Brill PW, Cooper R, Krauss AN, Peterson HD. Prevalence of "compressed"

ultrasound findings in infants with major congenital heart disease. *Acta Paediatr* 

and asymmetric lateral ventricles in healthy full-term neonates: sonographic study.

sickle cell applications. *Curr Probl Diagn Radiol* 2009; 38:218–227

window to the posterior fossa. *J Ultrasound Med* 1993; 12:205–210

with old histological finding. *Arch Dis Child* 2004; 89:426

Rumack C, Wilson S, Charboneau J. *Diagnostic ultrasound*. St. Louis, MO: Mosby, 2005

prematurelyborn adolescents. *Brain* 2009; 132:661–670

alternative explanation for subependymal pseudocysts. *Pediatr Radiol* 1997; 27:895–

closure of the cavum septi pellucidi and developmental outcome in premature

beyond. *Pediatr Radiol* 2005; 35:54–65

infants. *J Child Neurol* 2007; 22:314–316

simulate disease. *Ultrasound Clin* 2009; 4:497–512

Osborn A. *Handbook of neuroradiology*. St. Louis, MO: Mosby-Year Book, 1991

*Pediatr Radiol* 2004; 34:720–732

Year Book, 2009:377

1990; 175:753–755

1981; 136:277–286

2005; 94:1597–1603

*AJR* 1986; 146

897

2002

Ischemic stroke is one of the leading causes of persistent disability in Western countries (Bejot *et al.*, 2007). It results from cessation of blood supply due to an occlusion of a cerebral artery. Many patients benefit from thrombolysis with the approved drug recombinant tissue plasminogen activator (rtPA). Nevertheless, the clinical effect of intravenously administered rtPA is variable (Hallevi *et al.*, 2009; Wahlgren *et al.*, 2008) which is of particular importance for middle cerebral artery (MCA) stroke: It has been demonstrated that early artery recanalisation yields unevenly distributed, circumscribed infarct lesions within the MCA territory with a great potential for functional recovery; in contrast, failed recanalisation results in large infarcts with a limited potential for functional recovery (Figure 1). Accordingly, an important factor contributing to recovery from stroke is the early restoration of cerebral blood flow. Spontaneous recovery is known to continue for the subsequent weeks to months (Cramer, 2008). Furthermore, recovery can be facilitated by dedicated rehabilitative training with greater effects in greater dosing of training (Kwakkel, 2006) even years after the stroke (Stinear *et al.*, 2007).

Animal studies (Dancause *et al.*, 2005) as well as imaging and electrophysiological studies in humans (Butefisch *et al.*, 2006) have suggested that recovery is brought about by cerebral plasticity. Cerebral plasticity pertains to *functional* changes such as synaptic efficiency as well as *structural* changes such as synaptic sprouting (Dancause *et al.*, 2005; Nudo *et al.*, 1996). Even in the adult brain, a loss of hand motor function due to small cortical lesions within the sensorimotor cortex can be completely restored (Binkofski and Seitz, 2004). However, there are limits to plasticity. For example, severe damage to major pathways such as the pyramidal tract (PT) can be compensated for to some extent, but full functional recovery is often not possible (Lang and Schieber, 2004).

To date, neuroimaging studies of brain infarcts have mostly examined grey matter alterations. Recent advances in diffusion tensor imaging (DTI) and lesion-symptom

Impact of White Matter Damage After Stroke 235

recently (Seitz and Donnan, 2010). Note the close topographic correspondence of the mean area of the most severe perfusion deficit, the DWI abnormalities, and the lesion overlap in the periventricular white matter found in the patients with severe MCA stroke (Figure 2). Since the structural alterations project onto the corona radiate, the corresponding damage of well-defined fibre bundles—such as corticospinal motor tracts—can be assessed specifically by electrophysiology and MRI techniques such as DTI in order to correlate imaging

Fig. 2. Lesion pattern in severe MCA stroke. a) Area of the maximal PWI deficit in severely as compared to slightly affected patients. b) Area of common DWI-changes before acute stroke therapy (n=64). c) Overlap of the residual infarct lesions in hemispheric white matter

DTI allows for inferences of the microstructural status of regions of interest in the white matter or reconstructed tracts (Beaulieu, 2009). DTI is a DWI technique that uses the measurement of Brownian motion of water molecules in different directions to reconstruct three-dimensional images of diffusivity (Jones, 2008). Whereas molecules can diffuse relatively freely in water, structural boundaries such as cell membranes or myelin sheaths cause restrictions and yield anisotropic diffusion (Beaulieu, 2002). The degree of diffusion anisotropy can then be used to characterise neural tissue and reveal potential pathological processes (Beaulieu, 2002; Jones, 2008). As an example, Figure 3 shows images of fibre distributions according to the main directions of diffusivity in each voxel of the image. Here, the colour-coding allows for the detection of diffusion abnormalities. Main diffusion directions of single voxels also provide the basis for deterministic tractography, which reconstructs trajectories through a combination of adjacent voxels with similar main directions. Probabilistic tractography, in contrast, propagates numerous pathways through the tensor field so that each voxel can be coded with a number that reflects its likelihood of being connected with a given seed region from which the tracking is started (see (Jones,

With both the deterministic and probabilistic approaches, major fibre bundles can be reliably reconstructed (Mori and Zhang, 2006; Wakana *et al.*, 2004). Furthermore,

measures with parameters of functional outcome.

(n=13). Adapted from (Seitz *et al.*, 2009; Stoeckel *et al.*, 2007).

2008) for a review).

**3. Diffusion tensor imaging: Methodological considerations** 

mapping techniques provided novel ways to investigate the white matter in the context of recovery from stroke (Johansen-Berg *et al.*, 2010). The crucial role of the white matter for functional outcome can be illustrated by the observation that small cortical infarcts, e.g. in the precentral gyrus, typically allow for profound recovery from stroke, whereas infarcts of similar volume in the peri-ventricular white matter or the internal capsule may induce a severe and persistent hemiparesis (Kretschmann, 1988; Wenzelburger *et al.*, 2005). Focusing on DTI and lesion mapping, we will discuss recent studies that established white matter damage as an important factor for functional outcome in the acute stroke phase. Furthermore, alterations of fibre tracts will be presented as a critical determinant of functional recovery due to cerebral plasticity in the subacute and chronic phases after stroke.

Fig. 1. Neurological deficit as assessed with the NIHSS in 108 MCA stroke patients. Successful thrombolysis with early MCA recanalization resulted in a significant neurological improvement (\*: p<0.0001). Adapted from (Seitz *et al.*, 2009).

### **2. Lesion mapping in the acute phase after stroke**

Different modalities of magnetic resonance imaging (MRI) are widely used to visualise brain lesions. In acute stroke, perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) can identify the area of acute ischemia. After reperfusion, PWI deficits can be resolved (Davis *et al.*, 2008; Seitz *et al.*, 2005), and also DWI alterations are partly reversible (Kranz and Eastwood, 2009). By use of lesion mapping it has been found that the hemispheric white matter is preferentially affected in patients with major MCA stroke as compared to patients with lesion regression (Stoeckel *et al.*, 2007). Similarly, patients with a lacking response to rtPA and no recanalization of the MCA, showed larger brain lesions with greater hemispheric white matter damage than those with successful thrombolysis (Seitz *et al.*, 2009). The large infarct lesions in patients non-responsive to thrombolysis occurred adjacent to the insular cortex and basal ganglia in the internal capsule and periventricular white matter and were predicted by the maximal perfusion deficit in the acute phase of stroke. These infarcts corresponded to the type II.2 MCA infarcts as described

mapping techniques provided novel ways to investigate the white matter in the context of recovery from stroke (Johansen-Berg *et al.*, 2010). The crucial role of the white matter for functional outcome can be illustrated by the observation that small cortical infarcts, e.g. in the precentral gyrus, typically allow for profound recovery from stroke, whereas infarcts of similar volume in the peri-ventricular white matter or the internal capsule may induce a severe and persistent hemiparesis (Kretschmann, 1988; Wenzelburger *et al.*, 2005). Focusing on DTI and lesion mapping, we will discuss recent studies that established white matter damage as an important factor for functional outcome in the acute stroke phase. Furthermore, alterations of fibre tracts will be presented as a critical determinant of functional recovery due to cerebral plasticity in the subacute and chronic phases after stroke.

Fig. 1. Neurological deficit as assessed with the NIHSS in 108 MCA stroke patients.

improvement (\*: p<0.0001). Adapted from (Seitz *et al.*, 2009).

**2. Lesion mapping in the acute phase after stroke** 

Successful thrombolysis with early MCA recanalization resulted in a significant neurological

Different modalities of magnetic resonance imaging (MRI) are widely used to visualise brain lesions. In acute stroke, perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) can identify the area of acute ischemia. After reperfusion, PWI deficits can be resolved (Davis *et al.*, 2008; Seitz *et al.*, 2005), and also DWI alterations are partly reversible (Kranz and Eastwood, 2009). By use of lesion mapping it has been found that the hemispheric white matter is preferentially affected in patients with major MCA stroke as compared to patients with lesion regression (Stoeckel *et al.*, 2007). Similarly, patients with a lacking response to rtPA and no recanalization of the MCA, showed larger brain lesions with greater hemispheric white matter damage than those with successful thrombolysis (Seitz *et al.*, 2009). The large infarct lesions in patients non-responsive to thrombolysis occurred adjacent to the insular cortex and basal ganglia in the internal capsule and periventricular white matter and were predicted by the maximal perfusion deficit in the acute phase of stroke. These infarcts corresponded to the type II.2 MCA infarcts as described recently (Seitz and Donnan, 2010). Note the close topographic correspondence of the mean area of the most severe perfusion deficit, the DWI abnormalities, and the lesion overlap in the periventricular white matter found in the patients with severe MCA stroke (Figure 2). Since the structural alterations project onto the corona radiate, the corresponding damage of well-defined fibre bundles—such as corticospinal motor tracts—can be assessed specifically by electrophysiology and MRI techniques such as DTI in order to correlate imaging measures with parameters of functional outcome.

Fig. 2. Lesion pattern in severe MCA stroke. a) Area of the maximal PWI deficit in severely as compared to slightly affected patients. b) Area of common DWI-changes before acute stroke therapy (n=64). c) Overlap of the residual infarct lesions in hemispheric white matter (n=13). Adapted from (Seitz *et al.*, 2009; Stoeckel *et al.*, 2007).

### **3. Diffusion tensor imaging: Methodological considerations**

DTI allows for inferences of the microstructural status of regions of interest in the white matter or reconstructed tracts (Beaulieu, 2009). DTI is a DWI technique that uses the measurement of Brownian motion of water molecules in different directions to reconstruct three-dimensional images of diffusivity (Jones, 2008). Whereas molecules can diffuse relatively freely in water, structural boundaries such as cell membranes or myelin sheaths cause restrictions and yield anisotropic diffusion (Beaulieu, 2002). The degree of diffusion anisotropy can then be used to characterise neural tissue and reveal potential pathological processes (Beaulieu, 2002; Jones, 2008). As an example, Figure 3 shows images of fibre distributions according to the main directions of diffusivity in each voxel of the image. Here, the colour-coding allows for the detection of diffusion abnormalities. Main diffusion directions of single voxels also provide the basis for deterministic tractography, which reconstructs trajectories through a combination of adjacent voxels with similar main directions. Probabilistic tractography, in contrast, propagates numerous pathways through the tensor field so that each voxel can be coded with a number that reflects its likelihood of being connected with a given seed region from which the tracking is started (see (Jones, 2008) for a review).

With both the deterministic and probabilistic approaches, major fibre bundles can be reliably reconstructed (Mori and Zhang, 2006; Wakana *et al.*, 2004). Furthermore,

Impact of White Matter Damage After Stroke 237

compensate for motor impairment after severe damage to the PT (Lang and Schieber, 2004). In monkeys and cats, the cortico-reticulo-spinal and cortico-rubro-spinal tracts may mediate motor functions in case of PT lesions (Canedo, 1997), whereas these tracts have been described as functionally redundant in healthy animals (Kennedy, 1990). In more detail, it has been observed that damage to the PT and the rubro-spinal tract of monkeys yielded therapy-refractory impairment of the contralateral upper extremity, but monkeys with lesions to the PT that spared the rubro-spinal tract were able to recover considerably (Lawrence & Kuypers, 1968a; Lawrence & Kuypers, 1968b). Furthermore, changes in the synaptic organization of rubro-spinal neurons in response to PT lesions have been reported

The first neuroimaging study that translated these findings into motor recovery after human stroke combined structural MRI and electrophysiology to demonstrate that, despite severe degeneration of the PT, motor evoked potentials (MEP) could still be elicited from the ipsilesional motor cortex in patients who had recovered from stroke (Fries *et al.*, 1991). Similarly, patients with hemiparesis due to focal PT lesions were still able to execute individuated finger movements contralateral to the lesion, but with reduced selectivity (Lang and Schieber, 2004). These studies in humans illustrate the role of aMF after stroke

Using diffusivity parameters and tractography, researchers can examine fibre degeneration at different stages of motor recovery after stroke (Kang *et al.*, 2000; Lindberg *et al.*, 2007; Thomalla *et al.*, 2004; Werring *et al.*, 2000). In the chronic stage, structural damage to the PT could be related to measures of functional impairment (Schaechter *et al.*, 2009; Stinear *et al.*, 2007). Besides the PT, DTI has been applied to reconstruct aMF using deterministic fibre tracking algorithms and, thereby, to explore their role for motor recovery after stroke (Lindenberg *et al.*, 2010). Consistent with previous animal and human studies mentioned above, the differential affection of PT and aMF yielded a three-tier classification system suggesting that (1) when both PT and aMF could be reconstructed, patients showed only mild impairment, (2) when damage occurred to the PT but aMF remained relatively preserved, patients were only moderately impaired, and (3) when pronounced damage to both the PT and aMF was visible, patients was most severely impaired (Figure 4). In addition, DTI-based tractography allows to topographically relate lesions to corticospinal fibres and provides insights into their somatotopic organisation (Konishi *et al.*, 2005; Kunimatsu *et al.*, 2003; Lee *et al.*, 2005; Nelles *et al.*, 2008; Newton *et al.*, 2006; Yamada *et al.*, 2004). Furthermore, the calculation of the overlap between lesion and tracts can explain

in monkeys (Belhaj-Saïf & Cheney, 2000).

similar to that observed in non-human primates.

some of the variance in motor outcome after stroke (Zhu *et al.*, 2010).

**5. Predicting functional potential for motor recovery using DTI** 

One of the most important clinical questions after stroke is a patient's potential for recovery from stroke-induced deficits. Small cortical infarcts in the precentral gyrus typically allow for a profound recovery from hemiparesis. In contrast, infarcts of similar volume in the periventricular hemispheric white matter or the posterior limb of the internal capsule may induce a severe persistent hemiparesis (Kretschmann, 1988). Electrophysiological studies suggest that the functional integrity of ipsilesional motor circuits as well as interhemispheric interactions play a major role in motor recovery from hemiparesis after stroke (Perez and Cohen, 2009). Although transcranial magnetic stimulation (TMS) has been shown to strongly correlate with motor impairment in the acute and subacute phase after stroke, its

tractography not only allows for the visualisation of tract alterations after lesions, but can be used to quantify those alterations (Johansen-Berg and Behrens, 2006). Furthermore, fractional anisotropy (FA) has been used to describe microstructural abnormalities of white matter. FA indicates the coherence of aligned fibres and is calculated from directional diffusivities (axial and radial). Based on animal experiments, axial diffusivity is thought to primarily reflect axonal integrity whereas radial diffusivity has been suggested to relate to myelin degradation (Acosta-Cabronero *et al.*, 2009; Naismith *et al.*, 2009; Sidaros *et al.*, 2008; Song *et al.*, 2003; Sun *et al.*, 2008). However, the model of a specific relationship of directional diffusivities with discrete pathological processes such as axonal damage or demyelination is controversial, especially in regions of complex fibre architecture (Wheeler-Kingshott and Cercignani, 2009). Interpretations of these parameters with respect to "fibre integrity" should therefore be made with caution.

Fig. 3. DTI image of a patient with persistent hemiplegia in a striatocapsular infarct. Arrows point to severe diffusion alteration of corticospinal fibres descending in the posterior limb of the internal capsule and the cerebral pedunculus. The colour bar indicates the spatial orientation of fibres; blue: predominantly inferior—superior orientation, green: predominantly anterior—posterior orientation, red: predominantly left—right orientation.

### **4. Assessing the impact of white matter damage on motor function using DTI**

Although the concept of disconnection syndromes is well established and helps explaining functional deficits after lesions (Geschwind, 1965a; Geschwind, 1965b), the involvement of the white matter in stroke has not received much attention until recently (e.g., (Catani and ffytche, 2005). White matter damage has been found to be particularly prominent in large cerebral infarcts with hemispatial neglect, apraxia and severe hemiparesis (Karnath *et al.*, 2009; Pazzaglia *et al.*, 2008; Seitz *et al.*, 2009; Stoeckel *et al.*, 2007). However, it is not merely the size of the infarct but preferentially its location that determines the functional outcome after stroke (Binkofski *et al.*, 1996; Chen *et al.*, 2000; Zhu *et al.*, 2010).

The importance of corticospinal fibres for recovery of motor function after stroke has been demonstrated with different imaging modalities as well as electrophysiological measures (Binkofski *et al.*, 1996; Fries *et al.*, 1991; Schaechter *et al.*, 2008; Stinear *et al.*, 2007). Based on animal studies, it has been suggested that so-called alternate motor fibres (aMF) can

tractography not only allows for the visualisation of tract alterations after lesions, but can be used to quantify those alterations (Johansen-Berg and Behrens, 2006). Furthermore, fractional anisotropy (FA) has been used to describe microstructural abnormalities of white matter. FA indicates the coherence of aligned fibres and is calculated from directional diffusivities (axial and radial). Based on animal experiments, axial diffusivity is thought to primarily reflect axonal integrity whereas radial diffusivity has been suggested to relate to myelin degradation (Acosta-Cabronero *et al.*, 2009; Naismith *et al.*, 2009; Sidaros *et al.*, 2008; Song *et al.*, 2003; Sun *et al.*, 2008). However, the model of a specific relationship of directional diffusivities with discrete pathological processes such as axonal damage or demyelination is controversial, especially in regions of complex fibre architecture (Wheeler-Kingshott and Cercignani, 2009). Interpretations of these parameters with respect to "fibre integrity"

Fig. 3. DTI image of a patient with persistent hemiplegia in a striatocapsular infarct. Arrows point to severe diffusion alteration of corticospinal fibres descending in the posterior limb of the internal capsule and the cerebral pedunculus. The colour bar indicates the spatial orientation of fibres; blue: predominantly inferior—superior orientation, green:

predominantly anterior—posterior orientation, red: predominantly left—right orientation.

**4. Assessing the impact of white matter damage on motor function using DTI**  Although the concept of disconnection syndromes is well established and helps explaining functional deficits after lesions (Geschwind, 1965a; Geschwind, 1965b), the involvement of the white matter in stroke has not received much attention until recently (e.g., (Catani and ffytche, 2005). White matter damage has been found to be particularly prominent in large cerebral infarcts with hemispatial neglect, apraxia and severe hemiparesis (Karnath *et al.*, 2009; Pazzaglia *et al.*, 2008; Seitz *et al.*, 2009; Stoeckel *et al.*, 2007). However, it is not merely the size of the infarct but preferentially its location that determines the functional outcome

The importance of corticospinal fibres for recovery of motor function after stroke has been demonstrated with different imaging modalities as well as electrophysiological measures (Binkofski *et al.*, 1996; Fries *et al.*, 1991; Schaechter *et al.*, 2008; Stinear *et al.*, 2007). Based on animal studies, it has been suggested that so-called alternate motor fibres (aMF) can

after stroke (Binkofski *et al.*, 1996; Chen *et al.*, 2000; Zhu *et al.*, 2010).

should therefore be made with caution.

compensate for motor impairment after severe damage to the PT (Lang and Schieber, 2004). In monkeys and cats, the cortico-reticulo-spinal and cortico-rubro-spinal tracts may mediate motor functions in case of PT lesions (Canedo, 1997), whereas these tracts have been described as functionally redundant in healthy animals (Kennedy, 1990). In more detail, it has been observed that damage to the PT and the rubro-spinal tract of monkeys yielded therapy-refractory impairment of the contralateral upper extremity, but monkeys with lesions to the PT that spared the rubro-spinal tract were able to recover considerably (Lawrence & Kuypers, 1968a; Lawrence & Kuypers, 1968b). Furthermore, changes in the synaptic organization of rubro-spinal neurons in response to PT lesions have been reported in monkeys (Belhaj-Saïf & Cheney, 2000).

The first neuroimaging study that translated these findings into motor recovery after human stroke combined structural MRI and electrophysiology to demonstrate that, despite severe degeneration of the PT, motor evoked potentials (MEP) could still be elicited from the ipsilesional motor cortex in patients who had recovered from stroke (Fries *et al.*, 1991). Similarly, patients with hemiparesis due to focal PT lesions were still able to execute individuated finger movements contralateral to the lesion, but with reduced selectivity (Lang and Schieber, 2004). These studies in humans illustrate the role of aMF after stroke similar to that observed in non-human primates.

Using diffusivity parameters and tractography, researchers can examine fibre degeneration at different stages of motor recovery after stroke (Kang *et al.*, 2000; Lindberg *et al.*, 2007; Thomalla *et al.*, 2004; Werring *et al.*, 2000). In the chronic stage, structural damage to the PT could be related to measures of functional impairment (Schaechter *et al.*, 2009; Stinear *et al.*, 2007). Besides the PT, DTI has been applied to reconstruct aMF using deterministic fibre tracking algorithms and, thereby, to explore their role for motor recovery after stroke (Lindenberg *et al.*, 2010). Consistent with previous animal and human studies mentioned above, the differential affection of PT and aMF yielded a three-tier classification system suggesting that (1) when both PT and aMF could be reconstructed, patients showed only mild impairment, (2) when damage occurred to the PT but aMF remained relatively preserved, patients were only moderately impaired, and (3) when pronounced damage to both the PT and aMF was visible, patients was most severely impaired (Figure 4). In addition, DTI-based tractography allows to topographically relate lesions to corticospinal fibres and provides insights into their somatotopic organisation (Konishi *et al.*, 2005; Kunimatsu *et al.*, 2003; Lee *et al.*, 2005; Nelles *et al.*, 2008; Newton *et al.*, 2006; Yamada *et al.*, 2004). Furthermore, the calculation of the overlap between lesion and tracts can explain some of the variance in motor outcome after stroke (Zhu *et al.*, 2010).

### **5. Predicting functional potential for motor recovery using DTI**

One of the most important clinical questions after stroke is a patient's potential for recovery from stroke-induced deficits. Small cortical infarcts in the precentral gyrus typically allow for a profound recovery from hemiparesis. In contrast, infarcts of similar volume in the periventricular hemispheric white matter or the posterior limb of the internal capsule may induce a severe persistent hemiparesis (Kretschmann, 1988). Electrophysiological studies suggest that the functional integrity of ipsilesional motor circuits as well as interhemispheric interactions play a major role in motor recovery from hemiparesis after stroke (Perez and Cohen, 2009). Although transcranial magnetic stimulation (TMS) has been shown to strongly correlate with motor impairment in the acute and subacute phase after stroke, its

Impact of White Matter Damage After Stroke 239

measures can serve as predictors of a patient's potential for spontaneous recovery as well as

**6. Impact of white matter damage for functional deficits beyond hemiparesis**  Brain infarcts with white matter involvement lead to disconnection of areas in perilesional tissue, but also remote locations. This has been shown using positron emission tomography of cerebral blood flow and metabolism as well as with MRI (Feeney and Baron, 1986). Lesion analysis by use of statistical parametric mapping revealed that cortical infarcts result in remote changes in the ipsilesional thalamus, while striatocapsular infarcts induce changes in the contralesional cerebellum (Seitz *et al.*, 1994). Consequently, functional changes occur in regions spatially distant from the area of infarction, an event which has been termed diaschisis. In the chronic phase after stroke, scar formation and fibre degeneration have been shown to result in brain atrophy (Kraemer *et al.*, 2004). Many patients retain functional impairments which can be documented by dedicated investigations including neuropsychology, electrophysiology and DTI. A clinical example is ataxic hemiplegia resulting from infarct lesions around the internal capsule with cortico-cerebellar disconnection (Classen *et al.*, 1995). Similarly, callosal infarcts can induce a lasting decoupling of both hands (Seitz *et al.*, 2004). Infarcts in the frontal parasagittal white matter can produce a deficit of visual face processing probably due to disruption of frontooccipitotemporal projections (Schafer *et al.*, 2007). Lesion studies in neglect have demonstrated subcortical white matter involvement in the peri-insular area and the internal capsule (Karnath *et al.*, 2004). In Gerstmann's syndrome it has been shown recently that the different parietal cortical subareas which process finger naming, colour naming, right-left orientation, and calculation can all be impaired by a single subcortical white matter lesion affecting the point of convergence of their subcortical projections (Rusconi et al. 2009). These data are of considerable interest given the impact of white matter abnormalities for cognitive decline and the development of dementia after stroke (Dufouil *et al.*, 2009). Taken together, many clinically well-established syndromes are likely to result from cortico-

in response to different types of neurorehabilitation techniques.

cortical and cortico-subcortical disconnections.

**7. Fibre tract changes in white matter and cerebral plasticity** 

As observed in lesion experiments, intensive rehabilitation allowed animals with damage of corticospinal tracts to recover considerably (Maier *et al.*, 2008). In these animals, collateral fibres increased their innervation density and extended toward the ventral and dorsal horn in response to forced limb use. In contrast, animals that were impeded in their usage of the affected limbs remained impaired and did not show such plastic changes. This highlights the importance of examining white matter structures to determine the extent of potential recovery. In monkeys it has been found that damage of white matter adjacent to lesions in the visual cortex determined the extent of remote and transneural degeneration in the dorsal geniculate and retina (Cowey *et al.*, 1999). Preliminary results in humans undergoing intonation-based speech therapy for chronic aphasia suggest plastic changes in the contralesional arcuate fasciculus associated with improvement in speech production (Schlaug *et al.*, 2009). In healthy subjects, it has already been demonstrated that DTI allows for the detection of white matter changes in response to training, as indicated by an increase in FA after training (Scholz *et al.*, 2009). Taken together, homologous contralesional regions

predictive value appears unclear in the chronic stage (Talelli *et al.*, 2006). However, a combination of TMS and DTI-derived parameters of corticospinal tracts proved to be useful in estimating a patient's potential for recovery when undergoing motor rehabilitation even years after the stroke (Stinear *et al.*, 2007). Similarly, DTI in the acute stroke phase helped predicting outcome at three months (Jang *et al.*, 2008).

Fig. 4. The course of the pyramidal tract (PT) and alternate motor fibres (aMF) from the white matter underlying the precentral gyrus to the brainstem in a healthy subject.

In order to define predictors of therapeutic response to novel rehabilitation techniques such as non-invasive brain stimulation, it may be useful to examine transcallosal motor fibres as well. Using transcranial direct current stimulation (tDCS) or repetitive TMS, it has been demonstrated that both the up-regulation of intact portions of the ipsilesional and downregulation of contralesional motor cortices facilitates motor recovery after stroke (Schlaug *et al.*, 2008). Together with evidence from electrophysiological investigations (Perez and Cohen, 2009) and functional MRI (Carter *et al.*, 2009; Grefkes *et al.*, 2008), there is ample evidence for the importance of inter-hemispheric interactions in functional recovery from a stroke. To complement these findings, a study in healthy subjects revealed an association of function and microstructure of transcallosal motor connections (Wahl *et al.*, 2007). In chronic stroke patients, DTI-derived measures of transcallosal motor fibres as well as ipsilesional corticospinal tracts (PT and aMF) could be used to explain the therapeutic response to rehabilitation: the more the diffusivity profiles resembled those observed in healthy subjects, the greater a patient's potential for functional recovery (Lindenberg *et al.*, 2011). Thus, diffusivity profiles of motor tracts, particularly, in combination with electrophysiological

predictive value appears unclear in the chronic stage (Talelli *et al.*, 2006). However, a combination of TMS and DTI-derived parameters of corticospinal tracts proved to be useful in estimating a patient's potential for recovery when undergoing motor rehabilitation even years after the stroke (Stinear *et al.*, 2007). Similarly, DTI in the acute stroke phase helped

Fig. 4. The course of the pyramidal tract (PT) and alternate motor fibres (aMF) from the white matter underlying the precentral gyrus to the brainstem in a healthy subject.

PT

In order to define predictors of therapeutic response to novel rehabilitation techniques such as non-invasive brain stimulation, it may be useful to examine transcallosal motor fibres as well. Using transcranial direct current stimulation (tDCS) or repetitive TMS, it has been demonstrated that both the up-regulation of intact portions of the ipsilesional and downregulation of contralesional motor cortices facilitates motor recovery after stroke (Schlaug *et al.*, 2008). Together with evidence from electrophysiological investigations (Perez and Cohen, 2009) and functional MRI (Carter *et al.*, 2009; Grefkes *et al.*, 2008), there is ample evidence for the importance of inter-hemispheric interactions in functional recovery from a stroke. To complement these findings, a study in healthy subjects revealed an association of function and microstructure of transcallosal motor connections (Wahl *et al.*, 2007). In chronic stroke patients, DTI-derived measures of transcallosal motor fibres as well as ipsilesional corticospinal tracts (PT and aMF) could be used to explain the therapeutic response to rehabilitation: the more the diffusivity profiles resembled those observed in healthy subjects, the greater a patient's potential for functional recovery (Lindenberg *et al.*, 2011). Thus, diffusivity profiles of motor tracts, particularly, in combination with electrophysiological

aMF

predicting outcome at three months (Jang *et al.*, 2008).

measures can serve as predictors of a patient's potential for spontaneous recovery as well as in response to different types of neurorehabilitation techniques.

### **6. Impact of white matter damage for functional deficits beyond hemiparesis**

Brain infarcts with white matter involvement lead to disconnection of areas in perilesional tissue, but also remote locations. This has been shown using positron emission tomography of cerebral blood flow and metabolism as well as with MRI (Feeney and Baron, 1986). Lesion analysis by use of statistical parametric mapping revealed that cortical infarcts result in remote changes in the ipsilesional thalamus, while striatocapsular infarcts induce changes in the contralesional cerebellum (Seitz *et al.*, 1994). Consequently, functional changes occur in regions spatially distant from the area of infarction, an event which has been termed diaschisis. In the chronic phase after stroke, scar formation and fibre degeneration have been shown to result in brain atrophy (Kraemer *et al.*, 2004). Many patients retain functional impairments which can be documented by dedicated investigations including neuropsychology, electrophysiology and DTI. A clinical example is ataxic hemiplegia resulting from infarct lesions around the internal capsule with cortico-cerebellar disconnection (Classen *et al.*, 1995). Similarly, callosal infarcts can induce a lasting decoupling of both hands (Seitz *et al.*, 2004). Infarcts in the frontal parasagittal white matter can produce a deficit of visual face processing probably due to disruption of frontooccipitotemporal projections (Schafer *et al.*, 2007). Lesion studies in neglect have demonstrated subcortical white matter involvement in the peri-insular area and the internal capsule (Karnath *et al.*, 2004). In Gerstmann's syndrome it has been shown recently that the different parietal cortical subareas which process finger naming, colour naming, right-left orientation, and calculation can all be impaired by a single subcortical white matter lesion affecting the point of convergence of their subcortical projections (Rusconi et al. 2009). These data are of considerable interest given the impact of white matter abnormalities for cognitive decline and the development of dementia after stroke (Dufouil *et al.*, 2009). Taken together, many clinically well-established syndromes are likely to result from corticocortical and cortico-subcortical disconnections.

### **7. Fibre tract changes in white matter and cerebral plasticity**

As observed in lesion experiments, intensive rehabilitation allowed animals with damage of corticospinal tracts to recover considerably (Maier *et al.*, 2008). In these animals, collateral fibres increased their innervation density and extended toward the ventral and dorsal horn in response to forced limb use. In contrast, animals that were impeded in their usage of the affected limbs remained impaired and did not show such plastic changes. This highlights the importance of examining white matter structures to determine the extent of potential recovery. In monkeys it has been found that damage of white matter adjacent to lesions in the visual cortex determined the extent of remote and transneural degeneration in the dorsal geniculate and retina (Cowey *et al.*, 1999). Preliminary results in humans undergoing intonation-based speech therapy for chronic aphasia suggest plastic changes in the contralesional arcuate fasciculus associated with improvement in speech production (Schlaug *et al.*, 2009). In healthy subjects, it has already been demonstrated that DTI allows for the detection of white matter changes in response to training, as indicated by an increase in FA after training (Scholz *et al.*, 2009). Taken together, homologous contralesional regions

Impact of White Matter Damage After Stroke 241

Cowey A, Stoerig P, Williams C. Variance in transneuronal retrograde ganglion cell

Cramer SC. Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery.

Dancause N, Barbay S, Frost SB, Plautz EJ, Chen D, Zoubina EV, et al. Extensive cortical

Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, et al. Effects of alteplase

Fries W, Danek A, Witt TN. Motor responses after transcranial electrical stimulation of

Hallevi H, Albright KC, Martin-Schild SB, Barreto AD, Morales MM, Bornstein N, et al.

Jang SH, Bai D, Son SM, Lee J, Kim DS, Sakong J, et al. Motor outcome prediction using diffusion tensor tractography in pontine infarct. Ann Neurol 2008; 64: 460-5. Johansen-Berg H, Behrens TE. Just pretty pictures? What diffusion tractography can add in

Johansen-Berg H, Scholz J, Stagg CJ. Relevance of structural brain connectivity to learning

Jones DK. Studying connections in the living human brain with diffusion MRI. Cortex 2008;

Kang DW, Chu K, Yoon BW, Song IC, Chang KH, Roh JK. Diffusion-weighted imaging in

Karnath HO, Fruhmann Berger M, Kuker W, Rorden C. The anatomy of spatial neglect

Karnath HO, Rorden C, Ticini LF. Damage to white matter fiber tracts in acute spatial

Konishi J, Yamada K, Kizu O, Ito H, Sugimura K, Yoshikawa K, et al. MR tractography for

Kraemer M, Schormann T, Hagemann G, Qi B, Witte OW, Seitz RJ. Delayed shrinkage of the

based on voxelwise statistical analysis: a study of 140 patients. Cereb Cortex 2004;

the evaluation of functional recovery from lenticulostriate infarcts. Neurology 2005;

brain after ischemic stroke: preliminary observations with voxel-guided

clinical neuroscience. Curr Opin Neurol 2006; 19: 379-85.

and recovery from stroke. Front Syst Neurosci 2010; 4: 146.

Wallerian degeneration. J Neurol Sci 2000; 178: 167-9.

Geschwind N. Disconnexion syndromes in animals and man. I. Brain 1965a; 88: 237-94. Geschwind N. Disconnexion syndromes in animals and man. II. Brain 1965b; 88: 585-644. Grefkes C, Nowak DA, Eickhoff SB, Dafotakis M, Kust J, Karbe H, et al. Cortical connectivity

cortical lesion. Vision Res 1999; 39: 3642-52.

Feeney DM, Baron JC. Diaschisis. Stroke 1986; 17: 817-30.

day 7. Cerebrovasc Dis 2009; 28: 341-8.

neglect. Cereb Cortex 2009; 19: 2331-7.

morphometry. J Neuroimaging 2004; 14: 265-72.

rewiring after brain injury. J Neurosci 2005; 25: 10167-79.

with cerebrovascular disease history. Stroke 2009; 40: 2219-21.

Ann Neurol 2008; 63: 272-87.

646-50.

44: 936-52.

14: 1164-72.

64: 108-13.

Neurol 2008; 63: 236-46.

degeneration in monkeys after removal of striate cortex: effects of size of the

beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008; 7: 299-309. Dufouil C, Godin O, Chalmers J, Coskun O, MacMahon S, Tzourio-Mazoyer N, et al. Severe

cerebral white matter hyperintensities predict severe cognitive decline in patients

cerebral hemispheres with a degenerated pyramidal tract. Ann Neurol 1991; 29:

after subcortical stroke assessed with functional magnetic resonance imaging. Ann

Recovery after ischemic stroke: criteria for good outcome by level of disability at

or partially preserved perilesional areas and their associated fibre tracts seem to exhibit plastic reorganisation upon dedicated training. However, more work in experimental animals is needed to come to a better understanding which microstructural and physicochemical changes underlie the signal changes assessed with DTI in men. In the future, DTI may serve as a surrogate marker of cerebral plasticity and help evaluating a patient's response to rehabilitation.

### **8. Conclusions**

White matter changes after stroke are important determinants for presentation and severity of the neurological deficits as well as for prospects of recovery or secondary cognitive decline. Notably, DTI appears to be a valuable tool for predicting the individual patient's perspective for recovery in order to tailor an optimized rehabilitation regime.

### **9. References**


or partially preserved perilesional areas and their associated fibre tracts seem to exhibit plastic reorganisation upon dedicated training. However, more work in experimental animals is needed to come to a better understanding which microstructural and physicochemical changes underlie the signal changes assessed with DTI in men. In the future, DTI may serve as a surrogate marker of cerebral plasticity and help evaluating a

White matter changes after stroke are important determinants for presentation and severity of the neurological deficits as well as for prospects of recovery or secondary cognitive decline. Notably, DTI appears to be a valuable tool for predicting the individual patient's

Acosta-Cabronero J, Williams GB, Pengas G, Nestor PJ. Absolute diffusivities define the

Beaulieu C. The basis of anisotropic water diffusion in the nervous system - a technical

Beaulieu C. The biological basis of diffusion anisotropy. In: Johansen-Berg H, Behrens TE,

Bejot Y, Benatru I, Rouaud O, Fromont A, Besancenot JP, Moreau T, et al. Epidemiology of

Binkofski F, Seitz RJ. Modulation of the BOLD-response in early recovery from sensorimotor

Binkofski F, Seitz RJ, Arnold S, Classen J, Benecke R, Freund HJ. Thalamic metabolism and

Butefisch CM, Kleiser R, Seitz RJ. Post-lesional cerebral reorganisation: evidence from

Canedo A. Primary motor cortex influences on the descending and ascending systems. Prog

Carter AR, Astafiev SV, Lang CE, Connor LT, Rengachary J, Strube MJ, et al. Resting inter-

Catani M, ffytche DH. The rises and falls of disconnection syndromes. Brain 2005; 128: 2224-

Chen CL, Tang FT, Chen HC, Chung CY, Wong MK. Brain lesion size and location: effects

Classen J, Kunesch E, Binkofski F, Hilperath F, Schlaug G, Seitz RJ, et al. Subcortical origin

of visuomotor apraxia. Brain 1995; 118 ( Pt 6): 1365-74.

landscape of white matter degeneration in Alzheimer's disease. Brain 2009: Epub

editors. Diffusion MRI: From quantitative measurement to in vivo neuroanatomy.

stroke in Europe: geographic and environmental differences. J Neurol Sci 2007; 262:

corticospinal tract integrity determine motor recovery in stroke. Ann Neurol 1996;

functional neuroimaging and transcranial magnetic stimulation. J Physiol Paris

hemispheric fMRI connectivity predicts performance after stroke. Ann Neurol 2009;

on motor recovery and functional outcome in stroke patients. Arch Phys Med

perspective for recovery in order to tailor an optimized rehabilitation regime.

patient's response to rehabilitation.

ahead of print.

review. NMR Biomed 2002; 15: 435-55.

London: Academic Press; 2009. p. 105-26.

stroke. Neurology 2004; 63: 1223-9.

**8. Conclusions** 

**9. References** 

85-8.

39: 460-70.

67: 365-75.

39.

2006; 99: 437-54.

Neurobiol 1997; 51: 287-335.

Rehabil 2000; 81: 447-52.


Impact of White Matter Damage After Stroke 243

Rusconi E, Pinel P, Eger E, LeBihan D, Thirion B, Dehaene S, et al. A disconnection account

Schaechter JD, Fricker ZP, Perdue KL, Helmer KG, Vangel MG, Greve DN, et al.

Schaechter JD, Perdue KL, Wang R. Structural damage to the corticospinal tract correlates

Schafer R, Popp K, Jorgens S, Lindenberg R, Franz M, Seitz RJ. Alexithymia-like disorder in

Schlaug G, Marchina S, Norton A. Evidence for plasticity in white-matter tracts of patients

Schlaug G, Renga V, Nair D. Transcranial direct current stimulation in stroke recovery. Arch

Scholz J, Klein MC, Behrens TE, Johansen-Berg H. Training induces changes in white-matter

Seitz RJ, Donnan GA. Role of neuroimaging in promoting long-term recovery from ischemic

Seitz RJ, Kleiser R, Butefisch CM, Jorgens S, Neuhaus O, Hartung HP, et al. Bimanual recoupling by visual cueing in callosal disconnection. Neurocase 2004; 10: 316-25. Seitz RJ, Meisel S, Weller P, Junghans U, Wittsack HJ, Siebler M. Initial ischemic event:

Seitz RJ, Schlaug G, Kleinschmidt A, Knorr U, Nebeling B, Wirrwar A, et al. Remote

to motor and somatosensory functions. Hum Brain Mapp 1994; 1: 81-100. Seitz RJ, Sondermann V, Wittsack HJ, Siebler M. Lesion patterns in successful and failed thrombolysis in middle cerebral artery stroke. Neuroradiology 2009; 51: 865-71. Sidaros A, Engberg AW, Sidaros K, Liptrot MG, Herning M, Petersen P, et al. Diffusion

Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH. Diffusion tensor imaging detects

Stinear CM, Barber PA, Smale PR, Coxon JP, Fleming MK, Byblow WD. Functional potential

Stoeckel MC, Wittsack HJ, Meisel S, Seitz RJ. Pattern of cortex and white matter involvement in severe middle cerebral artery ischemia. J Neuroimaging 2007; 17: 131-40. Sun SW, Liang HF, Cross AH, Song SK. Evolving Wallerian degeneration after transient

clinical outcome: a longitudinal study. Brain 2008; 131: 559-72.

perfusion-weighted MR imaging and apparent diffusion coefficient for stroke

depressions of cerebral metabolism in hemiparetic stroke: Topography and relation

tensor imaging during recovery from severe traumatic brain injury and relation to

and differentiates axon and myelin degeneration in mouse optic nerve after retinal

in chronic stroke patients depends on corticospinal tract integrity. Brain 2007; 130:

retinal ischemia in mice characterized by diffusion tensor imaging. Neuroimage

right anterior cingulate infarction. Neurocase 2007; 13: 201-8.

654-62.

3461-74.

2008; 39: 1370-82.

Neurol 2008; 65: 1571-6.

Ann N Y Acad Sci 2009; 1169: 385-94.

architecture. Nat Neurosci 2009; 12: 1370-1.

evolution. Radiology 2005; 237: 1020-8.

ischemia. Neuroimage 2003; 20: 1714-22.

170-80.

2008; 40: 1-10.

stroke. J Magn Reson Imaging 2010; 32: 756-72.

of Gerstmann syndrome: functional neuroanatomy evidence. Ann Neurol 2009; 66:

Microstructural status of ipsilesional and contralesional corticospinal tract correlates with motor skill in chronic stroke patients. Hum Brain Mapp 2009; 30:

with bilateral sensorimotor cortex reorganization in stroke patients. Neuroimage

with chronic Broca's aphasia undergoing intense intonation-based speech therapy.


Kranz PG, Eastwood JD. Does diffusion-weighted imaging represent the ischemic core? An evidence-based systematic review. AJNR Am J Neuroradiol 2009; 30: 1206-12. Kretschmann HJ. Localisation of the corticospinal fibres in the internal capsule in man. J

Kunimatsu A, Aoki S, Masutani Y, Abe O, Mori H, Ohtomo K. Three-dimensional white

Kwakkel G. Impact of intensity of practice after stroke: issues for consideration. Disabil

Lang CE, Schieber MH. Reduced muscle selectivity during individuated finger movements

Lee JS, Han MK, Kim SH, Kwon OK, Kim JH. Fiber tracking by diffusion tensor imaging in

Lindberg PG, Skejo PH, Rounis E, Nagy Z, Schmitz C, Wernegren H, et al. Wallerian

Lindenberg R, Renga V, Zhu LL, Betzler F, Alsop D, Schlaug G. Structural integrity of

Lindenberg R, Zhu LL, Rüber T, Schlaug G. Predicting functional motor potential in chronic

Maier IC, Baumann K, Thallmair M, Weinmann O, Scholl J, Schwab ME. Constraint-induced

Mori S, Zhang J. Principles of diffusion tensor imaging and its applications to basic

Naismith RT, Xu J, Tutlam NT, Snyder A, Benzinger T, Shimony J, et al. Disability in optic

Nelles M, Gieseke J, Flacke S, Lachenmayer L, Schild HH, Urbach H. Diffusion tensor

Newton JM, Ward NS, Parker GJ, Deichmann R, Alexander DC, Friston KJ, et al. Non-

Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of

Pazzaglia M, Smania N, Corato E, Aglioti SM. Neural underpinnings of gesture discrimination in patients with limb apraxia. J Neurosci 2008; 28: 3030-41. Perez MA, Cohen LG. Interhemispheric inhibition between primary motor cortices: what

corticospinal tract. Neuroradiology 2003; 45: 532-5.

Neurorehabil Neural Repair 2007; 21: 551-60.

neuroscience research. Neuron 2006; 51: 527-39.

matter tractography by diffusion tensor imaging in ischaemic stroke involving the

in humans after damage to the motor cortex or corticospinal tract. J Neurophysiol

corticospinal tract stroke: Topographical correlation with clinical symptoms.

degeneration of the corticofugal tracts in chronic stroke: a pilot study relating diffusion tensor imaging, transcranial magnetic stimulation, and hand function.

corticospinal motor fibers predicts motor impairment in chronic stroke. Neurology

stroke patients using diffusion tensor imaging. Hum Brain Mapp 2011; epub ahead

movement therapy in the adult rat after unilateral corticospinal tract injury. J

neuritis correlates with diffusion tensor-derived directional diffusivities.

pyramidal tractography in patients with anterior choroidal artery infarcts. AJNR

invasive mapping of corticofugal fibres from multiple motor areas--relevance to

rehabilitative training on motor recovery after ischemic infarct. Science 1996; 272:

Anat 1988; 160: 219-25.

Rehabil 2006; 28: 823-30.

Neuroimage 2005; 26: 771-6.

Neurosci 2008; 28: 9386-403.

Neurology 2009; 72: 589-94.

Am J Neuroradiol 2008; 29: 488-93.

stroke recovery. Brain 2006; 129: 1844-58.

have we learned? J Physiol 2009; 587: 725-6.

2004; 91: 1722-33.

2010; 74: 280-7.

of print.

1791-4.


**0**

**13**

*USA*

**Tissue Fate Prediction from Regional Imaging**

Stroke is a leading cause of death and a major cause of long term disabilities worldwide. According to the World Health Organization (WHO), a total of 15 million people suffer from a stroke each year comprising 5 million with a fatal outcome and another 5 million with permanent disabilities. While prevention research identifies factors and specific drugs that may lower the risk of a future stroke, the treatment of ischemic stroke patients aims at maximizing the recovery of brain tissue at risk. It is typically done by arterial recanalization of the vessel where the clot is located. Identification of salvageable brain tissue is essential during the clinical decision-making process. As a general rule for the decision to intervene, the expected benefits of the intervention should outweigh its potential risks and costs. To identify viable brain tissue, time is considered as a determining factor in the treatment of stroke patients. A perfect illustration of this timing issue is the thrombolytic therapy which uses specific drugs to break-up or dissolve the blood clot. As shown in a recent study (Hacke et al, 2008), thrombolysis applied with recombinant tissue plasminogen activator (rt-PA) is effective for acute ischemic stroke patients when administered intra-venously within a specific time window (3 hours, or 4 hours 30 min for patients meeting additional criteria). However, this time frame is arbitrary and might be too restrictive for some patients (Schaefer et al., 2007). For example, some patients could have benefited from this therapy but, instead, have been unnecessarily excluded. Beyond this ongoing debate about the length of the time window, there is a recognized need for accurate strategies to quantify the extent of viable tissue for victims of ischemic strokes and therefore to be able to identify the patients who could benefit

Estimating the dynamic of infarct growth in ischemic stroke is extremely complex and its mechanisms are still poorly understood. Various factors such as quality of collateral perfusion, energy delivery, and age of the patient are known to have a significant impact on the outcome. However, their interactions over time is not clearly established and has not been quantified. The most commonly used techniques currently available to predict tissue outcome are based on imaging. It is widely accepted that the combination of diffusion (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) provide useful information to identify the tissue at risk at an early stage. Several groups (Chen et al., 2008; Fisher & Ginsberg, 2004; Kidwell et al., 2004; Schlaug et al., 1999) have studied the mismatch between DWI and PWI to determine the penumbral tissue. However, DWI-PWI mismatch approaches have limitations: increased diffusion signals may be reversible (although a recent

**1. Introduction**

from such a therapy.

**Features in Acute Ischemic Stroke**

Fabien Scalzo, Xiao Hu and David Liebeskind

*University of California, Los Angeles (UCLA)*

