Non invasive mapping of corticofugal fib

Trajectory of connections between the cerebral peduncle and M1 In the series of axial sections immediately inferior to the

cortex, we found that connections between the cerebral ped- uncle and M1 rapidly form a concentrated bundle as they enter the corona radiata (Fig. 2). On entering the corona radiata they maintain a fixed location in successive inferior sections, suggesting that fibres descending from this region stream vertically through the corona radiata. At the level of the internal capsule, the peduncular–M1 connections are located between the posterior portion of the putamen and the thalamus in the posterior limb of the internal capsule and continue to suggest a vertical course of the related fibres. In both the corona radiata and internal capsule the connections between the cerebral peduncle with M1 are located most posteriorly of all the motor system connections. Connections to M1 are located laterally in the cerebral peduncle, though there is a strong overlap with the connections to PMd, and more medially with the SMA (Fig. 6).

Trajectory of connections between the cerebral peduncle and PMd As with the peduncular–M1 connections, the concentration

of connections immediately inferior to the cortex suggests a rapid aggregation of fibres from the PMd region as they enter the corona radiata. Once in the corona radiata, they also run vertically, located anteriorly to connections originating from M1, though there is a large degree of overlap between connections from these two precentral areas (Fig. 6). As the connections from PMd enter the internal capsule, the most

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Fig. 2 Trajectory variability maps for the peduncle/M1 connections shown on representative sections of the average of the T 1 -weighted structural. Colour bar shows number of subjects with connections in each voxel: range = 2–12. The top panel shows sagittal slices x=

24 and x = +24 either side of coronal slice y = 18. The lower two panels show transverse slices. The right side of the brain is depicted on the right side of the transverse and coronal images.

anterior connections overlap with those of the SMA (Fig. 6) As shown in Fig. 4, there is a rapid medial shift of and PMv (Supplementary Fig. 3), whereas the most posterior

connections immediately inferior to the PMv. The resulting connections overlap with M1 connections. Connections to

bundle tends to be located more anteriorly than the majority PMd are also located laterally in the cerebral peduncle, though

of PMd fibres, though overlap does occur (Supplementary there is considerable overlap with the origins of connections

Fig. 3). The trajectory of peduncle–PMv connections follows reaching each of the motor cortical areas (Fig. 6).

a mostly vertical route through the corona radiata and pos- terior limb of the internal capsule, with an anterior shift

Trajectory of connections between the

relative to the majority of M1 and PMv connections visible

cerebral peduncle and PMv

at these levels. At the level of the peduncle the PMv con- Connections between the peduncle and PMv were identified

nection origins do not extend as laterally as those of M1 and in 10 of the 12 control subjects. The consistency of trajec-

PMd (Supplementary Fig. 3).

tories within this subset of subjects was high and revealed a continuous tract between the peduncle and the cortex (Fig. 4). However, after thresholding of the variability maps

Trajectory of connections between the

to visualize the voxels through which connections passed in

cerebral peduncle and the SMA

eight or more individuals, a common route was observed Connections to the SMA are located progressively more lat- between the peduncle and the inferior level of the corona

erally in successive axial slices at the levels below the SMA radiata, though not to the cortex (Supplementary Fig. 3).

until the approximate level of the lateral ventricles (Fig. 5).

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Fig. 3 Trajectory variability maps for the peduncle/PMd connections shown on representative sections of the average of the T 1 -weighted structural. Colour bar shows number of subjects with connections in each voxel: range = 2–12. The top panel shows sagittal slices x=

24 and x = +24 either side of coronal slice y = 16. The lower two panels show transverse slices. The right side of the brain is depicted on the right side of the transverse and coronal images.

In addition, the SMA connections shift in a posterior direc-

Structural consequences of damage to

tion on subsequent inferior axial planes from the cortex to

the descending motor fibres

the peduncle, suggesting that fibres from the SMA course For each patient, voxel-wise comparison of FA with the caudally and inferiorly in the subcortical white matter. The

control group revealed focal reductions in anisotropy route of the SMA connections passes close to the caudal

(Table 2). All patients showed relative FA reductions in portion of the head of the caudate in the genu and anterior

the internal capsule and/or corona radiata, which extended limb of the internal capsule at its most superior level, before

beyond the margins of the lesion(s) as seen on the corre- passing over the putamen and shifting to the posterior limb

sponding T 1 -weighted structural image. Figure 7 illustrates of the internal capsule at more inferior levels. SMA connec-

the intersection of FA reductions in each patient with the tions tend to be located anterior to those of any of the three

combined trajectory maps, and shows voxels through which precentral regions, though there is some overlap of these

streamlines pass to each cortical area for eight or more con- connections with those of other non-primary regions, as

trol subjects. The maximal overlap of damaged white matter well as with M1 connections, though only at inferior levels

on the most common connections to each cortical area is of the internal capsule and the peduncle (Fig. 6). At the level

reported for each patient in Table 3.

of the cerebral peduncle, the SMA-connected seed points As shown in Fig. 7A and Table 3, the region of reduced tend to be found in more ventral and medial locations

anisotropy in the corona radiata of Patient A intersected than those of the precentral region.

mostly with the connections of M1 and PMd. There was

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Fig. 4 Trajectory variability maps for the peduncle/PMv connections shown on representative sections of the average of the T 1 -weighted structural. Colour bar shows number of subjects with connections in each voxel: range = 2–12. The top panel shows sagittal slices x=

24 and x = +24 either side of coronal slice y = 12. The lower two panels show transverse slices. The right side of the brain is depicted on the right side of the transverse and coronal images.

minimal overlap with SMA projections located rostral to this connecting to M1 and PMd. Patient B had more extensive region of reduced FA. No voxels at the level of this damaged

damage anteriorly, implying a disconnection of PMv, as well area were common to the PMv trajectories of eight or more

as M1 and PMd. The lesions in Patient C were even more subjects. In addition, the other region of significantly

anterior and spared the connections to the motor areas we reduced anisotropy in Patient A, located at the level of

considered. We therefore predicted that Patients A and B the internal capsule, did not overlap with any motor system

would show abnormal patterns of cortical responses in the connections (Fig. 7A). In Patient B, there was significant

ipsilesional motor system and that Patient C would show no overlap between the region of reduced FA and connections

abnormalities. This is largely what we observed. to all precentral regions. The highest proportion (80%) of damaged voxels overlapped with connections to PMv and no more than 10% to SMA (Table 3, Fig. 7B). The region of

Functional consequences of damage to

reduced FA in Patient C was located anterior to connections

the descending motor fibres

from the precentral components of the motor system; there Comparison of the activations associated with grip of the was minimal overlap with SMA projections (Table 3,

affected hands in individual stroke patients with activations Fig. 7C).

in the control group revealed only relative increases in task- In summary, the subcortical lesions (as inferred by analysis

related activation in the patients (Table 2). In Patient A, of FA) in Patient A interrupted more posterior trajectories

there were two clusters of overactivation in the ipsilesional

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Fig. 5 Trajectory variability maps for the peduncle/SMA connections shown on representative sections of the average of the T 1 -weighted structural. Colour bar shows number of subjects with connections in each voxel: range = 2–12. The top panel shows sagittal slices x=

24 and x = +24 either side of coronal slice y = 12. The lower two panels show transverse slices. The right side of the brain is depicted on the right side of the transverse and coronal images.

precentral sulcus in regions corresponding to rostral PMd in high-angular resolution DWI and probabilistic tractography the depth of the sulcus, extending into the middle frontal

in a group of healthy adults. These findings are in agreement gyrus, and PMv (though this cluster was only significant at

with previous clinical and anatomical findings in humans uncorrected P < 0.001 level) (Fig. 8A). In Patient B, peaks of

(Englander et al., 1975; Ross, 1980; Fries et al., 1993; Seitz relative overactivation were observed on the ipsilesional

et al ., 1998; Pineiro et al., 2000; Wenzelburger et al., 2005) precentral gyrus, encompassing portions of PMd and M1

and reveal many similarities between the organization of (though not the hand knob region) as shown in Fig. 8B,

these connections in humans and other primates, as inves- and contralesional PMv. The activation pattern of Patient C

tigated with neuronal tracer methods (Fries et al., 1993; did not significantly differ from those of the control group.

Morecraft et al., 2002).

The position and degree of overlap of corticofugal fibres from each cortical motor area, particularly in the internal

Discussion

capsule, have been of interest for many years as a means of

Anatomical findings

furthering understanding of the relationship between loca- We have demonstrated, in standard anatomical space, the

lized white matter damage and restitution of motor function. most probable trajectories of the corticofugal connections

We found that the connections from M1 to the cerebral of the major divisions of the cortical motor system using

peduncle passed through the posterior limb of the internal

Organization of corticofugal connections Brain (2006), 129, 1844–1858 1853

Downloaded from

http://brain.oxfordjournals.org/ Fig. 6 Sections showing the overlap between the thresholded trajectory variability maps (eight or more subjects) for M1, PMd and

SMA on axial and sagittal sections. Coordinates for x and z correspond to MNI space.

Table 2 Single patient versus control group comparisons Patient

Significant decreases in anisotropy

Significant increases in fMRI activation

Coordinates in MNI space

Region

Coordinates in MNI space

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A 30, 16, 38

4.38 R PMd (rostral border) 24, 12, 14

4.03 R CR

3.69 R PMv † B 32,

3.72 R IC

4.37 L CR

5.25 L PMd

5.04 R PMv

– The table shows regions in which there were significant decreases in anisotropy (left) and significant increases in task-related activation between

C 16, 6, 16, 5.14

R IC

each stroke patient and the control group. Coordinates represent peak voxels within significant clusters. Significance was set at P < 0.001 (uncorrected) for clusters of 10 or more voxels for the anisotropy analysis. For the fMRI analysis, significance was defined at P < 0.05 corrected in search volume consisting of cortical motor system areas of relevant hemisphere. y

Cluster not significant with correction (FWE, P < 0.05)—significant uncorrected P < 0.001; L = left; R = right; CR = corona radiata; IC = internal capsule.

capsule, as previously found in anatomical (Englander et al., connections occupied more anterior locations compared 1975; Ross, 1980) and tractography-based (Guye et al., 2003)

with the majority of those linked to PMd. In contrast, con- studies in humans, as well as in tracer studies in non-human

nections to the SMA were found to pass through the genu primates (Fries et al., 1993; Morecraft et al., 2002). The

and anterior limb of the internal capsule at superior levels connections we found linking PMd to the peduncles also

followed by a gradual shift to the posterior limb on more ran through the posterior limb, though, in agreement

inferior sections—an observation that parallels that of pre- with tracing-derived evidence, these connections tended to

vious tracer studies (Fries et al., 1993; Morecraft et al., 2002).

be located more anteriorly than those linked to M1 Correct identification of neuronal pathways with tracto- (Morecraft et al., 2002). In contrast to earlier findings in

graphy is dependent on accurate classification of the diffu- the non-human primates, we did not find evidence of

sion profile in each voxel of the brain, as this model will PMv fibres transiting the genu of the internal capsule

determine the possible directions sampled by the tracto- (Morecraft et al., 2002), though we did find that PMv

graphy algorithm. When tracing descending fibres of the

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Fig. 7 Sections showing the regions of reduced anisotropy in each patient (black outline) overlaid on the maps of the overlap between the thresholded trajectory variability maps (eight or more subjects) for M1, PMd and SMA shown on the T 1 -weighted image for the respective patient. Colour key as for Fig. 6.

Table 3 Details of maximal overlap between lesion and peduncle–motor system connections Patient M1

On Prop (z)

Section In On

Prop Section In

On

Prop Section In

On

Prop Section In

lesion section

(z)

lesion section

(z)

lesion section

(z)

lesion section

A 36 6 21 0.29 34 12 32 0.38 All

0 n/a

36 1 36 0.03 B 28 6 26 0.23 22 10 36 0.28 22 8 10 0.80 22 3 31 0.10

0.00 12 1 29 0.03 The table shows the number of voxels that formed the tract connecting the peduncle to each cortical area in eight or more subjects on the

transaxial section on which there was the greatest overlap between the respective tract and the area of reduced anisotropy (‘On section’ values). The number of voxels in the area of overlap is also shown (‘In lesion’ values). The degree of overlap is also expressed as a proportion (‘Prop’) of ‘In lesion’ voxels divided by ‘On section’ voxels. Hence, if ‘Prop’ = 1 on a particular transaxial section then the entire cross-section of the tract to the respective cortical area overlaps with the area of reduced anisotropy. If ‘Prop’ = 0, then there is no overlap between the damaged area and the tract on any transaxial section. The transaxial section where this overlap was greatest for each cortical area and patient is also reported [‘Section (z)’] where z = z-coordinate in MNI space.

motor system, some streamlines would be expected to functions describing the possible diffusion directions in encounter voxels where corticospinal fibres are crossing

each voxel were based on either a single tensor or bi-tensor other tracts such as the superior longitudinal fasciculus

model, depending on the best fit to the data (Alexander (SLF) or transcallosal fibres. Here, the probability density

et al ., 2002; Parker and Alexander, 2003). This method

Organization of corticofugal connections Brain (2006), 129, 1844–1858 1855

Fig. 8 fMRI results for Patients A and B shown on individual patient’s volume-rendered T 1 -weighted images. (A) Regions of significantly greater left (affected) hand-grip activation for Patient A compared with the control group. Cut-out reveals cluster in right PMd in the depth of the precentral sulcus (x = 33, y =

3, z = +42). (B) Region of significantly greater right (affected) hand-grip activation for Patient B Downloaded from compared with the control group. Cut-out reveals cluster in left precentral gyrus (x =

3, z = +51). CS = central sulcus, PCS = precentral sulcus, HK = hand knob region of M1.

48, y =

has been shown to resolve two fibre populations in the proportions of fibres connecting the peduncle to each cor- relevant region of the corona radiata likely to contain cross-

tical region will differ between humans and other primates http://brain.oxfordjournals.org/ ing of the descending fibres and either the SLF or transcal-

owing to differences in the relative size of these regions; for losal fibres (Alexander et al., 2002; Parker and Alexander,

example, the proportion of prefrontal connections in the 2003). However, using more recently developed methods, a

peduncle of humans has been shown to exceed that of the smaller number of voxels in this region have been modelled

macaque in parallel with an increase in grey matter volume as the site of crossings of all three fibre populations (Tuch

of the prefrontal cortex (Ramnani et al., 2005). This obser- et al ., 2003; Parker and Alexander, 2005; Tuch et al., 2005).

vation may explain why PMv connections were not observed Such voxels would have been incorrectly modelled in the

to transit the genu of the internal capsule in the current current study; this would have resulted in poorly informed

study, in contrast with the results of tracer studies (Fries by guest on June 9, 2013

dispersion of streamlines at these points. This may have et al ., 1993; Morecraft et al., 2002). As assessed using tracto- resulted in highly variable ‘connections’ in individuals,

graphy, the relative contribution of the premotor cortex to though it is also conceivable that incorrect pathways may

the cerebral peduncle is significantly lower in humans com- have been reliably identified in the group data, as such cross-

pared with macaques, whereas the opposite relation was seen ings may occur in similar locations across individuals. How-

for the contribution of the prefrontal cortex (Ramnani et al., ever, as the number of voxels classified as the site of three

2005). The shift in the balance between prefrontal and fibre populations appears fairly low, we may assume that use

premotor cortices may result in a posterior shift of the ante- of this simpler multi-tensor approach would have provided

rior limit of the premotor connections in the internal cap- reasonable approximations of the location of the descending

sule. This suggestion is supported by the trajectory variability connections of the cortical motor system.

map of the peduncle–prefrontal connections that suggest The presence of incorrectly modelled voxels containing

that these fibres pass through the anterior limb and the crossings of the descending fibres, SLF and transcallosal

genu of the internal capsule in humans, though only connections would most likely affect the correct identifica-

through the anterior limb in the macaque cases (Ramnani tion of connections to the most lateral components of the

et al ., 2005).

cortical motor system such as PMv. Streamlines destined for Comparison of the trajectories of corticofugal connections the PMv that pass through such voxels may be diverted to

described here in humans with invasive tracing data from other cortical areas or may not reach the cortex owing to

other primates is also complicated by differences in the excessive curvature of the streamline route resulting from the

techniques used. An important limitation of DWI measure- incorrect model of the diffusion profile. These scenarios may

ments and the tractography approach is the inability to dis- account for why peduncle–PMv connections were not iden-

tinguish afferent and efferent pathways of axonal tracts. tified in two of the control subjects, as well as the increased

Therefore, when using tractography to identify connections variability in the location of these connections close to the

between the peduncle and the cortical motor areas we may cortex in the other 10 subjects.

also be identifying inputs to the cortical areas as well Though our findings suggest strong similarities between

as the descending fibres. However, as such inputs are the organization of the multiple corticofugal pathways

multi-synaptic, it seems unlikely that such connections are in humans and other primates, it must be noted that the

strongly represented in this data, as tracking through grey strongly represented in this data, as tracking through grey

be corticofugal pathways, though in future studies it may be prudent to define subcortical grey matter areas and discard any streamlines that pass through these regions.

Investigations of subcortical routes of corticofugal fibres have employed anterograde tracing techniques that involve injection of tracer compounds into limited portions of each motor cortical area. Both studies limited the initial labelling to specific limb representations—either those of the arm as localized by intracortical mapping (Morecraft et al ., 2002), or various combinations of hand, face and foot representations (Fries et al., 1993). Even in the latter case the circumscribed nature of tracer injections results in a narrower definition of the trajectories of corticofugal fibres from each area than that obtained with tractography. Here, tractography identified the route of streamlines from the cerebral peduncle to the total extent of each cortical region, encompassing connections to all representations simulta- neously. Therefore, we expect the overlap of fibres to be greater than that in tracer studies. We predict that use of functionally defined representations of arm or hand movements as target cortical areas in future studies will reveal an even more distributed organization of these multiple pathways.

The relative compression and extensive overlap of specific corticofugal pathways at inferior brain levels com- pared with the more distributed arrangement seen at super- ior levels, as described in non-human primates using tracing methods (Morecraft et al., 2002), is replicated here using probabilistic tractography. The maps of connectivity gener- ated using tractography are formed by iterations of the streamline process that sample the uncertainty in the orien- tation of the principal directions of diffusion in each voxel (Behrens et al., 2003; Parker and Alexander, 2003, 2005; Parker et al., 2003; Tournier et al., 2003). Hence, streamlines are dispersed further owing to the propagation of uncer- tainty as they pass through successive voxels. Stopping criteria are used to prevent biologically implausible curvature of streamlines (>180 on the scale of a single voxel) or attempts to transit non-brain voxels. The continual disper- sion of streamlines may result in overestimation of overlap between connections from different cortical motor areas. Our observation of distinct and consistent topographic organization in the internal capsule and corona radiata suggests that the use of probabilistic tractography does not result in gross overestimation of the spread of cortico- fugal fibres as would be expected with greater dispersion at superior levels. Tractography methods will never achieve the resolution of tracing studies owing to the partial volume effect inherent in the magnetic resonance imaging technique.

However, by constructing maps of the most likely routes of connections between brain regions and the peduncle across a group of subjects, we have reduced the influence of low-probability connection routes.

Relating tract damage to functional recovery and activation changes after stroke Definition of the locations of the most common motor

corticofugal fibres in a group of healthy control subjects was used to infer damage to these connections in patients with lesions restricted to the subcortical white matter. Super- imposition of regions of reduced anisotropy in individual patients on these trajectory maps revealed varying pro- portions of damage to corticofugal pathways from each com- ponent of the cortical motor system. In the patients we studied, we found that greater damage to the connections is related to increased hand-grip-related activity in the ipsi- lesional motor system.

Patients B and C had very similar outcome profiles despite considerable disparity in the amount of damage to cortico- fugal pathways. In contrast to Patient B, the site of lesion in Patient C showed minimal overlap with putative corticofugal fibres from all cortical motor regions. The initial motor function deficits in both patients were also very similar— both showed only minimal motor impairment. In the case of Patient C, the site of lesion suggests that the acute symp- toms may have been the result of damage to basal ganglia circuitry rather than to corticofugal fibres. The opposite was the case for Patient B. Increased ipsilesional motor system activity in Patient B but not C suggests that redundancy in the motor corticofugal connections may be responsible; in Patient B, cortical neuronal activity may have increased in motor areas to drive intact corticofugal connections.

In Patients A and B, considerable damage to connections from the precentral gyrus to the peduncle was observed. Patient A, who had the worst initial motor deficit and sub- sequent recovery, also had the greater damage to connections to PMd and M1, though the difference in M1-related damage was minimal between the two individuals. Increases in hand- grip-related activity were found in ipsilesional PMd in both patients—in the precentral sulcus in Patient A and on the vertex of the precentral gyrus in Patient B, though in this patient the overactivation also included portions of M1 but excluded the hand knob region. Patient A also showed rela- tive overactivation of ipsilesional PMv, though this was only observed at a less stringent statistical threshold. The finding of overactivation of parts of M1 in Patient B, coupled with the lack of significant deactivation within M1 in either Patient A or B, suggests that recovery of function is probably related to intact descending fibres from M1. The importance of M1 fibres for restitution of hand dexterity was recently demonstrated by Wenzelburger et al. (2005); they showed that in patients with capsular stroke greater chronic motor deficits were associated with more posterior lesion locations

1856 Brain (2006), 129, 1844–1858 J. M. Newton et al.

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Organization of corticofugal connections Brain (2006), 129, 1844–1858 1857 within the posterior limb of the internal capsule and attrib-

and clinical outcome scores raises the possibility of defining uted this finding to the greater density of pyramidal fibres

a hierarchy of neural substrates for recovery. Given a lesion from M1 in these posterior locations. However, the over-

in a particular location it may be possible to estimate the activations in ipsilesional PMd and PMv support the view

initial deficit and potential degree of recovery in patients as a that non-primary motor areas also play a role in restitution

result of altered functional activity in intact frontal motor of normal motor function.

system components.

Damage to the connections was quantified by finding the maximum overlap between areas of reduced anisotropy

Supplementary material

and the locations of tracts connecting the peduncle with each Supplementary material cited in this article is available at of the cortical motor areas on a single axial section. This is an

Brain online.

approximate measure of the interaction between lesion and connections, as the geometry of a lesion relative to the axial sections is not considered and may result in an underestima-

Acknowledgements

tion of overlap. Previous studies using tractography in stroke We would like to thank Peter Aston and Eric Featherstone patients have used qualitative description of lesion location

(Wellcome Department of Imaging Neuroscience) for the relative to the corticospinal tract as defined by traced

design and programming involved in creating the hand-grip pathways in that individual patient. This approach identified

manipulandum. We would also like to thank Professor Dick Downloaded from relationships between the overlap of lesion and tract and

Passingham and Dr Henrik Ehrsson for their advice. J.M.N. measures of motor outcome (Kunimatsu et al., 2003;

is supported by Action Medical Research, UK. N.S.W., R.D., Yamada et al., 2004; Lee et al., 2005; Konishi et al., 2005).

K.J.F. and R.S.J.F. are supported by the Wellcome Trust. However, it may be difficult to assess the full extent of the

corticospinal tract with tractography in these patients by http://brain.oxfordjournals.org/ virtue of the diffusion properties of their lesions. For exam-

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