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. 2011 Sep 19;33(12):2856–2872. doi: 10.1002/hbm.21407

Parieto‐frontal network in humans studied by cortico‐cortical evoked potential

Riki Matsumoto 1,2,✉, Dileep R Nair 2, Akio Ikeda 1, Tomoyuki Fumuro 1, Eric LaPresto 2, Nobuhiro Mikuni 3,4, William Bingaman 2, Susumu Miyamoto 3, Hidenao Fukuyama 5, Ryosuke Takahashi 1, Imad Najm 2, Hiroshi Shibasaki 1,6, Hans O Lüders 7
PMCID: PMC6870075  PMID: 21928311

Abstract

Parieto‐frontal network is essential for sensorimotor integration in various complex behaviors, and its disruption is associated with pathophysiology of apraxia and visuo‐spatial disorders. Despite advances in knowledge regarding specialized cortical areas for various sensorimotor transformations, little is known about the underlying cortico‐cortical connectivity in humans. We investigated inter‐areal connections of the lateral parieto‐frontal network in vivo by means of cortico‐cortical evoked potentials (CCEPs). Six patients with epilepsy and one with brain tumor were studied. With the use of subdural electrodes implanted for presurgical evaluation, network configuration was investigated by tracking the connections from the parietal stimulus site to the frontal site where the maximum CCEP was recorded. It was characterized by (i) a near‐to‐near and distant‐to‐distant, mirror symmetric configuration across the central sulcus, (ii) preserved dorso‐ventral organization (the inferior parietal lobule to the ventral premotor area and the superior parietal lobule to the dorsal premotor area), and (iii) projections to more than one frontal cortical sites in 56% of explored connections. These findings were also confirmed by the standardized parieto‐frontal CCEP connectivity map constructed in reference to the Jülich cytoarchitectonic atlas in the MNI standard space. The present CCEP study provided an anatomical blueprint underlying the lateral parieto‐frontal network and demonstrated a connectivity pattern similar to non‐human primates in the newly developed inferior parietal lobule in humans. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.

Keywords: apraxia, cortico‐cortical evoked potential, epilepsy, parieto‐frontal network, functional connectivity, praxis movement

INTRODUCTION

Parieto‐frontal network is essential for sensorimotor integration in various complex behaviors, and its disruption is associated with pathophysiology of apraxia. Apraxia comprises a wide spectrum of impairment of skilled, learned movements that result from acquired brain diseases. It was a landmark proposal by Hugo Liepmann and Norman Geschwind when they posited that apraxia occurred as a result of disconnection of anatomically separate cortical regions [Liepmann, 1920; Geschwind 1965a, b]. This concept was further developed by Damasio, Mesulam, and coworkers [Geschwind and Damasio, 1985; Mesulam, 2000], in which the contemporary neuroanatomical framework underlying apraxia involved the parieto‐frontal network connecting multiple specialized cortical areas. These areas were further grouped into territories which were thought to be connected through parallel, bidirectional pathways [see Catani and ffytche, 2005; Leiguarda and Marsden, 2000 for review]. In monkeys, multiple parallel parieto‐frontal circuits engaged in specific sensorimotor transformations have been described [Rizzolatti et al., 1998]; for example, visual and somatosensory transformations for reaching [MIP‐F2]; transformation about the location of body parts necessary for the control of movements [PE‐F1]; visuomotor transformation for grasping [AIP‐F5]; and internal representation of action [PF‐F5]. It has been hypothesized that unimodal apraxia such as optic ataxia [Balint 1909] and tactile apraxia [Binkofski et al., 2001] is due to impairment of modality‐selective sensorimotor transformation, while supramodal apraxia such as ideational and ideomotor apraxia is due to impairment of supra‐modal sensory integration [Freund, 2001].

Lesion studies and functional activation studies have provided evidence for such a modular organization in the cortex [see Leiguarda and Marsden, 2000; Freund, 2001; Wheaton and Hallett, 2007 for review]. These studies also revealed functional lateralization of the parieto‐frontal network: left hemisphere dominance for supramodal ideational and ideomotor apraxia and right hemisphere dominance for impairment of spatial awareness or hemispatial neglect [Corbetta and Shulman, 2002]. In contrast, anatomical knowledge of connecting pathways has, until recently, relied on tracer studies in non‐human primates [Mesulam, 2005]. However, the development of a higher‐order association area in the human parietal lobe, especially the inferior parietal lobule (IPL: Brodmann's area (BA) 39 and 40), made it difficult, if not impossible, to directly extrapolate the connectivity findings obtained in non‐human primates [Brodmann, 1905; Eidelberg and Galaburda, 1984; Grefkes and Fink, 2005; Van Essen et al., 2001].

In vivo connectivity studies in humans have only recently begun using noninvasive methods, diffusion tractography in particular [Behrens et al., 2003; Catani et al., 2002; Wakana et al., 2004]. With the development of new algorithms such as multifiber probabilistic diffusion tractography, investigation of detailed cortico‐cortical pathways, not only limited to the dense white mater bundles, has just begun [Tomassini et al., 2007]. These pathways, however, are solely determined by mathematical calculation of anisotropy of water molecules. Thus, further work is needed to understand the anatomical organization of the parieto‐frontal network by means of different modalities. We have recently developed an in vivo electrical tract tracing method to study cortico‐cortical connections in humans [cortico‐cortical evoked potential (CCEP)] [Matsumoto et al., 2004a, b, 2007a]. By means of subdural electrodes implanted for presurgical evaluation of patients with intractable partial epilepsy or brain tumor, electrical pulses were applied directly to the cortex, and evoked cortical potentials were recorded from remote cortical regions. This technique provides a unique opportunity to electrophysiologically track functional connectivity among different cortical regions. In this study, we investigated the lateral parieto‐frontal network underlying execution of praxis movements and its disturbance, apraxia by means of CCEP. We also attempted to provide a standardized connectivity map in reference to the Jülich cytoarchitectonic atlas by coregistering CCEP connectivity findings obtained upon individual basis into the Montreal Neurological Institute (MNI) standard space.

MATERIALS AND METHODS

Subjects

Seven patients, six with partial epilepsy and one with brain tumor, who underwent chronic subdural electrode placement covering the lateral fronto‐parietal area for the presurgical evaluation, were studied (Table I). In Patient 1‐3, the epileptic foci were outside the lateral fronto‐parietal area. Patient 4 had astrocytoma in the middle third of the left precentral gyrus. Patient 5‐7 had the epileptic foci in the lateral fronto‐parietal area: in the superior frontal gyrus (dysembryoplastic neuroepithelial tumor, Patient 5), the basal temporal region and the posterior part of the lateral temporo‐parietal region (Patient 6), and the frontal operculum (Patient 7). Neurological examination was unremarkable except Patient 4 who showed mild weakness of the right hand and dysarthria. The implanted electrodes were made of platinum, measuring 3.97 mm (Cleveland Clinic, Cleveland, OH) (Patient 1‐3) or 2.3 mm (Ad‐Tech, Rachine, WI) (Patient 4‐7) in diameter with a center‐to‐center interelectrode distance of 1 cm. As a part of the routine presurgical evaluation, high frequency (50 Hz) electrical stimulation was performed for the purpose of functional cortical mapping [Lüders et al., 1987]. Cortical regions for electrical stimulation were determined solely for clinical purposes, and cortical mapping of the perirolandic area was performed in Patient 1 and 4‐7. Normal configuration of the sensorimotor cortices was observed except for Patient 4 in whom the sensorimotor area was spilt by the tumor in the precentral gyrus. To define the precise location of each electrode on the surface of the brain, subdural electrodes were co‐registered to three‐dimensional volume‐rendered MRIs, which were reconstructed from MPRAGE (Patient 1‐3, 5‐7) or FSPGR (Patient 4) sequences (1.5 T) performed after grid implantation. The location of each electrode was identified on the 2D MRIs using its signal void due to the property of the platinum alloy. Details of the methodology have been described elsewhere [Matsumoto et al., 2003, 2004b]. Major sulci in the lateral convexity were identified using the atlas of the cerebral sulci by Ono et al. [1990] as a reference.

Table I.

Patient profile

Patient 1 2 3 4 5 6 7
Age, gender, handedness 33M R 37F R 39M R 54M R 17M R 32F R 23F R
Etiology MTLE MTLE Partial epilepsya Astrocytoma DNT FCD Type IA FCD Type IA
Implanted hemisphere R L R L R L R
Number of electrode pairs stimulated on the parietal cortex 14 11 12 4 4 10 9
Number of recording electrodes placed on the frontal cortex 15 23 22 19 13 11 17
Neurological examination Normal Normal Normal Mild R hand weakness & dysarthria Normal Normal Normal
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MTLE, mesial temporal lobe epilepsy; DNT, dysembryoplastic neuroepithelial tumor; FCD, focal cortical dysplasia.

a

Epileptic focus was nonlocalizable.

The present study was approved by the Institutional Review Board Committee at Cleveland Clinic (IRB No. 4513) and by the Ethics Committee of Kyoto University Graduate School of Medicine (No. 443). Informed consent was obtained from all patients. Patient 2, 3, 5, and 7 have been reported elsewhere for entirely different purposes [Ikeda et al., 2009; Matsumoto et al., 2004b, 2007a, 2011]

Stimulus Condition and Data Acquisition of CCEP

Details of the CCEP methodology have been described elsewhere [Matsumoto et al., 2004a, b, 2007a]. In brief, electrical stimulation was applied in a bipolar manner to a pair of adjacently placed subdural electrodes by a constant‐current stimulator (Grass S88, Astro‐Med, Inc., RI, or Electrical Stimulator SEN‐7203, Nihon Kohden, Tokyo, Japan). The electrical stimulus consisted of a square wave pulse of 0.3 ms duration, which was given at a fixed frequency of 1 Hz in alternating polarity. The stimulus strength was 80–100% of the intensity that produced either clinical signs or afterdischarges (ADs) upon 50 Hz stimulation. If no clinical signs or ADs were elicited at 15 mA, the intensity was set at 12–15 mA. In the cortical areas where 50 Hz stimulation was not performed for clinical purposes, the current intensity was set at 12–15 mA after confirming the absence of ADs at 1‐Hz stimulation frequency. In cases in which excessive artifacts obscured the evoked potential recordings, the intensity was lowered stepwise by 1 mA until artifacts became small enough to visualize the evoked responses.

Electrocorticograms (ECoGs) were recorded with a bandpass filter of 1–1,000 Hz and a sampling rate of 2500 Hz in Patient 1‐3 (Axon Epoch 2000 Neurological Workstation, Axon Systems Inc., NY), with the filter of 0.5–1,500 Hz at a sampling rate of 5,000 Hz in Patient 4 and 5 (Biotop, NEC‐Sanei, Tokyo, Japan), and with the filter of 0.08–300/600 Hz at a sampling rate of 1,000/2,000 Hz in Patient 6 and 7 (EEG‐1100, Nihon Kohden, Tokyo, Japan). Recordings from subdural electrodes were referenced to a scalp electrode placed on the skin over the mastoid process contralateral to the side of electrode implantation. CCEPs were obtained by averaging ECoGs with a time window of 200 ms, time‐locked to the stimulus onset. In each session, at least two trials of 20–100 responses each were averaged separately to confirm the reproducibility of the responses. During the recording of CCEPs, the patients were requested not to perform any specific task. They were typically lying or sitting on the bed.

Electrode pairs in the lateral parietal area were stimulated and CCEPs were recorded from the lateral convexity of the frontal lobe. Four to 14 pairs of adjacent electrodes were stimulated per patient, amounting to 64 pairs in total (Table I). Stimulation was performed in the postcentral gyrus [i.e., primary somatosensory cortex (SI)] at 18 stimulus sites and in the parietal area caudal to the postcentral sulcus [i.e., posterior parietal cortex (PPC)] at 46 stimulus sites. CCEPs were recorded from subdural electrodes (11–23 electrodes per patient) placed on the lateral premotor (PM) and primary motor (MI) cortices (Table I). Since the extent of coverage by subdural electrodes was determined solely by clinical needs, the grids mainly covered the ventral half of the lateral parieto‐frontal area in Patient 2, 6, 7, and the dorsal half in Patient 5, while the other patients had coverage over both the dorsal and ventral regions. Possible reciprocal connections from the frontal cortex to the parietal cortex were not investigated in this study, because of the limited time allowed for the clinical study. The reciprocal connections seem to be a general rule in humans according to our previous CCEP studies on cortical motor and language networks [Matsumoto et al., 2004b, 2007a].

CCEP Analysis

In the previous CCEP study on the language system [Matsumoto et al., 2004b], the CCEP consisted of an early (N1) and a late (N2) negative potential. In this study, we focused on the analysis of the N1 potential since not all the responses showed a clear N2 peak. The N1 peak was visually identified as the first negative deflection that was clearly distinguishable from the stimulus artifact. The N1 amplitude was measured as reported elsewhere [Matsumoto et al., 2004b]. In brief, the amplitude was measured from the line connecting the preceding and following troughs to the N1 peak. This way of measurement was employed because the conventional trough‐to‐peak measurement was difficult due to the preceding stimulus artifact in some records.

The parieto‐frontal connections from the site of stimulation were traced according to the distribution of the CCEP field. The predominant connection was defined based on the most prominent CCEP field with the maximum N1 response. Besides the most prominent field, if any other field with a discrete N1 potential was spatially separated from the main field, that field was considered as a separate CCEP field, indicating multiple divergent connections.

To investigate the anatomical relationship between the site of stimulation and that of the maximum response, these sites from each patient were plotted on common coordinates. The stimulus site was defined as the midpoint of the pair of stimulating electrodes, and the site of the maximum response as the center of the electrode showing the maximum N1 potential (see Fig. 1). For both the parietal stimulus sites and the frontal recording sites, the relationship was displayed in the rostro‐caudal dimension (Fig. 1A) as well as in the dorso‐ventral dimension (Fig. 1B). For the rostro‐caudal dimension, the surface distance of the cortical sites from the central sulcus was displayed. To better describe the functional property in the dorso‐ventral dimension, the distance of the parietal stimulus sites was measured from the border between superior (SPL) and inferior (IPL) parietal lobules, namely intraparietal sulcus (IPS), and the distance of the frontal recording sites was measured from the border between the dorsal (PMd) and ventral (PMv) premotor areas. Because the functional motor mapping was not performed in all the patients and no macroscopic anatomical landmark existed to locate the border between PMd and PMv [Geyer et al., 2000; Picard and Strick, 2001; Rizzolatti et al., 1998], the virtual border was set arbitrarily as the line parallel to the AC‐PC line crossing the midpoint between the caudal ends of the superior (SFS) and inferior (IFS) frontal sulci. When the stimulus and response sites were situated, respectively, on the post‐ and pre‐central gyri, the distance was calculated from the extrapolated border drawn from the above‐described borderline toward the central sulcus.

Figure 1.

Figure 1

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Schematic diagram illustrating the coordinates for displaying the sites of stimulation and maximum CCEP response in the lateral parietal and frontal area. A: Distances from the central sulcus along the rostro‐caudal dimension are plotted for the parietal stimulus sites in the abscissa and for the frontal recording sites in the ordinate. The distance from the central sulcus was measured on a line drawn parallel to the AC‐PC line. B: Along the dorso‐ventral dimension, the parietal stimulus sites were measured from the intraparietal sulcus (IPS, dotted line) and the frontal recording sites were measured from the border between the dorsal and ventral premotor areas (broken line). CS, central sulcus; IFS, inferior frontal sulcus; IPS, intraparietal sulcus; PrCS, precentral sulcus; PMd, dorsal premotor area; PMv, ventral premotor area; SFS, superior frontal sulcus.

Standardization of the Connectivity Findings Obtained by CCEP

To better delineate the anatomical localization of the parietal stimulus and frontal response sites in the MNI standard space, electrodes identified on the T1 volume acquisition (MPRAGE or FSPGR) taken after grid implantation were nonlinearly coregistered to the T1 volume acquisition taken before implantation, then to the MNI standard space (ICBM‐152) using FNIRT of the FSL software (http://www.fmrib.ox.ac.uk/fsl/fnirt/). This method has been reported elsewhere for standardization of the electrode locations [Matsumoto et al., 2011]. Anatomical parcellation of the parietal stimulus site was identified in reference to the location of the midpoint of the pair of stimulating electrodes in the cytoarchitectonic probabilistic map of the Jülich histological atlas [Caspers et al., 2008; Eickhoff et al., 2006a; Scheperjans et al., 2008]. The parietal label having the highest probability was taken as the label of the stimulus site using Eickhoff's anatomy toolbox v1.5 incorporated in FSLView (http://www.fmrib.ox.ac.uk/fsl/fslview/) [Eickhoff et al., 2006b]. The label was chosen from the parietal labels on the lateral convexity: BA1, BA2, 5M, 5L, 7PC, 7A, 7P, hIP1‐3, OP1‐4, PF, PFcm, PFm, PFt, PFop, PGa, PGp. When the MNI coordinate of the stimulus site did not provide any probability of the cortical labels, i.e., the coordinate was on or slightly above the surface of the MNI standard brain, the location of the coordinate was shifted perpendicular toward the cortical surface (<5 mm) until the good probability was obtained in the probabilistic map. Regarding the frontal CCEP responses, the location of the electrode showing the maximum response, i.e., the target site of the predominant connection from the stimulus site, was identified in the same manner. If there were additional, separate CCEP fields, the electrode showing the maximum response of each additional field, i.e., the target site of the additional divergent connection from the stimulus site, was also identified. Because of our interest in parcellation along the dorsoventral axis, BA1, BA2 and BA6 were further divided into their dorsal and ventral subdivisions (e.g., BA1d, BA1v). The border between the dorsal and ventral subdivisions was set at z = 48 according to the recent parcellation of the premotor areas by probabilistic diffusion tractography [Tomassini et al., 2007]. BA6 was further divided into its rostral (BA6dr) and caudal subdivisions (BA6dc, BA6vc) in reference to the precentral sulcus [Matsumoto et al., 2003, 2007a; Picard and Strick, 2001]. Since cytoarchitechtonic parcellation was not completed in the frontal lobe in the Jülich histological atlas, we defined the dorsal half of the most caudal part of the middle frontal gyrus as BA6dr (the dorso‐rostral division of the premotor area). Accordingly, the frontal labels on the crown part of the lateral convexity were categorized into BA6dr, BA6dc, BA6vc, BA44, and BA45. Because BA44 was situated immediately rostral to the inferior precentral suclus, BA44 and 45 were regarded as the rostral part of PMv in this study.

For the 3D display purpose, the baview software [Yamamoto et al., 2011] was used to show the 3D view of the predominant and additional connections (i.e., stimulus and response sites) in the fsaverage brain that is constructed compatible to the initial MNI template (MNI305) in the FreeSurfer software (http://surfer.nmr.mgh.harvard.edu/).

RESULTS

Analysis of the Parieto‐Frontal Network in the Individual Space

In all the patients investigated, stimulation of the parietal lobe elicited CCEPs in the frontal lobe. CCEPs were recognized in a total of 52 out of 64 stimulus sites (81%, 2‐14 sites per patient). As shown in a representative case (see Fig. 2), the majority of CCEPs consisted of a surface negative potential (N1), and when the stimulus artifact was relatively small, a preceding small positive deflection could be recognized. The predominant parieto‐frontal connections from the stimulus sites were determined based on the maximum N1 response. In terms of the CCEP distribution along the rostro‐caudal dimension, stimulation of the postcentral gyrus (18 sites across all subjects) elicited the largest N1 almost exclusively in the precentral gyrus (14 sites; see Fig. 2C,F for example) and rarely in PM rostral to the precentral sulcus (2 site). In contrast, upon stimulation of PPC (46 sites), the majority of CCEPs were observed in PM rostral to the precentral sulcus (32 sites; Fig. 2A,D,E), and only a few responses were seen maximum in the precentral gyrus (4 sites; Fig. 2B). This near‐to‐near and distant‐to‐distant, mirror‐symmetric configuration across the central sulcus was substantiated in the regression analysis (Fig. 3A). In terms of the distance from the central sulcus along the rostro‐caudal dimension, a positive correlation was observed between the sites of stimulation and maximum response (R = 0.791, p < 0.0001). Namely, as the parietal stimulus site was more distant from the central sulcus, the maximum response recorded from the frontal area was more distant from the central sulcus. This mirror‐symmetric configuration was further supported by a significant positive correlation between the N1 peak latency and the surface distance from the parietal stimulus sites to the frontal recording sites (Fig. 3C, R = 0.683, p < 0.0001); the N1 latency was longer in proportion to the distance between the parietal stimulus sites and frontal recording sites. Regarding the network configuration in the dorso‐ventral dimension, the regression analysis showed a significant correlation between the parietal stimulus sites and the frontal recording sites in terms of the distance from the dorso‐ventral border in the same direction (either ventral or dorsal) (Fig. 3B, R = 0.758, p < 0.0001). The more dorsal parietal stimulation resulted in the more dorsal frontal response, and vice versa. In other words, the dorso‐ventral configuration (i.e., dorsal parietal to dorsal frontal and ventral parietal to ventral frontal areas) was preserved across the central sulcus.

Figure 2.

Figure 2

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CCEPs recorded from the lateral premotor area in a representative case (Patient 1). CCEPs are plotted with subaverages (black and grey waveforms) in reference to the major sulci identified on 3D MRI (left lower corner of each figure). The vertical line corresponds to the time of single pulse stimulation. On 3D MRI, each parietal stimulus site is shown as a pair of interconnected black electrodes and the whole area covered by the recording electrodes is shaded white. Maximum response of the main CCEP field is plotted as a white circle, while that of smaller, separate CCEP fields, if present, as a black circle. CCEPs elicited by parietal stimulation of the same dorso‐ventral division are displayed in the same row (A‐C and D‐F, respectively). Note that the more caudal the parietal stimulus site is located, the more rostral the frontal maximum response site is located (i.e., more distant from CS). Other conventions are the same as for Figure 1 except for Sylv = Sylvian fissure.

Figure 3.

Figure 3

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Spatial relationship between the sites of stimulation and maximum CCEP response in the rostro‐caudal coordinate (A) and in the dorso‐ventral coordinate (B). In (A), the distance of the parietal stimulus sites (abscissa) and of the frontal response sites (ordinate) was measured from the central sulcus. In (B), the distance of the parietal stimulus sites (abscissa) was measured from the intraparietal sulcus (IPS) that is the border between SPL and IPL, and that of the frontal response sites (ordinate) was measured from the border between PMv and PMd (see text for more details). In terms of the distance from the stimulus and response sites, regression analysis showed a positive correlation between the sites of stimulation and maximum response both for the rostrocaudal (A) and dorsoventral (B) axes. Consistent with the mirror‐symmetric configuration across the central sulcus as shown in (A), a positive correlation was observed between the surface distance from the parietal stimulus sites to the frontal response sites and the N1 peak latency of the maximum response (C). Conventions are the same as for Figure 1.

Besides the predominant parieto‐frontal connections as judged by the maximum CCEP response, additional frontal CCEP fields were identified in 29 out of 52 (56%) stimulus sites that elicited CCEPs upon stimulation (Fig. 2A–E, Fig. 4). In 13 out of the 29 stimulus sites (25% of total), three (12 sites) or four (1) independent fields were identified in the lateral frontal area (see Figs. 2A,B and 4).

Figure 4.

Figure 4

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Representative CCEP distribution indicative of multiple parieto‐frontal connections in Patient 2 (left) and 3 (right). Besides the predominant parieto‐frontal connection as judged by the prominent CCEP field (maximum response shown in white circle), additional connections were identified based on spatially separate fields (maximum response in black circle). Three separate connections were traced from the supramarginal gyrus to the ventral premotor area in Patient 2, while in Patient 3 stimulation of the postcentral gyrus revealed two separate connections to the adjacent precentral gyrus and ventral premotor area. Implanted hemispheres are shown on the same side for the sake of presentation by flipping the sides (Patient 2). See Figure 2 also for multiple connections in Patient 1. Conventions are the same as for Fig. 2.

In Patient 4 who had a tumor in the precentral gyrus, a ventral parieto‐frontal connection was preserved in the vicinity of the tumor (see Fig. 5). Stimulation of the supramarginal gyrus elicited a maximum response at PMv (supramarginal gyrus ‐ PMv circuit). The circuit configuration was similar to those found in other epilepsy patients (e.g., Fig. 2E). In none of the patients, seizures were provoked by single pulse stimulation of the lateral parietal area.

Figure 5.

Figure 5

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Functional connections from the ventral parietal area to the premotor area revealed in the vicinity of astrocytoma (shadowed) located in the precentral gyrus in Patient 5. Stimulation at the supramarginal gyrus elicited CCEP ventral to the tumor at around the ventral ramus of the precentral sulcus. CCEP was not observed rostral to the tumor. Note the network configuration was similar to that seen in an epilepsy patient (e.g., Fig. 2E), in whom epileptic foci were away from the area of investigation. Conventions are the same as for Figure 2.

Analysis of the Parieto‐Frontal Network in the Standardized Space

The locations of the parietal stimulus and frontal response sites in the MNI standard space were labeled according to the Jülich cytoarchitectonic atlas (Table II). Cortical regions located within the sulcal part of the parietal lobe (e.g., PFcm, hIP 1‐3, OP1‐3) were not identified as the most probable label. Stimulation of the postcentral gyrus (BA1, BA2) almost exclusively elicited the maximum CCEP responses in the precentral gyrus (at BA6dc, 6vc in 15/17 stimulus sites) with the preserved dorso‐ventral organization, i.e., from BA1v&2v to the ventral frontal areas, and from BA1d&2d to the dorsal frontal areas. In the inferior parietal lobule (30 stimulus sites), predominant connections were observed from the angular gyrus [PGa (3), PGp (3)] mostly to BA44 (3) and BA6dr (2); from the supramarginal gyrus [PFop (1), PFt (1), PF (12), PFm (7)] to BA44 (11), BA6dr (4), BA45 (3) and caudal BA6 (BA6dc, 6vc) (3); and from the parietal operculum [OP4 (3)] to BA6vc (2) and BA44 (1). The superior parietal lobule [7PC (2), 7A (3)] connected with BA6dr (2), caudal BA6 (2) and BA44 (1). Results of the additional connections revealed by additional, separate CCEP fields are also summarized in Table II. The parietal stimulus and frontal response sites from all the subjects (Patient 1‐7) are displayed together in the MNI standard space (see Fig. 6). The two major configurations of the parieto‐frontal network ‐ mirror symmetry across the central sulcus and preserved dorso‐ventral organization ‐ were also confirmed in this 3D view. The MNI coordinates and cytoarchitectonic labels of the parietal stimulus and frontal response sites are available for all the patients investigated in the present study in Table III.

Table II.

Summary of the parietal stimulus and frontal response sites in reference to the Jülich cytoarchitectonic atlas in the MNI standard space

Frontal response site
BA6dc BA6vc BA6dr BA44 BA45 subtotal
Parietal stimulus site
 BA1v −/− 3/2 −/− −/1 −/1 3/4
 BA2v −/− 1/1 −/− −/1 1/1 2/3
 OP4 −/1 2/− −/− 1/3 −/− 3/4
 PFop −/− −/− −/− 1/− −/− 1/−
 PFt −/− 1/− −/− −/1 −/− 1/1
 PF 1/2 1/8 1/1 6/2 3/2 12/15
 PFm −/− −/− 3/3 4/3 −/3 7/9
 PGa −/− 1/− 2/− −/1 −/− 3/1
 PGp −/− −/− −/− 3/− −/− 3/−
 BA1d 9/− −/1 1/2 −/1 −/− 10/4
 BA2d 2/1 −/− −/− −/1 −/− 2/2
 7PC 1/− 1/− −/− −/− −/− 2/−
 7A −/− −/− 2/− 1/− −/− 3/−
 subtotal 13/4 10/12 9/6 16/14 4/7 Total 52/43
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Number of the maximum (left, bold) and additional (right) responses is shown in each cell, ‐: no response. See definitions of BA1v, BA1d, BA2d, BA2v, BA6dr, BA6dc, BA6vc in the text.

Figure 6.

Figure 6

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3D display of the stimulus and response sites in the MNI standard space. The stimulus and response sites are accumulated from all the patients and coregistered into the MNI standard space. All the stimulus and response sites are collapsed onto the left convexity for a display purpose. Stimulus sites are labeled and displayed together according to the Jülich cytoarchitectonic atlas on the same 3D brain (see the label in the left upper corner of each 3D brain). Regarding the frontal CCEP responses, a large sphere represents the location of the electrode showing the maximum CCEP response, i.e., the target site of the predominant connection from the stimulus site. A small sphere represents the electrode showing the maximum response of the additional, separate CCEP field, i.e., the target site of the additional divergent connection from the stimulus site. Note the location of the maximum and additional response sites may be overlapped within the lateral frontal area. Also note that the parieto‐frontal connections were not equally distributed along the central sulcus partly due to the less electrode coverage in the dorsal part than the ventral part. The lateral view of the 3D brain in the right lower corner indicates the parietal segmentations of the Jülich atlas where electrical stimuli were applied.

Table III.

Individual cytoarchitectonic labels and MNI coordinates of the stimulus and response sites

Subject Parietal stimulus site Target site of the predominant connection Target sites of additional connections
Label MNI coordinate (x,y,z) Label MNI coordinate Label MNI coordinate Label MNI coordinate Label MNI coordinate
Patient 1 BA1d 52 ‐22 58 BA6dr 30 ‐2 64
Patient 1 BA1d 36 ‐38 70 BA6dc 34 ‐26 72
Patient 3 BA1d 30 ‐43 75 BA6dc 26 ‐14 76
Patient 3 BA1d 48 ‐34 62 BA6dc 34 ‐14 70 BA6vc 60 6 36
Patient 3 BA1d 30 ‐33 73 BA6dc 36 ‐24 72
Patient 3 BA1d 50 ‐24 62 BA6dc 44 ‐14 66 BA6vc 60 6 36
Patient 4 BA1d ‐53 ‐21 57 BA6dc ‐44 ‐10 57
Patient 5 BA1d 23 ‐34 77 BA6dc 28 ‐24 74 BA6dr 30 ‐4 70
Patient 5 BA1d 35 ‐37 70 BA6dc 28 ‐24 74 BA6dr 20 ‐4 74
Patient 6 BA1d ‐53 ‐19 54 BA6dc ‐49 ‐6 54 BA44 ‐62 10 12
Patient 6 BA1v ‐64 ‐7 27 BA6vc ‐63 0 16 BA44 ‐62 10 12
Patient 7 BA1v 65 ‐5 33 BA6vc 61 2 35 BA45 58 36 2 BA6vc 58 14 34
Patient 7 BA1v 60 ‐10 43 BA6vc 61 2 35 BA6vc 58 14 34
Patient 1 BA2d 31 ‐47 70 BA6dc 34 ‐26 72
Patient 6 BA2d ‐52 ‐33 55 BA6dc ‐49 ‐6 54 BA44 ‐62 10 12 BA6dc ‐48 4 49
Patient 1 BA2v 60 ‐21 48 BA6vc 56 ‐8 48 BA44 60 18 20
Patient 7 BA2v 61 ‐22 47 BA45 62 20 22 BA45 58 36 2 BA6vc 61 2 35
Patient 1 OP4 67 ‐7 25 BA6vc 60 8 34 BA44 60 18 20
Patient 6 OP4 ‐65 ‐16 30 BA6vc ‐62 4 27 BA44 ‐62 10 12 BA44 ‐49 12 47 BA6dc ‐49 ‐6 54
Patient 7 OP4 69 ‐7 17 BA44 62 16 12
Patient 1 PF 67 ‐30 33 BA44 60 18 20 BA6vc 58 0 46
Patient 4 PF ‐64 ‐32 37 BA44 ‐58 14 22
Patient 6 PF ‐61 ‐39 40 BA44 ‐62 10 12 BA6vc ‐58 10 38 BA6dc ‐49 ‐6 54
Patient 6 PF ‐64 ‐28 38 BA44 ‐62 10 12 BA6dc ‐49 ‐6 54 BA6vc ‐62 4 27
Patient 7 PF 68 ‐30 24 BA44 62 16 12
Patient 7 PF 68 ‐23 29 BA44 62 16 12 BA45 58 36 2 BA6vc 61 2 35
Patient 2 PF ‐63 ‐48 29 BA45 ‐49 34 22 BA44 ‐58 16 5
Patient 7 PF 68 ‐37 18 BA45 58 30 16
Patient 7 PF 60 ‐34 48 BA45 62 20 22 BA45 56 30 ‐8
Patient 1 PF 65 ‐40 35 BA6dr 46 3 54 BA6vc 58 0 46
Patient 1 PF 57 ‐32 52 BA6dc 45 ‐18 62 BA44 60 18 20 BA6dr 48 14 52
Patient 6 PF ‐47 ‐45 57 BA6vc ‐58 10 38 BA6vc ‐63 0 16 BA6vc ‐58 2 41
Patient 1 PFm 53 ‐44 55 BA44 60 18 20 BA6dr 48 14 52 BA6dr 30 ‐2 64
Patient 2 PFm ‐59 ‐57 33 BA44 ‐49 18 44 BA44 ‐58 16 5 BA45 ‐49 34 22
Patient 6 PFm ‐54 ‐59 44 BA44 ‐55 18 33
Patient 6 PFm ‐58 ‐49 42 BA44 ‐62 10 12 BA44 ‐55 18 33
Patient 1 PFm 49 ‐52 54 BA6dr 30 ‐2 64 BA44 60 18 20 BA6dr 48 14 52
Patient 1 PFm 61 ‐52 37 BA6dr 35 8 62
Patient 2 PFm ‐55 ‐53 43 BA6dr ‐47 4 51 BA45 ‐53 26 ‐2 BA45 ‐46 34 32
Patient 7 PFop 69 ‐18 22 BA44 62 16 12
Patient 1 PFt 67 ‐19 30 BA6vc 60 8 34 BA44 60 18 20
Patient 1 PGa 42 ‐63 55 BA6dr 30 ‐2 64 BA44 60 18 20
Patient 3 PGa 44 ‐55 56 BA6dr 30 ‐2 67
Patient 6 PGa ‐41 ‐55 59 BA6vc ‐58 10 38
Patient 2 PGp ‐42 ‐70 49 BA44 ‐55 16 37
Patient 2 PGp ‐45 ‐73 42 BA44 ‐49 18 44
Patient 2 PGp ‐49 ‐76 30 BA44 ‐49 18 44
Patient 2 7A ‐34 ‐69 57 BA44 ‐55 16 37
Patient 1 7A 26 ‐56 70 BA6dr 30 ‐2 64
Patient 5 7A 23 ‐53 74 BA6dr 20 ‐4 74
Patient 3 7PC 45 ‐44 60 BA6dc 34 ‐14 70
Patient 2 7PC ‐42 ‐50 60 BA6vc ‐62 4 32
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DISCUSSION

In this study, we were able to map a global topographical geometry of the lateral parieto‐frontal network. It was characterized by: (i) mirror symmetry across the central sulcus (the more caudal the parietal stimulus site, the more rostral the frontal response site, and vice versa), (ii) preserved dorso‐ventral organization of the predominant circuits (dorsal parietal to dorsal frontal and ventral parietal to ventral frontal areas), and iii) projections to more than one frontal cortical sites (predominant and additional circuits) in 56% of the explored connections. By incorporating CCEP connectivity findings into the MNI standard space, we were able to clarify the anatomical parcellation of the parietal stimulus and frontal response sites in reference to the Jülich cytoarchitectonic atlas. The modes of connectivity are discussed in the context of the functional organization of the parieto‐frontal circuits in special relation to apraxia.

Implication and Limitation of CCEP

Knowledge of cortico‐cortical connections in humans has been limited until very recently because of the paucity of the available in vivo techniques in humans [Mesulam, 2005]. The CCEP technique provides a unique opportunity to electrophysiologically track cortico‐cortical connections in vivo by stimulating a part of the cortex through subdural or depth electrodes and recording evoked cortical potentials that emanate from the remote cortical regions. This method has been successfully applied to delineate cortico‐cortical networks involved in language and motor systems [Matsumoto et al., 2004b, 2007a] as well as subcortico‐cortical networks [Lacruz et al., 2007; Rosenberg et al., 2009]. In contrast to diffusion tractography that is calculated solely by mathematical calculation of anisotropy of water molecules, the CCEP technique has an advantage of tracking the inter‐areal connectivity physiologically, providing directional as well as temporal information. In this regard CCEP may well be regarded as “functional tractography” as compared with “anatomical fiber tractography” visualized by diffusion tractography. By means of precise electrode localization in relation to individual sulci on 3D MRI, the functional tractography allows delineation of cortico‐cortical connectivity with spatial resolution of 1 cm. However, as the stimulation and recording was performed by subdural electrodes, the investigation was limited to the cortical surface, i.e., the crown part, and little information was available about the sulcal part such as IPS. Furthermore, this technique cannot identify the underlying anatomical pathways between the stimulus and response sites.

The precise generator mechanisms of CCEP still remain unknown. The possible mechanisms have been extensively discussed elsewhere [Matsumoto and Nair, 2007; Matsumoto et al., 2004b, 2007a]. In brief, we speculate that, upon cortical stimulation, orthodromic excitation of cortico‐cortical projection neurons occurs through direct depolarization of the initial segment as well as synaptic excitation in the local circuit. The latter is mainly mediated by ascending recurrent axon collaterals of the pyramidal neurons and partly by excitatory interneurons. With “oligo‐synaptic” excitation of the cortico‐cortical projection neurons, the impulse travels through cortico‐cortical projection fibers to the target cortex with some jitter, and then generates a relatively blunt N1 potential. Indeed, a similar blunt cortical potential called “direct cortical response (DCR)” was recorded in the immediately adjacent cortex upon local cortical stimulation in animals and humans [Adrian, 1936; Goldring et al., 1994]. Of note, DCR shares the morphology and latency (∼ 10 ms in humans) with the CCEP recorded from the very adjacent cortex to the stimulus site. Animal experiments have shown that DCR is oligosynaptic and local in origin since it is observed in completely isolated cortex [Jerva et al., 1960; Li and Chou, 1962]. The present findings provided some insight into the underlying anatomical pathway between the stimulus and target cortices. The linear correlation between the N1 peak latency and the surface distance from the parietal stimulus site to the frontal response site (Fig. 3C) favors the direct cortico‐cortical white matter pathway, because, as the surface distance is longer, the actual white matter pathway connecting the two cortical sites and accordingly its traveling time is expected to be proportionally longer. By contrast, this would not be the case for the indirect cortico‐subcortico‐cortical pathways. Since the distance between the cortical surface and the subcortical structures such as thalamus may not significantly differ depending on the location of the stimulus or response sites, the latency of CCEP may fail to correlate with the surface distance between the two cortical sites in that case.

Blueprint of the Human Lateral Parieto‐Frontal Network

By means of direct electrical cortical stimulation, the present CCEP study provided blueprint of the lateral parieto‐frontal network in humans. On the basis of the predominant circuits revealed by the maximum CCEP response, the dorso‐ventral configuration was preserved across the central sulcus (i.e., dorsal parietal to dorsal frontal area, and vice versa). This relationship is consistent with the known organization of the lateral parieto‐frontal circuits in monkeys: strong inputs from the superior parietal areas (MIP, PEip, posterior SPL, medial SPL, PEc, PGm and V6A) to PMd [Fang et al., 2005; Johnson et al., 1996; Matelli et al., 1998; Schmahmann and Pandya 2006; Stepniewska et al., 2006; Tanne et al., 1995; Wise et al., 1997] and from the inferior parietal areas (AIP, PF and PFG) to PMv [Cavada and Goldman‐Rakic, 1989; Lewis and Van Essen, 2000; Luppino et al., 1999; Matelli et al., 1986; Rizzolatti et al., 1998; Rozzi et al., 2006; Schmahmann and Pandya, 2006]. The preserved dorso‐ventral organization noted in the functional tractography study reported here complements the recent similar associations revealed by probabilistic diffusion tractography [Tomassini et al., 2007]. It serves as anatomical substrates for segregated parieto‐frontal circuits revealed by fMRI activation studies: SPL‐PMd circuit for reaching and arbitrary action selection [Astafiev et al., 2003; Grol et al., 2006; Prado et al., 2005; Simon et al., 2002], AIP‐PMv for grasping and manual exploration of 3D objects [Binkofski et al., 1999; Binkofski et al., 1998; Decety et al., 1994; Grafton et al., 1996; Hattori et al., 2009; Simon et al., 2002], left IPL‐PMv for tool‐use planning and execution [Fridman et al., 2006; Johnson‐Frey et al., 2005], and right IPL‐PMv and the adjacent prefrontal cortex for spatial awareness [Corbetta and Shulman, 2002]. Furthermore, the present study demonstrated that the similar principle might be applied to the newly emerged inferior parietal regions in humans (BA 39 and 40; see Figs. 2D–F and 4A, 6 for example), the key structures for multimodal convergence essential for higher cognitive functions such as tool‐use, language and calculation [Catani and ffytche 2005; Matsuhashi et al., 2004]. In fact, the ventral parieto‐premotor network is also activated during calculation and language tasks [Dehaene et al., 1999; Simon et al., 2004; Vigneau et al., 2006].

Regarding connectivity along the rostro‐caudal axis, the present study showed predominant connections from SI to MI for final execution of limb movements as expected, and from PPC to PM for sensorimotor transformations. Furthermore, regression analysis of the distance from the central sulcus to the stimulus sites and to the recording sites revealed that the more caudal PPC connected to the more rostral PM and vice versa. This mirror‐symmetric organization provides additional insights into the functional organization of the lateral parieto‐frontal network. PM, being situated between the prefrontal area and MI, plays a role in mediating the transition from cognitive to motor functions, with the more rostral parts primarily related to sensory or cognitive aspects of motor behavior and the more caudal parts to the movement execution itself. Microelectrode recording in monkeys and subdural macroelectrode recording in humans have revealed that neurons possessing sensory properties are more frequently found in the rostral PM and those possessing motor properties more frequently in the caudal PM [Johnson et al., 1996; Matsumoto et al., 2003; Weinrich et al., 1984]. A corresponding but oppositely oriented gradient was observed in SPL in an instructed‐delay reaching task in monkeys [Johnson et al., 1996]. Of note, in this task neurons of similar properties in PM and SPL were interconnected by cortico‐cortical projections. Interestingly, a similar reverse of functional gradient was observed in humans for tool‐use gestures in the left hemisphere [Fridman et al., 2006; Johnson‐Frey et al., 2005]. In PPC, planning‐related activation was located more caudal and ventral to that associated with execution, while in PMv the former was situated more rostrally to the latter. The mirror‐symmetric configuration seems to be a general organizational framework in the lateral parieto‐frontal network according to the fMRI analysis of various cognitive tasks using an automatized clustering algorithm [Simon et al., 2004]. A recent hypothesis of tension‐based cortical folding may further support the mirror‐symmetric organization, a principle that serves to minimize connection lengths in the brain [Van Essen 1997].

In order to further generalize the connectivity findings obtained by CCEPs in individual patients, we attempted to provide the standardized connectivity map by gathering the sites of stimulation and responses from all the patients in this study, and by coregistering them into the MNI standard space (see Table III for individual MNI coordinates). By employing the Jülich cytoarchitectonic probabilistic map that is based on quantitative, observer independent definitions of cytoarchitectonic borders, we were able to integrate physiological CCEP findings with the state‐of‐art anatomical parcellation of the human parietal lobe. The present standardized connectivity map would help us delineate the segregation of information flow for specific functions and sensorimotor integration in the parieto‐frontal network. In particular, by providing the origins and terminations of the parieto‐frontal connections (see Tables II and III and Fig. 6), the present connectivity findings complement the recent segmentations of the superior longitudinal fasciculus (SLF) by means of diffusion tractography [Makris et al., 2005; Rushworth et al., 2006]. Based on the knowledge of SLF subcomponents (SLF I, II, III) as revealed by invasive tracer studies in the monkey brain [Petrides and Pandya 1984; Schmahmann and Pandya 2006], fiber pathways were tracked from the stem portion of each subcomponent that had characteristic orientation. SLF I was located in the white matter of the superior parietal and superior frontal areas and extended from the superior and medial parietal areas to the dorsal premotor and dorsolateral prefrontal areas. SLF II occupied the central core of the white matter above the insula and extended from the posterior IPL to the caudal‐lateral prefrontal or premotor regions. SLF III was situated in the white matter of the parietal and frontal opercula and extended from the anterior IPL to the ventral premotor and prefrontal regions.

Several limitations should be noted to interpret the present connectivity findings. First, the extent of coverage by subdural electrodes was determined due to clinical needs by all means; SPL was less covered than IPL in the parietal lobe, and BA45 was less covered than BA44 in the frontal lobe. Second, the gender as well as hemispheric difference of the parieto‐frontal network could not be evaluated due to the limited number of patients. Further case accumulation is needed to investigate these differences. Third, possible effects of the pathology on the network should be noted in patients having a brain tumor or epileptic focus in the lateral parieto‐frontal area. This matter is discussed in the next section.

Clinical Relevance

In the sequential control of actions, sensorimotor integration leading to action is mainly processed in the dorsal pathway (PPC and PM), while the pragmatic process of visual information about object attributes or object recognition occurs through the ventral pathway (occipito‐temporal cortex) [Goodale and Milner 1992]. Consequently, lesions of the ventral stream produce visual agnosia, while those of the dorsal stream (parieto‐frontal circuits) give rise to deficits in sensorimotor transformation, namely, apraxia. Lesion studies show that a wide range of sensorimotor functions can be selectively disturbed in patients with parietal lobe damage. Lesions of the rostral and caudal SPL cause unimodal, somatosensorimotor‐selective, tactile apraxia [Binkofski et al., 2001] and visuomotor‐selective, optic ataxia [Balint 1909; Battaglia‐Mayer and Caminiti 2002; Karnath and Perenin 2005; Perenin and Vighetto 1988], respectively. Lesions involving the anterior lateral bank of IPS (human homologue of the anterior intraparietal area (AIP)) cause selective deficits in coordination of the finger movements required for grasping [Binkofski et al., 1998]. Lesions in IPL, IPS and partly SPL of the left hemisphere produced supramodal ideomotor apraxia [Haaland et al., 2000; Halsband et al., 2001; Heilman and Rothi 2003]. Ideomotor apraxia is characterized by impairment of skilled actions that cannot be explained by lower‐level perceptual or motor deficits [Leiguarda and Marsden, 2000; Wheaton and Hallett, 2007].

In contrast to discrete parietal lesions showing distinct apraxia, studies exploring possible clinical‐anatomical correlations in the frontal lobe largely have failed to unveil a consistent and specific lesion site [Leiguarda and Marsden, 2000]. Only a few studies have clarified PM lesions responsible for ideomotor [Faglioni and Basso, 1985; Haaland et al., 2000; Raymer et al., 1999] and limb‐kinetic [Kleist, 1931; Luria, 1980] apraxia. This is partly because lesions that involve the motor area projecting the corticospinal pathway (i.e., BA4 or caudal BA6) and Broca's area cause concomitant paresis and aphasia, respectively. Moreover, relative lack of selectivity of the frontal lesions for producing discrete apraxia could be ascribed to the divergent parieto‐frontal connections as seen in 56% of the connections in the present CCEP study. The divergent connections would lead to “cross‐talk” with the predominant parieto‐frontal connections. It could be argued that praxis movement is conducted by parallel anatomofunctional neuronal systems, each controlling specific processes, working in concert. The significance of the whole network in action generation is further supported by the fact that lesions not only in the cortex but also in the white matter in the left hemisphere could cause ideomotor apraxia [Papagno et al., 1993]. Moreover, increased cortico‐cortical coherence of electroencephalogram (EEG) between the left PPC and PM was observed during preparation and execution of praxis movements [Wheaton et al., 2005], indicating the importance of dynamic synchronization of the parieto‐frontal network in action generation.

Significance of the parieto‐frontal network is also appreciated for other higher cognitive functions, such as language and spatial awareness. The left ventral parieto‐frontal connections observed between the supramarginal and the ventral frontal cortex (i.e., connections from PF/PFm in Fig. 6) have a striking similarity with the anterior segment of the arcuate fasciculus of Catani et al., [ 2005]. Indeed, intraoperative electrical stimulation of the underlying subcortical pathway as well as the ventral parieto‐frontal cortices produced impairment of verbal fluency abilities [Duffau et al.,, 2003]. While the language and praxis functions are largely lateralized to the left hemisphere, spatial awareness is the right‐sided higher cognitive function involving the parieto‐frontal network [Corbetta and Shulman 2002; Thiebaut de Schotten et al., 2011]. Not only the lesions in the parieto‐frontal cortex but also the lesions in SLF II and III are reported to produce hemispatial neglect [Doricchi et al., 2008; Doricchi and Tomaiuolo, 2003; He et al., 2007]. Furthermore, intraoperative electrical stimulation of SLF II produced transient hemispatial neglect, supporting the importance of the parieto‐frontal connection in spatial awareness [Thiebaut de Schotten et al., 2005].

In this study, repetitive single pulse electrical stimulation was employed to map inter‐areal connectivity. Single pulse stimulation is usually not intense enough to produce any deficits in higher brain functions. For future clinical application to map out the network for praxis movement and other higher cognitive functions, high frequency stimulation is needed to better delineate behavioral impairment. It is expected to complement the present CCEP study by causing transient functional impairment of individual functions involved in the parieto‐frontal network. Although the present investigation was limited to the patients undergoing invasive presurgical evaluation, a combined CCEP and diffusion tractography study in this patient population will provide a rare yet valuable opportunity to better understand the contemporary disconnection framework that highlights both specialization of the association cortices and connections between those brain regions (Catani and ffytche 2005). Recently developed elaborate algorithms such as probabilistic diffusion tractography that incorporates multiple‐fiber estimation will be of significant benefit for delineating subcortical pathways linking the stimulus and recording cortical sites [Behrens et al., 2007]. For elucidating roles of the medial parieto‐frontal circuits as well as hemispheric difference of the parieto‐frontal network related to praxis movements and other cognitive functions, a future combined study based on the accumulation of further cases is warranted.

It should be noted that the present study was carried out in patients with intractable partial epilepsy or brain tumor. Although the parieto‐frontal connectivity was studied in the presumably normal cortex away from the epileptic focus in Patient 1‐3, Patient 5‐7 had the foci within the lateral parieto‐frontal area. While Patient 5 had dysembryoplastic neuroepithelial tumor 2 cm rostral to the precentral sulcus in the superior frontal gyrus, Patient 6 and 7 had normal MRI and the pathological diagnosis of focal cortical dysplasia (FCD) type 1A. Since “MRI‐negative” FCD is reported to have normal cortical functions and cortico‐cortical connections [Marusic et al., 2002; Matsumoto et al., 2007a] and normal somatotopy was indeed observed in the sensorimotor strip upon high frequency electrical stimulation in all the three patients, these patients most likely had normal connectivity pattern in the parieto‐frontal area. In Patient 4, the connectivity was investigated close to a perirolandic tumor. In this particular case, the CCEP investigation delineated a ventral parieto‐frontal circuit preserved in the vicinity of the lesion with the same global geometry as observed in other patients (see Fig. 5). Since CCEP studies are relatively easy to perform (each average from a given stimulus site takes only 1‐2 min and does not require much of the patients' cooperation) and a chance of provoking seizures is extremely low [Matsumoto and Nair 2007], the CCEP technique could be applicable in an intraoperative setting to identify and monitor the functionally important network in the vicinity of lesions such as tumors. In the present study, we did not recruit epilepsy patients who had core epileptogenic areas in the lateral parietal area. It is through the parieto‐frontal network that, in patients with parieto‐occipital lobe epilepsy, epileptic discharges spread to the frontal lobe and manifest ictal semiology of frontal lobe epilepsy [Ajmone‐Marsan and Ralston 1957; Ikeda et al., 2002]. By applying single pulse stimulation to the ictal onset zone, we could delineate cortico‐cortical network involved in spike propagation in each individual patient [Matsumoto et al., 2007b]. This would be clinically useful to differentiate “green” spread spikes from “red” spikes originating from the epileptogenic focus.

Acknowledgements

The authors wish to thank Timothy O'Connor, Karl Horning, Mary Jo Sullivan, Pin Liu and Dr. Rei Enatsu for technical assistance. They are also grateful for Dr. Hiroki Yamamoto for his assistance in standardization of the CCEP connectivity findings.

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