Brain Advance Access originally published online on October 17, 2006
Brain 2007 130(1):181-197; doi:10.1093/brain/awl257
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Functional connectivity in human cortical motor system: a cortico-cortical evoked potential study
1 Departments of Neurology, The Cleveland Clinic Foundation OH, USA 2 Neurosurgery, The Cleveland Clinic Foundation OH, USA 3 Department of Neurology, Kyoto University Graduate School of Medicine Kyoto, Japan 4 Human Brain Research Center, Kyoto University Graduate School of Medicine Kyoto, Japan Present addresses: 5Kansai Regional Epilepsy Center, National Hospital Organization Utano National Hospital Kyoto, Japan 6 Takeda General Hospital Kyoto, Japan
Correspondence to: Dileep R. Nair, MD, Section of Epilepsy, Department of Neurology, The Cleveland Clinic Foundation, 9500 Euclid Avenue S51, Cleveland, OH 44195, USA E-mail: naird{at}ccf.org
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In order to understand the complex functional organization of the motor system, it is essential to know the anatomical and functional connectivity among individual motor areas. Clinically, knowledge of these cortico-cortical connections is important to understand the rapid spread of epileptic discharges through the network underlying ictal motor manifestation. In humans, however, knowledge of neuronal in vivo connectivity has been limited. We recently reported a new method, ‘cortico-cortical evoked potential (CCEP)’, to electrically track the cortico-cortical connections by stimulating a part of the brain through subdural electrodes and recording the cortical evoked potentials that emanate from a distant region of the cortex via neuronal projections. We applied the CCEP methodology to investigate in vivo cortico-cortical connections between the lateral motor cortex [LMCx; sensorimotor (SM) and lateral premotor areas] and the medial motor cortex [MMCx; supplementary motor area proper (SMA), pre-SMA and foot SM]. Seven patients with intractable partial epilepsy were studied. These patients had chronic implantation of subdural electrodes covering part of the lateral and medial frontal areas. As a part of the routine pre-surgical evaluation, comprehensive cortical mapping was performed by electrical stimulation of the subdural electrodes, and the precise localization of the subdural electrodes was defined by MRI co-registration. Single-pulse electrical stimuli were delivered to MMCx (7 patients) and LMCx (4), and CCEPs time-locked to the stimuli were recorded by averaging electrocorticograms from LMCx and MMCx, respectively. Short-latency CCEPs were observed when stimulating MMCx and recording from LMCx (mean latency: 21.6 ms, range: 9–47 ms) and vice versa when stimulating LMCx and recording from MMCx (mean latency: 29.4 ms, range: 11–57 ms). In terms of the location of these stimulus sites and CCEP responses along the rostrocaudal axis, regression analysis revealed a consistent correlation between the sites of stimulation and maximum CCEP for stimulation of both MMCx and LMCx. Functionally, stimulation of the positive motor areas in MMCx elicited CCEPs at the somatotopically homologous regions in LMCx (71%). The same findings were observed in MMCx (82%) upon stimulation of LMCx. In four subjects in whom bi-directional connectivity was investigated by stimulating both MMCx and LMCx, reciprocality was observed in the majority of connections (78–94%). In conclusion, the present study demonstrated a human motor cortico-cortical network connecting (i) anatomically homologous areas of LMCx and MMCx along the rostrocaudal cognitive-motor gradient; and (ii) somatotopically homologous regions in LMCx and MMCx in a reciprocal manner.
Key Words: motor areas; functional connectivity; cortical stimulation; evoked potential; epilepsy
Abbreviations: CCEP, cortico-cortical evoked potential; CS, central sulcus; DTI, diffusion tensor imaging; FCD, focal cortical dysplasia; FEF, frontal eye field; LMCx, lateral motor cortex; MMCx, medial motor cortex; NMA, negative motor area; PM, lateral premotor cortex; PMd, dorsolateral premotor cortex; PMv, ventrolateral premotor cortex; PrCS, precentral sulcus; SM, primary sensorimotor area; SMA, supplementary motor area proper; TMS, transcranial magnetic stimulation; VAC, vertical anterior-commissural
Received April 27, 2006. Revised August 7, 2006. Accepted August 9, 2006.
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Introduction |
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The motor cortex is the agranular sector of the frontal lobe that occupies its caudal part. Brodmann (1909)
subdivided it into two regions: the primary motor cortex (MI) area 4 (BA4) and the non-primary or premotor cortex area 6 (BA6). Matelli et al. (1985, 1991) using modern cytoarchitectural and histochemical methods subdivided the non-primary motor cortex (BA6) of the non-human primates into three groups of areas: the medial premotor cortex (areas F3 and F6), the dorsolateral premotor cortex (F2 and F7: PMd) and the ventrolateral premotor cortex (F4 and F5: PMv). Each of these areas has anatomically and functionally distinct rostral and caudal subdivisions. Anatomically, the caudal parts of the medial premotor cortex [F3: supplementary motor area proper (SMA)], PMd (F2) and PMv (F4) send substantial projections to MI (F1) and directly to the spinal cord, whereas the rostral parts of the medial premotor cortex (F6: pre-SMA), PMd (F7) and PMv (F5) are closely interconnected with the prefrontal cortex rather than MI (F1) (He et al., 1993, 1995; Luppino et al., 1990; Matelli et al., 2004). Functionally, a cognitive-motor gradient exists along the rostrocaudal axis, with the rostral parts more related to sensory or cognitive aspects of the motor behaviour and the caudal parts more related to movement execution (Geyer et al., 2000; Matelli et al., 2004). In humans, there is also evidence from functional neuroimaging (see Geyer et al., 2000; Picard and Strick, 1996, 2001 for review) and direct cortical recordings of event-related potentials (Ikeda et al., 1999; Matsumoto et al., 2003) suggesting the existence of a similar functional gradient along the rostrocaudal axis in both the lateral and medial premotor cortex.
Precise definition of the connectivity between motor areas is essential to understand better the complex functional organization of the motor system. This could help us to elucidate the pathophysiology of ictal motor semiology and of rapid spread of epileptic discharges within the motor system. It has been speculated that the latter is one of the reasons for the relatively poor results of epilepsy surgery in patients with frontal lobe epilepsy (Engel et al., 2003).
Almost all the knowledge of the anatomical and functional connectivity of the motor system comes from non-primate studies using in vivo tract tracing techniques (e.g. horseradish peroxidase) in combination with single or multi-unit electrophysiological approaches. In humans, the connections between motor areas have been studied almost exclusively by gross dissections on the post-mortem human brain. In vivo connectivity studies have only recently begun using non-invasive methods, such as diffusion tensor imaging (DTI) (Behrens et al., 2003; Wakana et al., 2004) and combined use of transcranial magnetic stimulation and positron emission tomography/functional magnetic resonance imaging (TMS-PET/fMRI) (Paus et al., 1997; Siebner et al., 2000; Bestmann et al., 2003). Thus, further work is needed to compare the anatomical organization of the motor areas in the human and monkey frontal cortex.
We have recently developed an in vivo method to study cortico-cortical connections in humans [cortico-cortical evoked potential (CCEP)] (Matsumoto et al., 2004a, b, 2005). Electrical pulses are applied to chronically implanted subdural electrodes and evoked potentials elicited at distant cortical regions are recorded. This technique provides an opportunity to track functional connectivity among various motor areas that can be defined by cortical electrical stimulation and MRI-electrode co-registration. In this study, we investigated the functional connectivity of the cortical motor system using CCEP, focusing on the cortico-cortical network between lateral and medial motor areas.
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Subjects
Seven patients who underwent chronic subdural electrode placement for pre-surgical evaluation of medically intractable partial epilepsy were studied. All patients had subdural electrodes placed over the lateral convexity and the medial wall of the frontal lobe. The implanted electrodes were made of platinum, measuring 3.97 mm in diameter with a centre-to-centre interelectrode distance of 1 cm (custom-made in the Cleveland Clinic, OH). The clinical profiles of investigated patients are presented in Table 1. In four subjects, ictal onset zone was at the lateral premotor area (PM), rostral to the motor strip (Patients 2 and 7) or including the motor strip (Patients 1 and 3). In one subject (Patient 4) the ictal onset zone was non-localizable, and in two subjects (Patients 5 and 6) it was remote from the motor areas. MRI was unremarkable in all but Patient 5, in whom encephalomalacia in the left superior anterior parietal region was noted. Six subjects underwent resective surgery after the invasive evaluation, and the pathology was ‘MRI-negative’ focal cortical dysplasia (FCD) except for Patient 5 who had left hippocampal sclerosis. CCEP of Patient 5 has also been reported in another study for an entirely different purpose (Matsumoto et al., 2004b
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The present study was approved by the Institutional Review Board Committee at The Cleveland Clinic Foundation, and informed consent was obtained from all subjects (IRB #4513).
Functional and anatomical brain mapping
Cortical electrical stimulation was performed for functional mapping as a part of the routine pre-surgical evaluation. Repetitive square wave electrical currents of alternating polarity with a pulse width of 0.3 ms and a frequency of 50 Hz were delivered for 2–5 s (Grass S-88 and SUI-7, Astro-Med Inc., RI). Details of the methodology for cortical stimulation and the subsequent cortical mapping have been described elsewhere (Lüders et al., 1987). In short, positive motor and sensory areas were identified by positive motor response (muscle twitch) and subjective sensory sensation, respectively. Cortical sites where the stimulation interfered with tonic muscle contraction or rapid alternating movements were defined as the negative motor area (NMA). The region of cortical stimulation was determined solely for clinical purposes. All subjects underwent full investigation of the lateral and medial motor areas with electrical stimulation except Patients 4 and 5, who only had a partial stimulation study performed. Somatosensory evoked potentials (SEPs) were also recorded to identify the central sulcus (CS) in all subjects. In Patients 4 and 5, the positive motor response or muscle twitch was investigated during the preliminary 1 Hz electrical stimulation to find the appropriate stimulus intensity for the CCEP study (see the section on Stimulus condition and data acquisition of CCEP).
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 MP-RAGE sequences (1.5 T), using an in-house computer program working on a Silicon Graphics computer (Mountain View, CA). 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., 2004b). For anatomical identification of each electrode in reference to the cerebral sulci, the volume-rendered MRI was chamfered by 4–5 mm from the cortical surface to locate the sulci beneath the grids, avoiding the artefacts arising from subdural grids on the surface of the brain. Major sulci in the lateral and medial frontal areas were identified using the atlas of the cerebral sulci of Ono et al. (1990) as reference.
Nomenclature of the lateral and medial motor cortex
In the present study, the boundaries and subdivisions of PM were defined according to the recent proposals (Freund, 1996; Preuss et al., 1996; Roland and Zilles, 1996; Rizzolatti et al., 1998; Picard and Strick, 2001). PMd was defined as BA6a-ß and the dorsal part of BA6a-
, and PMv as the ventral part of BA6a- and BA44. In the rostrocaudal axis, the rostral boundary of PM at BA6 or BA44 was set, on the basis of the Talairach coordinates (Talairach and Tournoux, 1988). The rostral border became closer to CS as it extended ventrally, being situated 30–35, 15–30 and 15–20 mm rostral to the precentral sulcus (PrCS) in the superior, middle and inferior frontal gyri, respectively. Caudally, the border between PM and BA4 was not explicitly defined in this study. This was because the border is (i) histologically variable among individuals (Rademacher et al., 2001); and (ii) physiologically difficult to identify by cortical electrical stimulation (e.g. threshold difference) on the crown of the precentral gyrus. Instead, we anatomically referred to the location of the CCEP as PM if its field was located mostly rostral to CS, and as the primary sensorimotor area (SM) if its field clearly overlaid across CS. From a functional viewpoint, we refer to the positive motor area on the lateral convexity as ‘the precentral motor area’ since electrically excitable cortex extends 
2–3 cm rostral to CS beyond the anterior border of BA4 and thus contains both caudal BA6 and BA4 (Uematsu et al., 1992). As for the boundary between PMd and PMv, the physiologically determined frontal eye field (FEF), if present, served as a landmark. In its absence on cortical stimulation, the border was set between the precentral hand and face motor areas, which corresponds to the level of FEF in the dorsoventral axis (Matsumoto et al., 2002).
The medial premotor cortex or medial BA6, which is above the cingulate sulcus, was subdivided into the rostral (pre-SMA) and caudal (SMA) parts. The vertical anterior-commissural (VAC) line (Talairach and Tournoux, 1988) was used as a general landmark to differentiate between pre-SMA and SMA (Picard and Strick, 1996). In all patients but Patient 5, short-latency tibial SEPs were used to identify foot SM (Allison et al., 1991) because anatomical landmarks and electrical stimulation failed to identify a clear boundary between the foot portion of SMA and that of BA4 (Rademacher et al., 2001).
The purpose of this study was to investigate the functional connectivity between the lateral (LMCx) and medial motor cortex (MMCx). We defined PMd, PMv and SM as LMCx and pre-SMA, SMA and the foot portion of SM as MMCx.
Stimulus condition and data acquisition of CCEP
Details of the CCEP methodology have been described elsewhere (Matsumoto et al., 2004a, b). In brief, electrical stimulation was applied in a bipolar fashion to a pair of adjacently placed subdural electrodes by a Grass S-88 stimulator (Astro-Med, Inc., RI). The electrical stimulus consisted of a constant-current square wave pulse of 0.3 ms duration, which was given at a fixed frequency of 1 Hz. Polarity of stimulus current was alternated to (i) reduce the stimulus artefacts; (ii) avoid electrical charges building up at the cortex (a safety consideration); and (iii) avoid polarization of platinum electrodes, which can decrease the current density over time. The current was given at 80–100% of the intensity that produced either clinical signs or afterdischarges (ADs) during 50-Hz stimulation. The intensity was set at 10–12 mA if no clinical sign or ADs were present at 15 mA. In cases in which excessive artefact obscured the recordings, the intensity was lowered stepwise by 1 mA until artefacts became small enough to visualize the evoked responses. For Patients 4 and 5 in whom 50-Hz stimulation was not performed at all in the areas of functional interest, preliminary 1 Hz stimulation was performed to determine the stimulus intensity for the CCEP study. The current intensity was set at the threshold intensity, which produced muscle twitches, if present, and otherwise at 12 mA or, in the presence of artefacts, at relatively lower intensities. Electrocorticograms (ECoGs) were recorded with a bandpass filter of 1–1000 Hz and a sampling rate of 2500 Hz (Axon Epoch 2000 Neurological Workstation, Axon Systems Inc., NY). Recordings from the 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. In each session, at least two trials of 20–100 responses were averaged separately to confirm the reproducibility of the responses. During the recording of CCEPs, the subjects were not requested to perform any specific task; they had only to lie or sit on a bed.
Areas investigated in the lateral and medial motor cortex
CCEPs were first recorded at LMCx (16–47 electrodes per subject) by stimulating the electrode pairs in MMCx (Table 1). Three to seven pairs of electrodes were stimulated per subject, amounting to 38 pairs in total. LMCx was then stimulated to record CCEPs from MMCx (6–16 electrodes) in four subjects (Patients 1–4) in whom clinical conditions allowed further investigations during the limited invasive evaluation. A total of 48 electrode pairs (5–16 per subject) at LMCx were stimulated. To investigate the reciprocality of cortico-cortical connections, we stimulated LMCx electrodes that had shown the highest amplitude CCEPs by MMCx stimulation. Grid placements were planned exclusively for clinical purposes. In all patients, PMd, SMA and SM were well covered but pre-SMA was partially covered in five subjects (up to 0.3–2.8 cm rostral to VAC line) and PMv in seven subjects (four full and three partial coverage). Accordingly, the majority of single-pulse stimulation in MMCx was performed at SMA while that in LMCx was performed at PMd and SM. The rest of MMCx stimulation was given at pre-SMA (4 pairs) and around VAC line (4), and that of LMCx stimulation at PMv (11). In order to simplify the description of the results and discussion, we will use the following convention when discussing the region stimulated and the region where the CCEP responses were recorded. A descriptor labelled ‘CCEPX
Y’ will be used to indicate that CCEP is recorded from region ‘Y’ in response to stimulation of region ‘X’. For example, CCEPSMAPMd means CCEP recorded from PMd in response to stimulation of SMA.
Display and analysis of CCEPs
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 artefact. 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 fashion was employed because the conventional peak to trough measurement was occasionally difficult owing to the preceding stimulus artefact. The artefact usually consisted of a baseline drift that typically persisted for several milliseconds from the stimulus, and appeared to originate from either relatively poor electrode impedance or possibly the existence of the cerebrospinal fluid beneath the electrode.
In order to show the distribution of the activity over the cortex, a circle map was employed on the basis of the amplitude percentage distribution of CCEP fields. In this circle map, the diameter of the circle at each electrode represented the percentile to the maximal amplitude of the corresponding CCEP field. If, besides the most prominent CCEP field, any other field was spatially separated from the main field or its peak latency was clearly different even when spatially overlapped with the main field, that field was identified as a separate CCEP field. In the presence of multiple CCEP fields, different circles (e.g. filled circles for the main field, unfilled circles for the other fields) were employed to show the distribution of each individual field in the common circle map.
To investigate the anatomical relationship between the site of stimulation and that of the maximum CCEP response, these sites from each subject were plotted on a common coordinate. In order to describe their location in relation to the cognitive-motor gradient and somatotopic organization in LMCx and MMCx, the relationship was displayed in the following two dimensions—MMCx rostrocaudal versus LMCx rostrocaudal dimension (Fig. 1B) and MMCx rostrocaudal versus LMCx dorsoventral dimension (Fig. 1C). The site of stimulation was defined as the midpoint of the pair of stimulating electrodes, and that of the maximum CCEP as the centre of the electrode showing the maximum CCEP. For the rostrocaudal dimension, the axis denoted the distance of the stimulus or response site from VAC line for MMCx and that from CS for LMCx. For the dorsoventral or more precisely dorsomedial–ventrolateral dimension of LMCx, the axis represented the distance from the midline. The distance from VAC line and the midline was measured in centimetres. To display better the distance of the stimulus or response site in relation to PrCS, which was considered the border between the rostral and caudal subdivisions of PM (Picard and Strick, 2001), the distance from CS was expressed with respect to the width of the precentral gyrus. That is, a line was drawn parallel to the anterior commissure–posterior commissure (AC–PC) plane from the corresponding site toward CS. Then the width was measured from CS to PrCS along this line and defined as 1 for each individual plot. Thus, for example in Fig. 1B, y = 0, 0 < y < 1, y = 1 and y > 1 denote the virtual CS, precentral gyrus, PrCS and PM rostral to PrCS, respectively.
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Overall relationship between the sites of stimulation and CCEPs
In all subjects, stimulation of MMCx elicited CCEP in LMCx (CCEPMMCx
LMCx). CCEPMMCxLMCx was recorded in a total of 33 out of 38 stimulus sites (87%, 3–6 sites per subject). Likewise, stimulation of LMCx elicited CCEP in MMCx (CCEPLMCxMMCx) in 32/48 sites across all the four subjects studied for this direction of connectivity (67%, 3–12 sites per subject). As shown in a representative case (Fig. 2), the majority of CCEP consisted of a small positive deflection followed by a large negative potential (N1). There was a gradual shift of the CCEP distribution as the stimulus site moved along the rostrocaudal axis; the more rostral MMCx and LMCx stimulation elicited the more rostrally distributed CCEP in LMCx and MMCx, respectively (Fig. 2B and C). For instance, stimulation of pre-SMA (Fig. 2B1, pair 1) elicited CCEP maximum at rostral PMd while that of SMA (negative motor and arm motor areas; Fig. 2B2, pair 2) showed CCEP maximum at the precentral arm motor area. This observation was consistent across the subjects. In terms of the location of stimulation and CCEP responses along MMCx and LMCx rostrocaudal axes, regression analysis showed a positive correlation between the sites of stimulation and maximum CCEP both for MMCx and LMCx stimulations (Fig. 3A and C). That is, along the rostrocaudal axis, anatomically homologous areas of LMCx and MMCx connected with each other. Along MMCx rostrocaudal and LMCx dorsoventral axes, however, correlation was present, but was lower, in MMCx stimulation (Fig. 3B) and was not observed in LMCx stimulation (Fig. 3D). The mean N1 peak latency at the maximum CCEPMMCxLMCx was 21.6 ms (range: 9–47 ms) and that of the maximum CCEPLMCxMMCx was 29.4 ms (range: 11–57 ms). No seizures were provoked throughout the series of investigation.
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Individual connections between the lateral and medial motor cortex
In addition to the predominant connections between LMCx and MMCx based on the site of maximum CCEP response, additional CCEPMMCx
LMCx fields were present in 13 out of 33 (40%) positive stimulations of MMCx, most probably representing divergent connections from MMCx to LMCx. In contrast, multiple connections from LMCx to MMCx, as shown by multiple independent CCEPLMCxMMCx, were only infrequently observed (two stimulus sites in Patient 1; see Fig. 2C1, pair 1, for example). This could be related to the limited coverage of MMCx with a relatively small number of electrodes.
Among the multiple projections between LMCx and MMCx, SM had a unique connectivity pattern. A discrete CCEP field was distributed over SM in 10 MMCx stimulus sites across 6 subjects (Patients 1–6) (Fig. 4, shaded area in grey). The stimulus sites producing CCEPMMCxSM were always confined to SMA and foot SM. CCEPMMCxSM was the maximum response in four stimulus sites (Fig. 4, filled circles in SM), and a smaller CCEP field in the remaining six stimulus sites (unfilled circles). The CCEPMMCxSM fields spatially overlapped with the CCEPMMCxPM fields in four stimulus sites in three subjects (Fig. 4; Patients 2, 4, 5). The CCEPMMCxSM was clearly distinguishable from the CCEPMMCxPM because the CCEPMMCxSM had a shorter N1 peak latency (mean: 19.7 ms) than the CCEPMMCxPM (mean: 28.4 ms) (P < 0.05, paired t-test).
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In those subjects who had bi-directional investigations (Patients 1–4), stimulation of these SM fields elicited CCEPSM
MMCx in SMA and foot SM, but not in pre-SMA. In order to clarify the connections between medial SM and LMCx, the connectivity of foot SM in the medial wall was investigated by stimulating and recording from foot SM defined by tibial SEPs. Upon stimulation of foot SM, CCEPfootSMLMCx was always recorded in the pre- or post-central gyrus, that is, caudal PM or SM (see Fig. 3A, unfilled circles). As regards the projections from LMCx to foot SM, the maximum CCEPLMCxfootSM responses were always elicited by the stimulus sites within the pre- and post-central gyrus (Fig. 3C, unfilled circles).
It was only possible to study the connections between the ventrolateral convexity (PMv, FEF) and MMCx in those subjects who had grid coverage over PMv and FEF. MMCx stimulation elicited CCEPMMCxPMv/FEF as one of multiple CCEP fields in seven stimulus sites in four subjects (Patients 1, 2, 4, 5) (Fig. 5). The sites of stimulation that generated CCEPMMCxPMv responses were scattered throughout MMCx along the rostrocaudal axis (e.g. pre-SMA, SMA, foot SM). Stimulation at around VAC line, though observed only at a single stimulus site, elicited CCEPMMCxFEF (Patient 1, pair 1, circle c). In LMCx, stimulus was given at PMv and/or FEF in a total of 11 sites in 3 subjects (Patients 1, 2, 4). Six sites in two subjects (Patients 1, 2) elicited CCEPPMv/FEFMMCx (Fig. 6), while no responses were recorded in Patient 4. The lack of responses in this subject may have been related to the low stimulus intensity to reduce artefacts and the limited electrode coverage in MMCx (1 x 6 strip electrodes). CCEPPMv/FEFMMCx was recorded around VAC line with the maximum at 0.3 to 1.75 cm caudal to VAC line. Functionally the maximum CCEPPMv/FEFMMCx was located at face (1 site) and arm (2) SMA, NMA (2) and at one electrode that was not tested with 50-Hz stimulation.
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Functional correlation and reciprocality of the cortico-cortical connection
Functional correlation of the cortico-cortical connection was investigated by comparing cortical function at the site of stimulation with that at the sites where CCEP fields were elicited. Only those stimulating pairs whose functional profile was available with 50-Hz stimulation were included in this analysis. In 12 out of 17 MMCx stimulus sites (71%), the motor function somatotopically corresponding to the site of stimulation was observed within the CCEP field in LMCx (e.g. face SMA to face PM) (Fig. 7, pairs 1, 2). In LMCx stimulation, 18 out of 22 sites (82%) elicited CCEP fields encompassing homologous motor function in MMCx (Fig. 7, pairs 3, 4). With respect to the area generating maximum CCEP, the homologous motor function was seen in 5 (30%) MMCx and 11 (50%) LMCx stimulus sites.
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Reciprocality of the cortico-cortical connections was studied in four subjects (Patients 1–4) who underwent both MMCx and LMCx stimulations. It was investigated by evaluating whether the area of projection projected back to the initial site of stimulation. Taking MMCx as an initial site of stimulation, for example (Fig. 8A), the second site of stimulation was set at the site of LMCx showing the maximum CCEP to the first stimulation (CCEPMMCx
LMCx). Then reciprocality was evaluated by checking the overlap between the site of initial stimulation and the CCEP field elicited by the second stimulation (CCEPLMCxMMCx) in MMCx. In this way, reciprocality was analysed in both directions: initial stimulation at MMCx, first CCEP in LMCx, second stimulation at LMCx, second or ‘homing’ CCEP in MMCx (MMCxLMCxMMCx), and vice versa (LMCxMMCxLMCx). With MMCx being the initial site of stimulation, reciprocal connections were observed in 17 out of 18 stimulus sites (94%), with the maximum second CCEP exactly at the site of initial stimulation in 9 sites (50%) (Fig. 8B). For the initial stimulation at LMCx, reciprocal connections were seen in 25 (78%) out of 32 stimulus sites with the maximum second CCEP exactly at the site of initial stimulation in 8 (25%) (Fig. 8B).
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Discussion |
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In vivo functional connectivity was investigated between LMCx and MMCx in epilepsy patients who underwent invasive monitoring with subdural electrodes for pre-surgical evaluation. This study demonstrated a cortico-cortical network connecting (i) anatomically homologous areas along the rostrocaudal axis as well as (ii) somatotopically homologous regions between LMCx and MMCx in a reciprocal manner.
Implication and limitation of CCEP
We hypothesized that the external or surface electrical stimulation of the cortex generates orthodromic discharges in short or long cortico-cortical association fibres. The efficacy of surface cortical stimulation to activate projection neurons is supported by the observation that surface electrical stimulation of the motor cortex produces motor evoked potentials through activation of pyramidal tract neurons in humans (Ikeda et al., 2000) and that surface electrical stimulation produces stereotypical post-synaptic responses, called ‘the direct cortical response (DCR)’ in the immediately adjacent cortex in humans and other species (Adrian, 1936, Li and Chou, 1962). It is also supported by TMS-PET/fMRI studies, which showed that TMS of the cortex gave rise to increased cortical activity, as measured with an indirect haemodynamic response, in remote cortex (Paus et al., 1997; Siebner et al., 2000; Bestmann et al., 2003).
The generator mechanism of CCEP, however, is not precisely known. Three possible mechanisms are discussed here—orthodromic activation, antidromic activation and third-region mediation. First, in consideration of orthodromic activation, it should be noted that the alternating polarity of the stimulus current was employed in order to counterbalance the stimulus artefact and electric charges. Therefore, the stimulated neurons are indeed the mixture of different neuronal populations depolarized by anodal and cathodal stimulation and it is likely that the excitation of projection neurons in the stimulated cortex occurs through synaptic action by activation of afferent input as well as direct depolarization of the initial segment (Amassian et al., 1990; Rattay, 1999). The relatively long peak latency (10 ms) observed in the locally evoked DCRs supports the assumption that direct cortical stimulation produces oligo- or multi-synaptic responses in the local cortical circuits (Purpura et al., 1957; Goldring et al., 1994). This local jitter of synaptic activity at the site of stimulation and at the target cortex could account for the relatively long latency and blunt negative peak observed in the present study. The first positive deflection (usually several milliseconds in the absence of stimulus artefacts) at the target cortex might reflect the very first monosynaptic impulse projecting into the middle or deep cortical layer via large cortico-cortical projection fibres, giving rise to a surface positive potential (Felleman and Van Essen, 1991). Secondly, antidromic activation of the pre-synaptic axonal terminals of the association fibres could play a role in generation of CCEP. Compared with highly structured pyramidal neurons or interneurons, poorly organized arrangements of these small axon terminals are less favourable for effective direct activation (Nieuwenhuys, 1988). Nevertheless, extensive arborization of the pre-synaptic terminals may increase the chance to be excited by cortical surface stimulation. In this case, the antidromic activation of the pyramidal neurons in the deep cortical layer at the target cortex would be recognized as a small surface positive potential reflecting the very first volley of impulses. The following large blunted negative potential could then be produced at the target cortex upon the first impulse arrival or generated as a result of mixture of both orthodromic and antidromic excitation of the neurons in the target cortex. Lastly, in addition to the direct cortico-cortical pathway, the indirect pathway through the third region, namely, the cortico-subcortico-cortical pathway may be an alternative mechanism. Non-reciprocal cortico-thalamocortical circuits within the frontal lobe (McFarland and Haber, 2002) or the motor loop of the corticobasal ganglia-thalamocortical circuits (Alexander et al., 1986) could be candidates, and in fact, these mechanisms might account, at least in part, for the very late responses recorded occasionally (see Fig. 5). In addition to these possible mechanisms, there might be more factors to be understood, including ephaptic conduction. The actual generator mechanisms are likely to be a combination of the aforementioned mechanisms.
Although the CCEP technique is applicable only during invasive pre-surgical evaluations of intractable epilepsy patients, it provides a unique opportunity to track in vivo cortico-cortical networks and has advantages over other methods. Compared with TMS-PET/fMRI studies, the CCEP study provides (i) direct neuronal responses to the stimulation; (ii) more localized cortical stimulation with better temporal resolution; and thus (iii) opportunity to explore the connectivity from discrete parts of the precentral motor areas (e.g. face, arm, leg) in a consecutive study versus limited investigation (e.g. hand motor area alone) in the TMS study (Siebner et al., 2000; Bestmann et al., 2003). Moreover, in contrast to the DTI study, this technique is capable of providing the direction of connectivity, at least electrophysiologically, by stimulating both ends of connection. The CCEP study, however, cannot identify the actual anatomical pathway of the circuit, and in this regard it may well be regarded as ‘functional tractography’ as compared with ‘anatomical fibre tractography’ by DTI. DTI studies of the motor system have just begun (Guye et al., 2003; Johansen-Berg et al., 2004), and combination of the functional and anatomical fibre tractography will complement each other as tools to explore human in vivo connectivity.
Cortico-cortical network between the lateral and medial motor cortex
By means of CCEP, we performed ‘functional tractography’ of the cortical motor system, focusing on the connections between LMCx and MMCx. The connections from the site of stimulation were tracked with the distribution of CCEP. While some positive stimulus sites showed multiple divergent connections to the target areas as revealed by multiple independent CCEP fields following the stimulation of a single area, the predominant connection with the site of stimulation was determined as the field of the maximum CCEP. In terms of the location along the rostrocaudal axis, regression analysis revealed a consistent correlation between the sites of stimulation and maximum CCEP for both LMCx and MMCx stimulations (Fig. 3A and C). That is, there was a cortico-cortical network connecting the anatomically homologous areas of LMCx and MMCx (e.g. rostral PM to pre-SMA, caudal PM to SMA). There also existed within SMA the rostrocaudal gradient of connections to homologous LMCx. This supports the anatomical (Vorobiev et al., 1998) as well as functional (Grafton et al., 1996; Rao et al., 1997) subdivisions recently proposed within SMA. Furthermore, the reciprocality of connections was investigated by comparing the initial site of stimulation (e.g. face SMA) and the distribution of the second or ‘homing’ CCEP (e.g. CCEPLMCxMMCx) back on the side of initial stimulation (e.g. MMCx). The majority (78–94%) of connections were found to be reciprocal with the maximum ‘homing’ CCEP exactly at the site of initial stimulation in 25–50% of the connections. The cortico-cortical connection as revealed here is in good accordance with the in vivo tracer studies of the non-human primates. In the macaque, the rostral (F6) and caudal (F1, F3) medial motor areas connect, in a reciprocal fashion, mainly to the rostral (F5, F7) and caudal (F1, F2, F4) lateral motor areas, respectively (Luppino et al., 1990, 1993; Geyer et al., 2000).
As in the macaque in vivo tracer studies, the connection was not always restricted to a single area of the maximum CCEP, and multiple divergent connections were present (Figs 4 and 5). CCEPMMCxLMCx analysis revealed divergent connections from MMCx to PMd, PMv and SM in 40% of the positive stimulus sites. In contrast, only a few multiple projections were detected from LMCx to MMCx (e.g. Fig. 2C1 pair 1). This may be, at least in part, due to the limited coverage of MMCx with a small number of electrodes. Some individual connections deserve attention. First is the connectivity pattern of SM. Upon stimulation of MMCx, only SMA, not pre-SMA, had connections to SM on the lateral convexity. Similarly, stimulation of SM elicited CCEPs only in SMA, and not in pre-SMA. We also had a chance to study the connection between SM and PM by stimulating foot SM in MMCx. The connectivity was localized to the pre- and post-central gyrus in the lateral convexity, that is, caudal PM or SM. These findings fit well with the almost exclusive connectivity of MI (F1) to the caudal PM (F2, F3, F4) in monkeys (Matsumura and Kubota, 1979; Leichnetz, 1986; Ghosh et al., 1987; Luppino et al., 1990, 1993), and expand our knowledge of connectivity between MI and SMA in humans, which had been studied previously between the hand MI and SMA by TMS, DTI and ECoG coherence analysis (Siebner et al., 2000; Ohara et al., 2001; Bestmann et al., 2003; Guye et al., 2003).
Studies of the connections between the ventrolateral convexity (PMv, FEF) and MMCx are also of interest (Figs 5, 6 and 7). The present study provides the first direct evidence of in vivo connectivity between PMv/FEF and pre-SMA/SMA in humans. The observed connectivity pattern generally corresponds with the connectivity described in the non-human primates (Matelli et al., 1986; Barbas and Pandya, 1987; Huerta and Kaas, 1990; Luppino et al., 1990, 1993). The connection from FEF, however, was different from the findings of macaque studies, which showed its connection to the supplementary eye field (SEF) at the dorsomedial part of the lateral convexity (Huerta and Kaas, 1990; Luppino et al., 1990). In our study, stimulation of FEF elicited CCEPs in MMCx at or just caudal to VAC line in two subjects (Patients 1, 2; Fig. 6), and stimulation of the area around VAC line generated CCEPs at FEF in one (Patient 1; Fig. 5). In the macaque, in addition to SEF that corresponds to the medial part of cytoarchitectonic F7 (Schlag and Schlag-Rey, 1987; Matelli et al., 1991), a separate small oculomotor representation was observed in the rostral part of SMA (F3) by means of intracortical microstimulation (Mitz and Wise, 1987). Taken together with the converging human data from different modalities that support a similar oculomotor representation in the rostral SMA, our results probably represent connections between FEF and the oculomotor representation of SMA in humans (Lim et al., 1994; Luna et al., 1998; Grosbras et al., 1999; Yamamoto et al., 2004). Whether this oculomotor area is a cortical area distinct from SMA, that is, a human homologue of SEF, is out of scope of our study and needs to be clarified by future studies of detailed receptor distribution and cytoarchitectonics. Since the coverage of the ventrolateral convexity was limited and bipolar stimulation there occasionally resulted in stimulation of mixture of the two functionally different areas, the connectivity pattern of PMv or FEF was not studied as thoroughly as that of PMd. Further studies are warranted to establish it.
Functional consideration of the lateral and medial motor network
The existence of parallel cortico-cortical connections between anatomically homologous regions (e.g. rostral to rostral, caudal to caudal) of MMCx and LMCx gives us an insight into the functional organization of the cortical motor system. Being situated between the prefrontal and primary motor areas, both lateral and medial premotor areas most probably play 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 behaviour and the more caudal parts to the movement execution itself. Single unit recordings in monkeys have revealed that neurons with sensory properties are more frequently found in the rostral PM and those with motor properties more frequently in the caudal PM (Weinrich et al., 1984; Johnson et al., 1996). In humans, functional neuroimaging studies (see Picard and Strick, 1996, 2001; Geyer et al., 2000 for review) and direct cortical recordings of event-related potentials (Ikeda et al., 1999; Matsumoto et al., 2003) have also established a similar rostrocaudal cognitive-motor gradient in both LMCx and MMCx, for example, from complex to simple movements (Deiber et al., 1991; Shibasaki et al., 1993; Grafton et al., 1998), from intention to execution of actions (Boussaoud, 2001), from early to late motor learning stages (Jenkins et al., 1994; Hikosaka et al., 1996; Jueptner et al., 1997) and from non-routine to routine motor behaviours (Passingham, 1997). In terms of the functional differentiation between MMCx and LMCx, classical dichotomy has been challenged by recent monkey and human studies (Tanji, 1996). Simultaneous activations were observed in the anatomically and functionally homologous regions of MMCx and LMCx (e.g. pre-SMA and rostral PMd, SMA and caudal PMd) in fMRI/PET experiments employing the tasks previously considered to show functional dichotomy between MMCx and LMCx, for example, internally versus externally guided movements (Deiber et al., 1991; Remy et al., 1994; Weeks et al., 2001) and learning of sequence versus arbitrary associations (Sakai et al., 1999; Kurata et al., 2000). This relatively poor functional discrimination between MMCx and LMCx could be ascribed to the cortico-cortical circuits revealed in the present study between the homologous regions of MMCx and LMCx along the rostrocaudal cognitive-motor gradient.
Another important role of the lateral and medial premotor cortex is their influence upon motor output. In monkeys, retrograde tracer injection into the spinal cord revealed that the lateral and medial caudal premotor areas, together with the primary motor area, constitute the motor execution areas by directly projecting to the spinal cord (He et al., 1993, 1995). In humans, on the basis of surface electrical stimulation, which elicits positive motor responses and thus reveals mostly the origin of the spinal projection from the motor cortex, the lateral caudal BA6 (caudal PMd/PMv), together with BA4, constitutes the precentral motor strip with the face area lying most ventrally, while the medial caudal BA6 (SMA) composes another ‘motor homunculus’ in the medial cortex with the face area lying most rostrally (Penfield and Jasper, 1954; Lüders et al., 1987). The anatomical and functional connectivity between these two ‘motor homunculi’ was investigated in this study. Stimulation of the positive motor areas at MMCx and LMCx elicited CCEPs at the somatotopically homologous regions in LMCx (71%) and MMCx (82%), respectively. In four subjects in whom bi-directional connectivity was investigated by stimulating both LMCx and MMCx, reciprocality was observed in the majority of connections (78–94%). In summary, the somatotopically homologous regions were generally connected with each other in a reciprocal manner between the two motor strips in LMCx and MMCx. However, the reciprocal projections were not always exact between the somatotopically homologous regions and had overlaps with adjacent regions along the motor strips. These observations are consistent with the results obtained by intracortical microstimulation in monkeys (Gould et al., 1986; Huntley and Jones, 1991) and by activation studies in humans (Sanes et al., 1995), which revealed multiple, partially overlapping neuronal populations in the motor cortex.
Clinical relevance
Functional cortical mapping with 50-Hz electrical stimulation has shown that the contralateral or bilateral but asymmetric tonic stiffening of the limbs is the typical positive motor response of SMA while contralateral clonic movements are usually seen when stimulating MI. There are, however, exceptions to this rule. Stimulation of the superior frontal gyrus on the lateral convexity occasionally produces tonic contraction or SMA-type responses (Lim et al., 1994), and stimulation of SMA and the precentral motor area not infrequently elicits clonic and tonic positive motor responses, respectively (Lim et al., 1991). The tight connections revealed between PMd/SM and SMA in the present study could establish a network explaining these exceptions.
These cortico-cortical connections should also be taken into consideration to better understand the pathophysiology of ictal motor manifestation. A bilateral but asymmetric tonic seizure, or the so-called ‘SMA seizure’, only exceptionally arises from an epileptogenic focus within SMA. Usually this type of seizure arises from other parts of the frontal lobe, with the ictal discharge spreading into SMA via cortico-cortical connections (Jobst et al., 2000; Aghakhani et al., 2004). In fact, patients with early ‘SMA seizures’ frequently became seizure-free after resection of foci outside SMA (Aghakhani et al., 2004), supporting the hypothesis that cortico-cortical connections are important for ictal manifestation. Bi-directional connectivity, as revealed in the present study, may also explain spread of epileptic discharges in the opposite direction as well. By the detailed analysis of ictal semiology as well as spike propagation over subdural grids, Baumgartner et al. (1996) demonstrated that both ictal and interictal epileptiform discharges propagated or ‘jumped’ from a part of SMA to the somatotopically corresponding parts of the precentral motor area, explaining that the ictal semiology consisted initially of unilateral tonic manifestation and then of a clonic seizure involving the same body part. The time lag of the discharges in SMA and the precentral motor area averaged 25 ms (range of 10–40 ms) for interictal discharges, which was very similar to the latency of CCEPSMAPMd/SM. These observations suggest that the study of CCEP together with a detailed analysis of interictal and ictal discharges could give us a better understanding of the propagation of epileptic activity from the epileptic focus. This approach would be particularly useful in frontal lobe epilepsy in which the complex functional and anatomical organization of the frontal lobe with multiple reciprocal connections facilitates rapid spread of epileptic discharges (Jobst et al., 2000). CCEP studies are relatively easy to perform. Each average from a given stimulus site only takes 1–2 min; it does not require patient's cooperation, and the chance of provoking seizures is extremely low [no seizures in this study and others (Matsumoto et al., 2004a, b)].
In the present study, the epileptic focus was located in the lateral premotor/precentral area (rostral to or within the precentral motor strip) in four patients. All of the four patients had ‘MRI-negative’ FCD, which was confirmed by pathology. It is possible that in these patients the cortical functions might have been altered under bombardment of epileptic discharges. It is likely, however, that the ‘MRI-negative’ FCD had well-preserved normal functions. Marusic et al. (2002) reported that normal language or motor areas were co-localized with ‘MRI-negative’ epileptogenic regions where cortical dyslamination and columnar disorganization were noted in the absence of balloon cells. Taking into account the normal somatotopy of the precentral motor strip (e.g. Figs 2 and 7) and that the connectivity pattern in these patients was similar to the patients having the focus away from the motor areas, we speculate that these ‘MRI-negative’ patients most likely had a normal connectivity pattern within FCD. These connectivity findings in the motor system further support the co-existence of normal cortico-cortical connections within FCD reported in the language system (Matsumoto et al., 2004b) and between the primary motor and somatosensory areas (Matsumoto et al., 2005). Whether the excitability of these connections is enhanced abnormally in FCD or in the epileptic focus in general will be an important issue to be solved.
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Acknowledgements |
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We wish to thank Timothy O'Connor, Karl Horning and Mary Jo Sullivan for technical assistance. This work was partly supported by the Advanced International Clinical Fellowship Award from The Cleveland Clinic Foundation (R.M.), Research Grants from the Japan Epilepsy Research Foundation (R.M.) and Kanae Foundation for life and socio-medical science (R.M.), and Grants-in-Aid for Young Scientists (B) 17790578 from the Japan Ministry of Education, Culture, Sports, Science and Technology (MEXT) (R.M.).
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