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. 2026 Feb 10;11:126–132. doi: 10.1016/j.cnp.2026.02.002

Effective connectivity between homologous cortices mediated by the corpus callosum: An axono-cortical evoked potentials study

Takumi Mitsuhashi 1,2,⁎, Yasushi Iimura 1,2, Hiroharu Suzuki 1,2, Tetsuya Ueda 1,2, Kazuki Nishioka 1,2, Kazuki Nomura 1,2, Madoka Nakajima 1,2, Hidenori Sugano 1,2, Akihide Kondo 1,2
PMCID: PMC12925470  PMID: 41732345

Highlights

  • •

    Callosal stimulation showed effective connectivity to homologous cortical regions.

  • •

    Sum of callosal-to-cortex propagation latencies matched interhemispheric latency.

  • •

    Distribution of callosal-to-cortex effective and structural connectivities aligned.

Keywords: Corpus callosum, Axono-cortical evoked potentials, Effective connectivity, Structural connectivity, Electrocorticography, Intracranial electroencephalography, Functional brain mapping

Abstract

Objective

To demonstrate the role of the corpus callosum in interhemispheric effective connectivity and investigate the distribution of the connectivity originating from it using axono-cortical evoked potentials.

Methods

A 14-year-old girl with drug-resistant focal epilepsy underwent total callosotomy. Intraoperatively, we placed four subdural strip electrode contacts on the corpus callosum and eight on each hemisphere. We applied single-pulse electrical stimulation to eight pairs of contacts placed on the corpus callosum and cerebral cortex, recording axono-cortical, cortico-axonal, and cortico-cortical evoked potentials. Propagation latencies and anatomical distributions were determined based on the first negative deflection within 10–50 ms.

Results

Stimulation of the rostral to the anterior midbody elicited responses in bilateral anterior premotor cortices. The anterior to posterior midbody stimulation elicited responses in more posterior premotor cortices. The sum of latencies from the corpus callosum to each hemisphere (23.5 + 21.75 = 45.25 ms) approximated the interhemispheric neural propagation latency (44.5 ms). No significant responses were observed within the corpus callosum.

Conclusion

The corpus callosum mediated effective connectivity between homologous cortices aligned along the anterior–posterior axis, consistent with known structural connectivity.

Significance

This study provides the first direct neurophysiological evidence of the contribution of the corpus callosum to interhemispheric effective connectivity, highlighting its structural–functional correspondence and limitations in generating local field potentials.

1. Introduction

The corpus callosum is the largest interhemispheric commissure (van der Knaap and van der Ham, 2011). It connects homologous cortical regions and participates in primary and higher-order physiological functions (Bloom and Hynd, 2005). In addition, the corpus callosum is a critical pathway for the interhemispheric spread of epileptic activity, and callosotomy is an established palliative surgery for epilepsy (Asadi-Pooya et al., 2008). Fiber dissection and diffusion tensor imaging (DTI) studies have delineated the connection between the corpus callosum and the cortex (Shah et al., 2021, Wang et al., 2021). These approaches are limited to structural perspectives, and to our knowledge, no studies have directly demonstrated the involvement of the corpus callosum in interhemispheric effective connectivity or investigated the distribution of effective connectivity originating from it.

Cortico-cortical evoked potentials (CCEPs) and axono-cortical evoked potentials (ACEPs) are well-established neurophysiological tools for inferring effective connectivity (i.e., causal influence) between distinct cortical regions or between axonal and cortical regions (Yamao et al., 2014, Matsumoto et al., 2017). By delivering a single-pulse electrical stimulation to pairs of electrode contacts, the first negative deflection within 11–50 ms post-stimulus (i.e., N1) reflects a neural response induced by the single-axonal propagation from a given stimulus site (Matsumoto et al., 2017, Mitsuhashi et al., 2021). In a previous study, the stimulation of the human corpus callosum elicited a positive–negative biphasic potential in both hemispheres (Ono et al., 2002). Other studies showed that the CCEPs between both hemispheres decreased after callosotomy (Lehner et al., 2019, Kamada et al., 2020). These findings, however, provide only indirect evidence for the involvement of the corpus callosum in interhemispheric neural propagation. Thus, we aimed to demonstrate the role of the corpus callosum in interhemispheric effective connectivity and investigate the distribution of the connectivity originating from it using ACEPs and CCEPs.

To provide direct evidence, we tested two hypotheses in this study by delivering a single-pulse electrical stimulation directly to the corpus callosum and recording evoked cortical responses using intracranial electroencephalography (EEG).

  • Hypothesis 1: The sum of neural propagation latencies from the corpus callosum to each hemisphere approximates the latency of interhemispheric CCEPs, reflecting the time required for single-axonal propagations through callosal fibers.

  • Hypothesis 2: The stimulation of the corpus callosum elicits evoked potentials in the homologous cortical areas of both hemispheres corresponding to the anterior-posterior direction.

These hypotheses were based on previous studies demonstrating that most of the N1 peak latency is attributed to the time required for a single-axonal propagation, as latency increases with the length of the white matter pathway. The synaptic delay is short (Matsumoto et al., 2017, Mitsuhashi et al., 2021). Previous DTI studies demonstrated that the corpus callosum connects homologous cortices (Shah et al., 2021, Wang et al., 2021).

2. Methods

2.1. Case presentation

The patient was a right-handed 14-year-old girl with drug-resistant focal epilepsy. She was born on the 25th week of gestation with a birth weight of 608 g. Since birth, she presented with lissencephaly predominantly involving the bilateral parietal, occipital, and temporal lobes. She developed epileptic spasms and tonic seizures at the age of 9 years. Levetiracetam was initiated, followed by add-on therapy with topiramate. Her seizures were primarily epileptic spasms and remained drug-resistant, with daily episodes persisting before surgery. Magnetic resonance imaging showed lissencephaly and subcortical band heterotopia (Fig. 1A). In addition, 18F-fluorodeoxyglucose positron emission tomography demonstrated hypometabolism corresponding to areas of cortical malformation. Scalp EEG showed frequent bilaterally synchronous spike and wave discharges with maximal amplitude in the bilateral central and parietal regions. At 14 years old, the Suzuki–Binet Intelligence Scale revealed her developmental age to be 4 years and 10 months.

Fig. 1.

Fig. 1

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Magnetic resonance imaging findings and anatomical locations of subdural electrode contacts. (A) T1-weighted axial images. The bilateral temporal, occipital, and parietal lobes showed reduced gyration, cerebral cortical thickening, and subcortical band heterotopia. (B) The green spheres denote the locations of subdural electrode contact sites. Contacts were labeled sequentially from the ventral side: C1–C4 for the corpus callosum, R1–R8 for the right hemisphere cortex, and L1–L8 for the left hemisphere cortex.

She underwent a total corpus callosotomy under general anesthesia with propofol to alleviate the epileptic seizures. We opened the interhemispheric fissure and exposed the corpus callosum. Furthermore, we recorded intracranial EEG and measured ACEPs and CCEPs before callosotomy, as mentioned below. We completed the surgical procedures without complications. After the surgery, the patient developed mutism consistent with disconnection syndrome, which improved gradually. At 3 years and 10 months after surgery, she had weekly epileptic spasms classified as International League Against Epilepsy outcome class 4.

We obtained written informed consent from the patient’s parents. The Juntendo University Institutional Review Board approved the present study.

(A) T1-weighted axial images. The bilateral temporal, occipital, and parietal lobes showed reduced gyration, cerebral cortical thickening, and subcortical band heterotopia. (B) The green spheres denote the locations of subdural electrode contact sites. Contacts were labeled sequentially from the ventral side: C1–C4 for the corpus callosum, R1–R8 for the right hemisphere cortex, and L1–L8 for the left hemisphere cortex.

2.2. Intracranial electrode placement and EEG recording

We placed subdural platinum strip electrode contacts (Unique Medical, Tokyo, Japan) in the anterior-posterior direction: four contacts were placed on the corpus callosum (5 mm center-to-center distance; 1.5 mm diameter exposed), and eight were placed on each of the left and right hemispheres (10 mm center-to-center distance; 5 mm diameter exposed; Fig. 1B). The contacts were labeled sequentially from the ventral side: C1–C4 for the corpus callosum, R1-R8 for the right hemisphere cortex, and L1–L8 for the left hemisphere cortex. All contacts were covered with neurosurgical cotton putty to prevent displacement. We used a neuronavigation system (StealthStation S7®, Medtronic, Minnesota, USA) to determine the contact locations. Intracranial EEG recordings were obtained using a Nihon Kohden Neurofax EEG-1200 Digital System (Nihon Kohden, Tokyo, Japan) at a sampling frequency of 2000 Hz and an amplifier bandpass of 0.016–600 Hz. During EEG recording, the patient was managed with total intravenous anesthesia with propofol, and the bispectral index was maintained between 40 and 50.

2.3. Single-pulse electrical stimulation

As part of clinical management, during intraoperative monitoring, we delivered trains of electrical stimuli to eight pairs of electrode contacts (C1–C2, C3–C4, R1–R2, R4–R5, R7–R8, L1–L2, L4–L5, and L7–L8) at a frequency of 1 Hz for 50 s. Each electrical stimulus comprised a square-wave pulse of 0.3 ms duration, 8 mA intensity, and biphasic polarity (Neuromaster MEE-1232; Nihon Kohden, Tokyo, Japan) (Mitsuhashi et al., 2020, 2021). During each stimulation, cortical activity was simultaneously recorded from all other electrode contacts. No adverse effects, such as afterdischarges, were noted.

2.4. ACEP and CCEP quantification

Intracranial EEG signals were re-referenced to a common average reference (Sinai et al., 2005, Mitsuhashi et al., 2020, 2021). We excluded channels within 3 cm of the midpoint between the stimulus contacts (Silverstein et al., 2020, Mitsuhashi et al., 2020, 2021). In addition, we segmented the EEG signals into 1,000-ms epochs time-locked to stimulus onset. Baseline correction was performed by subtracting the mean voltage of the pre-stimulus period (−200 ms to −50 ms) from each data point. Subsequently, baseline-corrected data were averaged across trials to improve the signal-to-noise ratio. Evoked voltage deflections exceeding 5 standard deviations above the baseline period were considered evidence of axono-cortical or cortico-cortical connectivity (Trebaul et al., 2018, Silverstein et al., 2020).

We defined a neural propagation latency as the peak latency of the N1 within a 10–50 ms post-stimulus (Silverstein et al., 2020, Mitsuhashi et al., 2021). We started the N1 window at 10 ms to minimize potential stimulation artifact contamination (Conner et al., 2011, Matsumoto et al., 2017, Silverstein et al., 2020). To ensure validity, the peak detection results were independently reviewed and confirmed by two board-certified epileptologists (T.M. and Y.I.) to minimize the risk of misinterpreting artifacts as true ACEPs or CCEPs. We defined the coordinates of the contacts using the Right, Anterior, Superior coordinate system along the anterior commissure-posterior commissure line. We calculated the distance between the coordinates of the stimulus site (the midpoint of the pair of stimulated contacts) and the contacts that showed evoked potentials in the anterior-posterior direction.

2.5. Data and code availability

All intracranial EEG data, as well as the Matlab-based code used in this study, are available upon request to the corresponding author.

3. Results

Contact C1 was placed on the rostral body of the corpus callosum, contacts C2–C3 were placed on the anterior midbody, and contact C4 was placed on the posterior midbody (Fig. 1B) (Witelson, 1989, Hofer and Frahm, 2006). In both hemispheres, contacts R1–R4 and L1–L4 were placed on the premotor cortex, R5–R6 and L5–L6 were on the primary motor cortex, and R7–R8 and L7–L8 were placed on the primary somatosensory cortex.

Single-pulse electrical stimulation elicited ACEPs and CCEPs. Fig. 2 illustrates an example of ACEP waveforms evoked by stimulation of the C3–C4 electrode contacts. The stimulation of contacts C1–C2 elicited evoked potentials at contacts L2–L3 and R2–R4 (Fig. 3). The stimulation of contacts C3–C4 elicited responses at L3–L4 and R3-R4. Stimulation in either hemisphere elicited evoked potentials in the homologous region of the contralateral hemisphere. The corpus callosum did not show significant evoked potentials. The anteroposterior distance along the anterior commissure-posterior commissure line between the stimulus site (midpoint of the stimulus contact pair) and the contact with evoked potentials was 8.77 mm (median; interquartile range [IQR]: 5.38–14.86).

Fig. 2.

Fig. 2

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Example of axono-cortical evoked potentials (ACEPs). The figure shows z-score–normalized waveforms of ACEPs evoked by stimulation of the C3–C4 electrode contacts located on the anterior–posterior midbody of the corpus callosum. Colored circles on the central cortical surface indicate the locations of electrode contacts. In each waveform plot, the black vertical line represents the time of stimulation (0 ms), the red line indicates 10 ms, and the blue line indicates 50 ms. Stimulation was delivered at the magenta-colored contacts (C3 and C4), and significant N1 components exceeding a z-score of 5 between 10 and 50 ms after stimulation were observed at the red contacts (L3, L4, R3, and R4), which were located on the premotor cortices.

Fig. 3.

Fig. 3

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Summary of axono-cortical and cortico-cortical evoked potentials. C1–C4 are electrode contacts placed on the corpus callosum; R1–R8 and L1–L8 are contacts placed on the cerebral cortices of the right and left hemispheres, respectively. The green arrows indicate effective connectivity from the corpus callosum to both hemispheres. The blue arrows denote effective connectivity from the left hemisphere to the right hemisphere. The red arrows represent effective connectivity from the right hemisphere to the left hemisphere. The arrow thickness reflects the latency of evoked potentials, with thick arrows representing short latencies. CC: Corpus callosum.

The latencies of the evoked potentials elicited by the stimulation of the corpus callosum were 23.5 (IQR: 21.25–24.125) and 21.75 (IQR: 20.5–22.25) ms in the right and left hemispheres, respectively. The latencies of evoked potentials elicited by cortical stimulation were 44.5 (IQR: 43.5–45.0) and 46.0 (IQR: 41.875–49.5) ms for right-to-left and left-to-right propagations, respectively.

The figure shows z-score–normalized waveforms of ACEPs evoked by stimulation of the C3–C4 electrode contacts located on the anterior–posterior midbody of the corpus callosum. Colored circles on the central cortical surface indicate the locations of electrode contacts. In each waveform plot, the black vertical line represents the time of stimulation (0 ms), the red line indicates 10 ms, and the blue line indicates 50 ms. Stimulation was delivered at the magenta-colored contacts (C3 and C4), and significant N1 components exceeding a z-score of 5 between 10 and 50 ms after stimulation were observed at the red contacts (L3, L4, R3, and R4), which were located on the premotor cortices.

C1–C4 are electrode contacts placed on the corpus callosum; R1–R8 and L1–L8 are contacts placed on the cerebral cortices of the right and left hemispheres, respectively. The green arrows indicate effective connectivity from the corpus callosum to both hemispheres. The blue arrows denote effective connectivity from the left hemisphere to the right hemisphere. The red arrows represent effective connectivity from the right hemisphere to the left hemisphere. The arrow thickness reflects the latency of evoked potentials, with thick arrows representing short latencies. CC: Corpus callosum.

4. Discussion

4.1. Summary of the findings

This is the first study to demonstrate the distribution of axono-cortical evoked potentials from the human corpus callosum to both cerebral hemispheres through direct stimulation. The stimulation of the corpus callosum elicited evoked potentials in the homologous cortical areas of both hemispheres corresponding to the anterior-posterior direction. The sum of neural propagation latencies from the corpus callosum to each hemisphere approximated the latency of interhemispheric neural propagation. No significant evoked potentials were observed within the corpus callosum.

4.2. Contribution of the corpus callosum to the interhemispheric neural propagation

Our findings support the notion that the corpus callosum is the principal pathway for the propagation of CCEPs between both hemispheres. This study demonstrated that the sum of the evoked potential latencies recorded in the right and left hemispheres following callosal stimulation closely approximated the latency of interhemispheric neural propagation. The N1 component of the ACEP and CCEP reflects monosynaptic, direct axono-cortical and cortico-cortical propagation via white matter tracts. Previous studies have considered the synaptic delay to be approximately 0.5–1.1 ms (Taschenberger and von Gersdorff, 2000, Feldmeyer et al., 2006), which is considerably smaller than the observed latencies. Thus, previous studies assumed that the N1 latency primarily reflects the time required for action potentials to travel along axons (Matsumoto et al., 2012, Yamao et al., 2014, Mitsuhashi et al., 2021). A previous axono-cortical evoked potentials study demonstrated that the sum of latencies recorded in Broca’s and Wernicke’s areas following the stimulation of the arcuate fasciculus approximated the latency of neural propagation between these two language areas (Yamao et al., 2014). The authors concluded that these findings provided direct evidence that the arcuate fasciculus constitutes the propagation pathway between Broca’s and Wernicke’s areas. Consistent with this consideration, our results support the role of the corpus callosum in mediating interhemispheric neural propagation. However, previous studies have also suggested that epileptogenicity can alter synaptic transmission dynamics, impairing the temporal precision of excitatory–inhibitory interactions and thereby increasing synaptic delay (Bonansco and Fuenzalida, 2016). Further investigations, including data from non-epileptogenic regions, may therefore be necessary to confirm the plausibility of this interpretation.

4.3. Distribution of effective connectivity from the corpus callosum

Our findings validate the close relationship between effective and structural connectivities in the human brain. Previous studies suggested that effective connectivity depends on the structural architecture of white matter tracts (Sokolov et al., 2019). In the present study, the distribution of effective connectivity originating from the corpus callosum was consistent with the structural networks delineated in previous DTI studies. The stimulation of the rostral body to the anterior midbody (C1–C2) elicited evoked potentials in the anterior portion of the bilateral premotor cortex. The stimulation of the anterior to posterior midbody (C3–C4) elicited responses in the posterior portion of the bilateral premotor cortex. A previous DTI study showed that callosal fibers originating from the rostral body to the anterior midbody predominantly project to the premotor and supplementary motor areas, and those from the posterior midbody project to the primary motor cortex (Hofer and Frahm, 2006). The agreement between the distribution of effective connectivity observed in the present study and the structural connectivity reported in previous studies supports the notion that effective connectivity depends on the structural architecture.

4.4. Activity of the corpus callosum

Detecting evoked potentials within the corpus callosum may be challenging. In the present study, the stimulation of the cerebral cortex elicited evoked potentials in the contralateral homotopic cortex; however, no significant signal deflections were observed within the corpus callosum, which is presumed to mediate CCEP propagation. The corpus callosum primarily comprises myelinated axons originating from pyramidal neurons (Barbaresi et al., 2024). Axonal potentials are considerably weaker than cortical activity, and signal deflections in the white matter are usually dominated by volume-conducted activity from adjacent cortical sources (Mercier et al., 2017). In addition, the corpus callosum contains intracallosal neurons (Barbaresi et al., 2024), which project to and receive projections from the cerebral cortex. The early N1 component is believed to reflect excitatory postsynaptic potentials on pyramidal neurons (Bruyns-Haylett et al., 2017); however, N1 responses are absent. One possible explanation is that the number of intracallosal neurons is insufficient to generate detectable potentials. Further studies involving more sensitive recording techniques are warranted.

4.5. Methodological considerations

4.5.1. Influence of structural abnormalities, epileptogenicity, and anesthesia on effective connectivity

This study reports a single case. Therefore, it is difficult to determine the extent to which factors such as the structural abnormalities associated with lissencephaly, epileptogenicity, or anesthesia influenced the observed effective connectivity. Further investigations involving a larger cohort are needed to generalize the present findings.

In the present study, the latency of interhemispheric neural propagation was longer than that previously reported. The latency of neural propagation from the right to the left hemisphere was 44.5 ms (IQR: 43.5–45.0), and that from the left to the right hemisphere was 46.0 ms (IQR: 41.875–49.5). In contrast, previous studies using CCEPs or transcranial magnetic stimulation (TMS) have reported interhemispheric propagation latencies of approximately 10–30 ms. For instance, a cortico-cortical spectral response study using stereoelectroencephalography demonstrated that the early peak corresponding to the N1 component had a mean latency of 21.9 ms (Mitsuhashi et al., 2021). Other CCEP studies using electrocorticography reported N1 latencies of 25.4–39.4 ms or 28.9 ms for neural propagation between bilateral motor or sensory cortices (Terada et al., 2008, Terada et al., 2012). TMS studies have also shown fast transcallosal transmission in healthy individuals, with interhemispheric conduction times of about 13 ms based on the ipsilateral silent period (Meyer et al., 1995) and 22 ± 2 ms for contralateral cortical responses recorded with EEG (Komssi et al., 2002). By contrast, several studies have reported prolonged neural propagation latency in pathological networks. A CCEP study in patients with brain tumors demonstrated that alterations in white-matter microstructure—such as reduced axonal diameter, demyelination, and disorganized fiber orientation—can reduce conduction velocity and prolong neuronal propagation (Filipiak et al., 2021). Another CCEP study in patients with drug-resistant focal epilepsy showed prolonged CCEP latency within epileptogenic networks, likely due to microstructural and functional alterations including impaired axonal conduction and synaptic reorganization (Feys et al., 2024). Similarly, A TMS study in patients with multiple sclerosis reported significantly longer ipsilateral silent period latencies (41.25 ms) compared with controls (35.47 ms), reflecting dysfunction of interhemispheric inhibitory fibers connecting the primary motor cortices (Llufriu et al., 2012). Taken together, these findings suggest that microstructural and functional alterations related to lissencephaly and epileptogenicity in the present case may have contributed to the prolonged interhemispheric propagation latency.

On the other hand, the effect of propofol anesthesia on interhemispheric propagation latency is likely to be minimal. During CCEP recording, the patient was managed with total intravenous anesthesia using propofol. Yamao et al. reported that although N1 amplitude increased by an average of 25.8 % after emergence from propofol anesthesia, there was no significant change in N1 latency (Yamao et al., 2021).

4.5.2. Possibility of N1 components with latencies shorter than 10 ms

In this study, the N1 analysis window was set to start at 10 ms to minimize potential contamination by stimulation artifacts. In an electrocorticography study, stimulation artifacts were reported to contaminate the signal for approximately 5–10 ms after stimulation (Matsumoto et al., 2004). Similarly, in stereoelectroencephalography recordings, stimulation artifacts have been reported to last between 1 and 6 ms (Trebaul et al., 2016). Another stereoelectroencephalography study visually confirmed across all CCEP trials that the earliest clearly distinguishable N1 component appeared after the sharp transient stimulation artifact, with the earliest onset at 11 ms (Huang et al., 2023). In the present study as well, the stimulation artifact was confined to < 10 ms, as shown in Fig. 2. Based on these previous findings, signals within the first 10 ms after stimulation are generally considered to be at risk of artifact contamination; therefore, the N1 component is conventionally defined from 10 ms onward (Matsumoto et al., 2004, Matsumoto et al., 2017, Silverstein et al., 2020, Mitsuhashi et al., 2020, 2021).

However, Matsumoto et al. also noted that stimulation artifacts occurring within 5–10 ms may obscure early monosynaptic propagation through large-diameter fibers, and that responses observed after 10 ms might predominantly reflect activity transmitted through smaller-diameter fibers (Matsumoto et al., 2004). Given this background, further methodological studies are warranted to accumulate additional cases and to visually discriminate stimulation artifacts from genuine N1 responses. Such investigations could clarify how frequently clearly separable N1 components emerge earlier than 10 ms and determine whether these early responses represent fast-conducting monosynaptic activity that is typically masked by stimulation artifacts.

Data availability

All intracranial EEG data, as well as the Matlab-based code used in the present study, are available upon request to the corresponding author.

Funding sources

This work was supported by JSPS KAKENHI Grant Number 22K15648 to TM, AMED Grant Number JP24wm0625207 to YI, and MHLW Research program on rare and intractable diseases Grant Numbers JPMH23FC1013 and JPMH20FC1039.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Glossary

CCEPs

cortico-cortical evoked potentials

DTI

diffusion tensor imaging

EEG

electroencephalography

IQR

interquartile range

TMS

transcranial magnetic stimulation

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All intracranial EEG data, as well as the Matlab-based code used in this study, are available upon request to the corresponding author.

All intracranial EEG data, as well as the Matlab-based code used in the present study, are available upon request to the corresponding author.

Articles from Clinical Neurophysiology Practice are provided here courtesy of Elsevier

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