Complete section of the corpus callosum disrupts a massive component of interhemispheric anatomical connectivity. In the present case, we had the unique opportunity to obtain resting state fMRI data before and after this therapeutic intervention. This study is important because of the opportunity it offers to examine the relationship between the brain’s connectional anatomy and its large scale functional organization emerging from patterns of coherence in the spontaneous fluctuations of the fMRI BOLD signal.
While patterns of coherence in the fMRI BOLD signal characteristically show orderly relationships among areas consistent with known connectional anatomy, details regarding the role of anatomical connectivity are sparse. In the only study to date that directly addresses this question, Vincent et al (2007)
demonstrated that the correlation structure in the anesthetized monkey oculomotor system obtained from the fMRI BOLD signal corresponded exceptionally well with retrograde tracer studies of the connectional anatomy of that system. They further went on to show that patterns of coherence between peripheral and foveal V1 in the two hemispheres, areas of the brain of the monkey that have no direct connections, were likely sustained by polysynaptic pathways that respected visual retinotopy along the eccentricity axis. A clear test of the inferences to be drawn from these observations would be to interrupt the putative anatomical connections and demonstrate an effect on the functional connectivity demonstrated with fMRI BOLD imaging. The present observations serve that purpose.
Consistent with the hypothesis that the apparent functional connectivity demonstrated by fMRI BOLD imaging is related to the anatomical connectivity of the human brain, callosotomy dramatically reduced the shared variance in the BOLD signal between the two cerebral hemispheres. Over 88% of the shared variance was eliminated. We believe that this observation contributes significantly to mounting evidence favoring the neurobiological relevance of the spontaneous fluctuations in the fMRI BOLD.
Examining our results in more detail reveals striking loss of interhemispheric cortical coherence at the systems level with the possible exception of the somatomotor system, hippocampal formation, and the thalamus. With regard to the somatomotor system, the seed used for this study corresponds to the hand motor region. Anatomic tracer studies in multiple species have shown limited callosal connections between corresponding distal limb motor cortices. That somatomotor synchrony is less affected by callosotomy is consistent with the existence of these “callosal holes” (Myers, 1965
; Pappas and Strick, 1981
; Killackey et al., 1983
). Conversely, persistent somatomotor correlations after callosotomy may be due to synchronous ascending information transmitted via somatomotor thalamocortical projections.
Likewise, interhemispheric hippocampal and amygdala correlations were partially retained following callosotomy, specifically in the contralateral amygdala and anterior lateral temporal lobe. (, Supplementary Figure 1
). The known connectivity of anterior and mesial portions of the right and left temporal lobes via the anterior commissure may explain this retained post-callosotomy coherence. Anterograde autoradiographic tracing in the macaque demonstrates differential connectivity of the temporal lobes from rostral to caudal. The corpus callosum receives its most significant projections from the caudal third of the temporal lobe, with progressively fewer fibers found rostrally. The anterior commissure receives and transmits fibers from the entire temporal lobe, but is biased towards the rostral third of the temporal isocortex, including the temporal pole, superior and inferior temporal gyri, the parahippocampal gyrus, orbitofrontal cortex, prepyriform cortex and the amygdala (Demeter et al., 1990
; Schmahmann and D.N., 2006
). In addition, studies in both animals and humans have demonstrated the amygdala’s clear role in affective memory modulation (McGaugh et al., 1996
; Cahill and McGaugh, 1998
; Hamann et al., 1999
) via reciprocal projections to the ipsilateral anterior hippocampus (Pitkanen et al., 2000
) (Amaral et al., 1992
) and caudate nucleus (Packard and Wingard, 2004
More recent work using resting functional connectivity MRI in humans has demonstrated distinct pathways for the head (anterior lateral temporal cortex, entorhinal/perirhinal cortex) and body (inferior parietal lobule, retrosplenial cortex, posterior cingulate, and ventral medial prefrontal cortex) of the hippocampus (Kahn et al., 2008
). Residual interhemispheric coherence in the amygdalae and anterior lateral temporal lobes seen after callosotomy in both the anterior hippocampus and hippocampal body correlation maps (Supplementary Figure 1
) suggests that the anterior commissure may be an important mediator of interhemispheric transfer for the more rostral pathway.
Coherence between the left and right thalamus decreased just over 50%, suggesting that bilateral synchrony within the thalamus represents a contribution from callosal fibers to a portion of the shared variance between the cerebral cortex of one hemisphere and the contralateral thalamus plus a contribution likely emanating from afferent structures such as the brainstem reticular formation (Jones, 2007
Intrahemispheric patterns of functional connectivity remained following callosotomy in all systems. This observation is consistent with a large body of neuropsychological literature documenting independent functioning of each hemisphere in callosotomy patients (Devinsky and Laff, 2003
; Gazzaniga, 2005
). Our data are insufficient to assess the impact of a loss of interhemispheric coherence on a system such as the dorsal attention network (). However, future work combining imaging of the type presented here with detailed neuropsychological evaluation pre- and post-operatively could be most revealing in this regard.
Consistent with other published data (Kiviniemi et al., 2000
; Vincent et al., 2007
), the results of this investigation also demonstrate the presence of resting state functional connectivity in a child under general propofol anesthesia. This finding is of interest for two reasons. First, the persistence of coherent network synchrony suggests that resting state BOLD modulation represents a fundamental level of brain organization that transcends levels of arousal. Second, this observation suggests a possible future utility for resting functional connectivity analysis in younger children with surgically treatable epilepsy, specifically preoperative mapping of functional systems and postoperative evaluation where general anesthesia is required.
The patient's young age, developmental delay and history of epilepsy represent limitations of the present dataset. In addition, the data reported here may reflect an acute postoperative disconnection phenomenon and do not exclude the possibility of long-term reorganization and reconstitution of interhemispheric functional connectivity. Nonetheless, the clear loss of interhemispheric correlation with preservation of intrahemispheric networks is consistent with the view that the corpus callosum plays a major role in maintaining interhemispheric coherence of spontaneous BOLD fluctuations. These data provide unique information concerning the role of anatomic connectivity in the genesis of BOLD signal functional connectivity.
Recent publications have posited a significant role for non-neuronal factors (i.e., cardiac, respiratory, end tidal CO2 variations) in the genesis of BOLD signal correlations (Wise et al., 2004
; Birn et al., 2006
; Shmueli et al., 2007
). Our data suggest that this contribution is minor. In the present study the upper bound for such a contribution would be about 11%. However, given that signals from ventricles and white matter were removed from our data before analysis, it is likely that this contribution is even less.
Future work must seek to identify and implement strategies that selectively eliminate cardiac and respiratory contributions to the spontaneous fluctuations in the fMRI BOLD signal. In doing so we must be sensitive to the possibility that slow variations in cardiac and respiratory parameters might well have their origin within the brain. Thus, just as spontaneous variations in the fMRI BOLD signal contribute to variability in human behavior (Fox et al., 2007
), so also might variability in brain systems regulating cardiac and respiratory functions lead to variability in the functions themselves. This is a researchable question that deserves investigation.
Finally, we note that the data presented in this article are publicly available at http://www.brainscape.org/
along with software tools useful in their analysis.