HighlightsDetailed descriptions of connections comprising the cingulum bundle.Impact of cingulum bundle damage in rats, monkeys, and humans.Imaging evidence of cingulum abnormalities in multiple psychiatric conditions.Analyses of changing functions along the length of the cingulum.Contrasting effects of fornix and cingulum bundle damage on cognition.

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Human episodic memory is supported by networks of white matter tracts that connect frontal, temporal, and parietal regions. Degradation of white matter microstructure is increasingly recognized as a general mechanism of cognitive deterioration with aging. However, atrophy of gray matter regions also occurs and, to date, the potential role of specific white matter connections has been largely ignored. Changes to frontotemporal tracts may be important for the decline of episodic memory; while frontotemporal cooperation is known to be critical, the precise pathways of interaction are unknown. Diffusion-weighted MRI tractography was used to reconstruct three candidate fasciculi known to link components of memory networks: the fornix, the parahippocampal cingulum, and the uncinate fasciculus. Age-related changes in the microstructure of these tracts were investigated in 40 healthy older adults between the ages of 53 and 93 years. The relationships between aging, microstructure, and episodic memory were assessed for each individual tract. Age-related reductions of mean fractional anisotropy and/or increased mean diffusivity were found in all three tracts. However, age-related decline in recall was specifically associated with degradation of fornix microstructure, consistent with the view that this tract is important for episodic memory. In contrast, a decline in uncinate fasciculus microstructure was linked to impaired error monitoring in a visual object-location association task, echoing the effects of uncinate transection in monkeys. These results suggest that degradation of microstructure in the fornix and the uncinate fasciculus make critical but differential contributions to the mechanisms underlying age-related cognitive decline and subserve distinct components of memory.

Cognitive control, an important facet of human cognition, provides flexibility in response to varying behavioral demands. Previous work has focused on the role of prefrontal cortex, notably the anterior cingulate cortex. However, it is now clear that this is one node of a distributed cognitive network. In this emerging network view, structural connections are inherent elements, but their role has not been emphasized. Furthermore, lesion and functional imaging studies have contributed little knowledge about anatomical segregation, functional specialization, and behavioral importance of white matter connections. The relationship between cognitive control and microstructure of connections within the cingulum, a major white matter tract and conduit of projections to prefrontal sites, was probed in vivo in humans with diffusion MRI. Twenty healthy controls and 25 individuals with amnestic mild cognitive impairment (MCI), an early stage of age-associated cognitive deterioration, underwent cognitive testing, including several measures of cognitive control. For each individual, the anterior, middle, posterior, and parahippocampal portions of the cingulum bundle were reconstructed separately using deterministic tractography and anatomical landmarks. Microstructural variation in the left anterior cingulum was closely related to interindividual control based on verbal or symbolic rules. Errors in a task that involved maintenance of spatial rules were largely restricted to patients with MCI and were related, additionally, to right anterior cingulum microstructure. Cognitive control in MCI was also independently related to posterior parahippocampal connections. These results show how specific subpopulations of connections are critical in cognitive control and illustrate fine-grained anatomical specializations in the white matter infrastructure of this network.

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