During development, the healthy human brain constructs a host of large-scale, distributed, function-critical neural networks. Neurodegenerative diseases have been thought to target these systems, but this hypothesis has not been systematically tested in living humans. We used network-sensitive neuroimaging methods to show that five different neurodegenerative syndromes cause circumscribed atrophy within five distinct healthy human intrinsic functional connectivity networks. We further discovered a direct link between intrinsic connectivity and gray matter structure. Across healthy individuals, nodes within each functional network exhibited tightly correlated gray matter volumes. The findings suggest that human neural networks can be defined by synchronous baseline activity, a unified corticotrophic fate, and selective vulnerability to neurodegenerative illness. Future studies may clarify how these complex systems are assembled during development and undermined by disease.

Background: Behavioral variant frontotemporal dementia (bvFTD) strikes hardest at the frontal lobes, but the sites of earliest injury remain unclear.Objective: To determine atrophy patterns in distinct clinical stages of bvFTD, testing the hypothesis that the mildest stage is restricted to frontal paralimbic cortex.Design: A bvFTD cohort study.Setting: University hospital dementia clinic.Participants: Patients with bvFTD with Clinical Dementia Rating (CDR) scale scores of 0.5 (n=15), 1 (n=15), or 2 to 3 (n=15) age and sex matched to each other and to 45 healthy controls.Main Outcome Measures: Magnetic resonance voxel-based morphometry estimated gray matter and white matter atrophy at each disease stage compared with controls.Results: Patients with a CDR score of 0.5 had gray matter loss in frontal paralimbic cortices, but atrophy also involved a network of anterior cortical and subcortical regions. A CDR score of 1 showed more extensive frontal gray matter atrophy and white matter losses in corpus callosum and brainstem. A CDR score of 2 to 3 showed additional posterior insula, hippocampus, and parietal involvement, with white matter atrophy in presumed frontal projection fibers.Conclusions: Very mild bvFTD targets a specific subset of frontal and insular regions. More advanced disease affects white matter and posterior gray matter structures densely interconnected with the sites of earliest injury.

Behavioral variant frontotemporal dementia (bvFTD) disrupts our most human social and emotional functions. Early in the disease, patients show focal anterior cingulate cortex (ACC) and orbital frontoinsula (FI) degeneration, accentuated in the right hemisphere. The ACC and FI, though sometimes considered ancient in phylogeny, feature a large bipolar projection neuron, the von Economo neuron (VEN), which is found only in humans, apes, and selected whales-all large-brained mammals with complex social structures. In contrast to bvFTD, Alzheimer disease (AD) often spares social functioning, and the ACC and FI, until late in its course, damaging instead a posterior hippocampal-cingulo-temporal-parietal network involved in episodic memory retrieval. These divergent patterns of functional and regional impairment remain mysterious despite extensive molecular-level characterization of bvFTD and AD. In this report, we further develop the hypothesis that VENs drive the regional vulnerability pattern seen in bvFTD, citing recent evidence from functional imaging in healthy humans, and also structural imaging and quantitative neuropathology data from bvFTD and AD. Our most recent findings suggest that bvFTD and AD target distinct, anticorrelated intrinsic connectivity networks and that bvFTD-related VEN injury occurs throughout the ACC-FI network. We suggest that the regional and neuronal vulnerability patterns seen in bvFTD and AD underlie the divergent impact of these disorders on recently evolved social-emotional functions.

Most neurological lesion studies emphasize performance deficits that result from focal brain injury. Here, we describe striking gains of function in a patient with primary progressive aphasia, a degenerative disease of the human language network. During the decade before her language deficits arose, Anne Adams (AA), a lifelong scientist, developed an intense drive to produce visual art. Paintings from AA's artistic peak revealed her capacity to create expressive transmodal art, such as renderings of music in paint, which may have reflected an increased subjective relatedness among internal perceptual and conceptual images. AA became fascinated with Maurice Ravel, the French composer who also suffered from a progressive aphasia, and painted his best-known work, 'Boléro', by translating its musical elements into visual form. Later paintings, achieved when AA was nearly mute, moved towards increasing photographic realism, perhaps because visual representations came to dominate AA's mental landscape during this phase of her illness. Neuroimaging analyses revealed that, despite severe degeneration of left inferior frontal-insular, temporal and striatal regions, AA showed increased grey matter volume and hyperperfusion in right posterior neocortical areas implicated in heteromodal and polysensory integration. The findings suggest that structural and functional enhancements in non-dominant posterior neocortex may give rise to specific forms of visual creativity that can be liberated by dominant inferior frontal cortex injury.