Person:

Schmahmann, Jeremy

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

Pigmented orthochromatic leukodystrophy (POLD) and Hereditary diffuse leukoencephalopathy with spheroids HDLS are two adult onset leukodystrophies with neuroaxonal spheroids presenting with prominent neurobehavioral, cognitive, and motor symptoms. These are familial or sporadic disorders characterized by cerebral white matter degeneration including myelin and axonal loss, gliosis, macrophages, and axonal spheroids. We report clinical, neuroimaging and pathological correlations of four women ages 34–50 years with adult onset leukodystrophy. Their disease course ranged from 1.5–8 years. Three patients had progressive cognitive and behavioral changes whereas one had acute onset. Neuroimaging revealed white matter abnormalities characterized by symmetric, bilateral, T2 hyperintense and T1 hypointense MRI signal involving frontal lobe white matter in all patients. Extensive laboratory investigations were negative apart from abnormalities in some mitochondrial enzymes and immunologic parameters. Autopsies demonstrated severe leukodystrophy with myelin and axonal loss, axonal spheroids, and macrophages with early and severe frontal white matter involvement. The extent and degree of changes outside the frontal lobe appeared to correlate with disease duration. The prominent neurobehavioral deficits and frontal white matter disease provides clinical-pathologic support for association pathways linking distributed neural circuits subserving cognition. These observations lend further support to the notion that white matter disease alone can account for dementia.

Background: The cerebellum is a complex structure that can be affected by several congenital and acquired diseases leading to alteration of its function and neuronal circuits. Identifying the structural bases of cerebellar neuronal networks in humans in vivo may provide biomarkers for diagnosis and management of cerebellar diseases.
Objectives: To define the anatomy of intrinsic and extrinsic cerebellar circuits using high-angular resolution diffusion spectrum imaging (DSI). Methods: We acquired high-resolution structural MRI and DSI of the cerebellum in four healthy female subjects at 3T. DSI tractography based on a streamline algorithm was performed to identify the circuits connecting the cerebellar cortex with the deep cerebellar nuclei, selected brainstem nuclei, and the thalamus.
Results: Using in-vivo DSI in humans we were able to demonstrate the structure of the following cerebellar neuronal circuits: (1) connections of the inferior olivary nucleus with the cerebellar cortex, and with the deep cerebellar nuclei (2) connections between the cerebellar cortex and the deep cerebellar nuclei, (3) connections of the deep cerebellar nuclei conveyed in the superior (SCP), middle (MCP) and inferior (ICP) cerebellar peduncles, (4) complex intersections of fibers in the SCP, MCP and ICP, and (5) connections between the deep cerebellar nuclei and the red nucleus and the thalamus.
Conclusion: For the first time, we show that DSI tractography in humans in vivo is capable of revealing the structural bases of complex cerebellar networks. DSI thus appears to be a promising imaging method for characterizing anatomical disruptions that occur in cerebellar diseases, and for monitoring response to therapeutic interventions.