Techniques Used in Humans 1 Microstructure

In humans, methods for direct investigation of axon connectivity are restricted to noninvasive approaches. At the microlevel of individual axons, morphological techniques are limited to a small number of methods that can be applied in postmortem tissue or surgical biopsies. First, the classical Golgi stain can demonstrate aspects of axon structure, especially in young tissue, although the identity and full conformation of long axons are difficult to establish. Second, degeneration methods can be used with moderate success. In these methods (the precursors to the more physiological modern methods, which utilize axon transport of injected tracers), tissue is treated in a series of solutions that stain fragments of axons degenerating as a result of damage related to stroke or some other traumatic process. Third, some labeling can be achieved by intracellular fills of neurons or axons in tissue slices in vitro, but this technique is necessarily restricted to shorter connections or only incomplete portions of longer connections. Fourth, one class of tracers, lipophilic carbocyanine dyes (Dil and DiO), has been found to bind to the plasmalemma, even in postmortem tissue, and transport by diffusion. These tracers produce high-resolution, Golgi-like labeling, but only within a distance of 2-5 mm of the injection spot. Thus, although evidence supports the applicability of animal data to the human brain, there is a serious need for new techniques that might allow direct investigation of fine axon connectivity in human tissue. Finally, there is an increasing number of antibodies available for immu-nohistological investigation of neural structures. Many of these (e.g., antibodies against peptides, calcium binding proteins, transmitters, receptors, or cytoskeletal elements such as neurofilaments) can successfully be used in human biopsy or postmortem tissue. Most of these markers, however, are for cellular or subcellular components and not long-distance axons.

2. Macrostructure

In humans, long-distance cortical connections have been easier to investigate at the macrolevel of axon bundles or tracts. Major tracts include cortical com-missural fibers crossing in the corpus callosum to the contralateral hemisphere, projection fibers to and from subcortical nuclei (such as the thalamus, basal ganglia, and colliculi), and ipsilateral cortical association fibers.

The various white matter tracts were grossly identified more than 100 years ago by methods such as blunt dissection or myelin staining subsequent to localized lesions. These techniques were successfully used in identifying pathways such as the uncinate or arcuate fasciculi (respectively linking temporofrontal or occi-pito- and parietofrontal fields) or the cingulum (frontoparahippocampal) bundle.

Recently, specific pathways or tracts have been visualized in their stem portion by diffusion-weighted magnetic resonance (dwMR; "stem" refers to the compact coherent middle portion of an axon bundle, contrasted with its more fanned-out proximal or distal extremes). This technique detects the diffusivity of water molecules in three dimensions. For oriented tissue, such as fiber bundles, this diffusivity tends to be anisotrophic. Images of the location, size, and trajectory of major white matter bundles acquired by dwMR accord well with earlier postmortem studies based on histological myelin stains.

Visualization of white mater bundles in humans is important for issues of both clinical and basic science. In clinical neurology, there are many conditions, such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and traumatic head injury, that lead to pathological alterations in white matter tracts. Imaging techniques allow improved in vivo diagnosis and analysis of these conditions. These techniques also offer immense promise as a probe of normal connectivity in the human brain.

3. Electrophysiology

Electrophysiological studies of axon organization in humans are also highly constrained by the need for noninvasiveness. Considerable information, however, is available from methods such as evoked potentials, which can record populational responses through the skull. Evoked potential recordings can be in response to presented stimuli or, recently, to transcranial magnetic stimulation. Electroencephalogram coherence analysis is another method for studying connectivity in both the human brain and the animal brain.

The need for precise localization during neurosur-gical procedures provides another source of data. Surface electrodes are routinely used to map regions involved in cortical language processing, and in certain conditions depth electrodes may be placed in structures such as the amygdala, hippocampus, or sub-stantia nigra.

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