Neuronal Units Linked to Microvascular Modules in Cerebral Cortex: Response Elements for Imaging the Brain

0 Sechenov Institute of Evolutionary Physiology and Biochemistry, Academy of Sciences of Russia , St Petersburg, 194223 Russia 1 'Department of Neurology and Neurological Surgery and department of Cell Biology and Physiology, Washington University School of Medicine , St Louis, MO 63110 2 Notes C. Duncan and E. Valois prepared and imaged the specimen in Figure 9. Supported by NIH grants NS 07057 (M.H. and L.W.) , NS 17763, NS 28781, HL 41075, TW 00047 , the McDonnell Center for Studies of Higher Brain Function, an award from the Spastic Paralysis Foundation of the Illinois-Eastern Iowa District of the Kiwanis International and a Howard Hughes Fellowship (G.E.L.). Neurological Surgery , Box 8057 , Washington University School of Medicine , 660 South Euclid Avenue, St Louis, MO 63110 , USA How neuronal activity changes cerebral blood flow is of biological and practical importance. The rodent whisker-barrel system has special merits as a model for studies of changes in local cerebral blood flow (LCBF). Stimulus-evoked changes in neural firing and Intrinsic signals' recorded through a cranial window were used to define regions of interest for repeated flow measurements. Whisker-activated changes in flow were measured with intravascular markers at the pia. LCBF changes were always prompt and localized over the appropriate barrel. Stimulus-related changes in parenchymal flow monitored continuously with Hz electrodes recorded short latency flow changes initiated in middle cortical layers. Activation that increased flow to particular barrels often led to reduced flow to adjacent cortex. Dye was injected into single penetrating arterioles from the pia of the fixed brain and injected into arterioles in slices of cortex where barrels were evident without stains. Arteriolar and venular domains at the surface were not directly related to underlying barrels. Capillary tufts in layer IV were mainly coincident with barrels. The matching between a capillary plexus (a vascular module) and a barrel (a functional neuronal unit) is a spatial organization of neurons and blood vessels that optimizes local interactions between the two. The paths of communication probably include: neurons to neurons, neurons to glia, neurons to vessels, glia to vessels, vessels to vessels and vessels to brain. Matching a functional grouping of neurons with a vascular module is an elegant means of reducing the risk of embarrassment for energy-expensive neuronal activity (ion pumping) while minimizing energy spent for delivery of the energy (cardiac output). For imaging studies this organization sets biological limits to spatial, temporal and magnitude resolution. Reduced flow to nearby inactive cortex enhances local differences. - Introduction C. S. Roy and C. S. Sherrington began their classic paper (1890, p. 85) on changes in cerebral blood flow with the following observation: One marked characteristic of the literature dealing with the cerebral circulation is, we think, the contradictory nature of the results which have been obtained by different investigators. They observed changes in brain volume after electrical stimulation of the dog sciatic nerve. From experiments in which they used extracts containing metabolites from ischemic brain to mimic the evoked effect, they deduced the following mechanism (1890, p. 105): We conclude then, that the chemical products of cerebral metabolism contained in the lymph which bathes the walls of the arterioles of the brain can cause variations of the calibre of the cerebral vessels: that in this re-action the brain possesses an intrinsic mechanism by which its vascular supply can be This hypothesis, that cerebral blood flow changes in relation to neuronal activity, is the cornerstone of modern studies of an increasingly wide and interesting array of functions in the brain of the awake human (see Raichle, 1987). Kety and Schmidt (1945) ingeniously applied the Fick principal to measure global cerebral blood flow (CBF) to assay functional and disease-related specific CBF changes in awake humans (Kety, 1950). Initial studies disappointingly did not reveal significant global differences in CBF in mental tasks that were effortful, e.g. solving differential equations, and tasks that were effortless, e.g. sleep. These pioneering studies stimulated the development and application of new tools for the problem (Landau et al, 1955) which are now standard methods for investigation of regional cerebral metabolism and local cerebral blood flow (LCBF) (Sokoloff et al., \911; Sakurada etal, 1978). Investigators whose principal interests lay in the neurobiology of brain-specific connectivity, physiology and behavior quickly used them for investigating the 'functional anatomy' of integrated activity throughout the brain (e.g. Durham and Woolsey, 1977; Hubeletal, 1978). Metabolic and blood flow markers detected and rendered by positron emission tomography (PET; e.g. Raichle and Posner, 1994) and functional magnetic resonance imaging (fMRI; e.g. Sereno etal., 1995) offered a means to detect functional activity in the human brain. Blasdel and Salama (1986) and Grinvald and his colleagues (e.g. Grinvald et al, 1986; T'so et al, 1990) applied computer-based analysis to optical images of the brain surface recorded with sensitive cameras. Because signals reiated to changes in neural activity first from voltage-sensitive dyes and then from the brain itself are faint, these investigators averaged video sequences. The results were stunning for the twodimensional patterns of organization they revealed. Although movement artifacts from the pulse and respiration were carefully controlled, stimulus-related vessel changes which produced difference shadows or vessel 'artifacts' concerned both groups. Neuronal stimulation effects on directly observed cortical vessels emphasized the need for detailed studies of the functional and the anatomical relationship between neural activity, LCBF, cortical vessels and neuronal architecture. The rodent somatic sensorywhisker-barrel cortexoffered many significant practical advantages. The following summarizes our work on spatiotemporal changes in sensory-evoked LCBF and relates vessel patterns involved to known neuronal patterns and activities. For technical aspects of these studies, see the figure legends, Woolsey etal. (1996) and papers cited. The findings are of interest biologically and for imaging studies in humans and other animals since, 'the relationship between neuronal activity and local changes in blood flow or metabolism is largely unknown' (Naatanen et al., 1994). Whiskers and Barrels Large tactile hairs around the mouth are a common feature of many mammals. Early histologists described the substantial segregated innervation, intricate facial musculature and specialized structure of these hairs (Barker, 1901). The larger whiskers on the upper lip are organized in neat and predictable rows (Fig. 1), which in some species are actively whisked or (...truncated)