The biological substrate deals with the underlying physiological process which is used as a measure of functionality by each of the techniques. The biological substrate that is measured dictates whether a technique gives direct access to functionality (i.e. measures electrical activity of neurons) or by proxy (i.e. metabolisms or blood dynamics) through the so-called process of neurovascular coupling (NVC).
As neurons activate, they produce electrical activity known as action potentials through passive and/or active exchanges of ions across the neuron’s cell membrane. These electrical signals are measurable on a single-neuron level, as well as of groups of neurons (local field potentials) or full brain regions, as is the case for electro-encephalography (EEG). Detecting this electrical activity is a direct measure of neuronal activity and functional activation.
Conversely, administering electrical current to regions of interest to produce or interrupt functions can be used in an intra-operative setting to form an in-vivo cartography of the brain. One of the most wide-spread applications of the latter involves electrocortical stimulation mapping (ESM) during awake surgery (28).
The term Neurovascular Coupling (NVC) describes the mechanisms responsible for linking (electrical) neuronal activity to corresponding changes in blood dynamics (11,12). These mechanisms consist of intricate interplays between many different components including neurons, astrocytes, pericytes, and smooth muscle cells (SMC) of neighboring arterioles (13). With an increase in activation of neurons, energy consumption increases, which needs to be metabolized locally from glucose and oxygen supplied by blood through local vessels. In response to transient neural activity nearby vessels dilate, substantially increasing Cerebral Blood Flow (CBF) and Cerebral Blood Volume (CBV), known as ‘functional hyperemia’. Although the exact physiological processes underlying this coupling remain to be elucidated, many functional techniques use the changes in metabolism or blood dynamics as a proxy for the actual electrical neuronal activity, assuming that the increase in blood flow matches the metabolic need of the tissue (14). This means that temporally, the CBV impulse response function is thought to start at 0.3 s and peak at 1 s in response to ultrashort stimuli (300 μs), which is much slower than the underlying electrical activity (16). Spatially, the resolution of e.g. sensory-evoked CBV response can go down to one cortical column (∼100 μm) (16,17).
With the term ‘blood dynamics’ we encompass the range of vascular-related changes which correspond to the increase in energy consumption produced by activated neurons. These changes include an increase in CBF, changes in vessel diameter (dilatation/constriction) as well as changes in Cerebral Blood Volume (CBV) (14). In contrast to the electrical activity, which is a direct measure of neuronal activation, blood dynamics serve as a proxy, with significant latencies between neuronal activity and hemodynamic response. Many of the efforts within blood-dynamics-based functional techniques, such as fMRI, focus on understanding these response characteristics using so-called hemodynamic response function (HRF), applying this knowledge to improve statistical models used for identification of active regions (29). The physiological processes underlying this response remain unelucidated, especially in light of the potential neurovascular variances or even neurovascular decoupling which might be present in neurological disease.
In addition to the blood dynamics, objectifying the metabolic processes coupled to the neuronal activation can also provide functional information. Positron Emission Tomography (PET), for example, makes use of radioactively labeled chemicals which have a metabolic role (30). An example of such a radiotracers is 18F-FDG, which labels glucose as it is metabolized in the brain. Detection of this radioactively-labeled glucose, can indicate a regional increase in energy consumption – and by definition – a regional functional response to for example a functional task. Metabolic techniques such as PET are also used to visualize generalized brain metabolism, which can be an indication of pathologies such as Parkinson’s or Alzheimer’s disease (31).