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follows blood oxygen changes induced by anesthetics … that alter metabolic demand of blood flow’.⁹⁴ Following Roy and Sherrington’ s insights, this immediately suggested that the BOLD signal in a particular volume of the brain should vary in proportion to the neurons in that volume that had been activated more or less during the normal workings of the brain. Ogawa and his colleagues immediately put this to the test and showed that the BOLD signals in the primary visual cortex increase when a human is engaged in visual perception.⁹⁵ So changes in local cerebral blood flow and oxygen consumption, indicating changes in metabolic responses, provide a non-invasive method of determining the local neural activity, through the use of what came to be known as functional magnetic resonance imaging (fMRI).

       BOLD measurements during psychological tests

      At the time of writing (2020) there are 556, 052 papers listed on PubMed that refer to this fMRI technique. These papers are overwhelmingly concerned with detection of BOLD changes in relation to various psychological tests presented to the subject whose head is in the MRI scanner. This procedure is carried out in order to determine the brain region engaged during the particular test, in the hope of providing a functional map of cortical areas supporting the psychological phenomena. It is of interest that Roy and Sherrington’ s comment that the ‘chemical products of cerebral metabolism contained in the lymph which baths the walls of the arteriole of the brain can cause variations of the calibre of the cerebral vessel’ (i.e. the mechanism by which changes in neuronal electrical activity produces changes in blood flow) has still not been elucidated in detail.

       BOLD measurements in the absence of psychological tests

An exciting discovery made by Bharat Biswal and his colleagues in 1995 was that coupled BOLD signal variations between different areas of the brain could be detected when the subject was at rest in the scanner, that is when no psychological testing was taking place, indicating what they referred to as ‘manifesting a functional connectivity of the brain’ between these different areas using what is referred to as resting-state fMRI.⁹⁶ Some of these areas showing ‘functional connectivity’ with resting-state fMRI were later shown to be connected by identified nerve tracts. Resting-state measurements have been utilized extensively in the past twenty-five years, with one of the discoveries due to Marcus Raichle and colleagues generating intense interest.⁹⁷ They showed that when a subject in the scanner was lying quietly with eyes closed, particular areas of cortex displayed strong correlated activity, located in the posterior cingulate cortex, precuneus and medial prefrontal cortex; however these areas were depressed when the subject was engaged in goal-directed activity as in a psychological test. Raichle and his colleagues dubbed these areas as constituting a ‘default mode’ network. There has been much speculation concerning the purpose of this network, for example that it supports mind wandering. However this enthusiasm was dampened somewhat with the discovery that the network remains active not only during rest but also when the subject is anesthetized, that is unconsciousness.⁹⁸

       Glucose consumption detected in the cortex as a measure of neuronal activity

Louis Sokoloff and his colleagues developed a method of introducing radiolabelled analogues of glucose [¹⁸F-2-deoxy-2-fluoro-D-glucose] at non-toxic levels into the brain so that the concentration of these analogues could serve as a quantitative measure of cerebral metabolism.⁹⁹ The analogue could be ‘used as a tracer for the exchange of glucose between plasma and brain and its phosphorylation – local glucose consumption could be calculated’.¹⁰⁰ This technique now uses positron emission tomography (PET) to determine non-invasively brain regions with high levels of glucose metabolism and therefore of neuron excitability. The technique of using radiolabeled analogues of glucose to measure metabolism was developed well before that of fMRI, and has the advantage of giving a quantitative absolute measure of metabolism compared with the relative measures of activity provided by the BOLD technique, however the latter can follow activity with much better temporal resolution.

      1.6.2 Caveats concerning the use of fMRI to determine the areas of cortex involved in supporting psychological powers

The genius that was manifest in all of Sherrington’ s experiments was his capacity to elicit profound observations from relatively simple techniques, including that for establishing correlations between cortical blood flow in an area of the brain and the activity of the cortex in that area. When, a century later, Seiji Ogawa led the way in the use of a much more elaborate technique, namely fMRI, he too, like Sherrington, was careful not to ask that the technique deliver more on its own than it was capable. Unfortunately, this has not been the case with many of those following in his path in using fMRI. Here a number of potentially serious technical problems need to be mentioned that should put on guard readers of papers using fMRI that make various claims concerning cortical localization of functions supporting psychological powers. These caveats may be responsible for a significant lack of reproducibility in fMRI measurements.¹⁰¹

       The shapes of BOLD signals over the cortex of single subjects during a neuropsychological test

It has been traditional when analysing the fMRI signals to restrict such analyses to ‘box-car’-shaped signals, that is those which have a rectangular-like waveform that may be considered, for example, as a convolution of a gamma-variate function with a box-car function. The assumption that such signals are the only relevant ones has not been sustained by any analytical argument. It seems to have been based on spurious reasoning that those easily computed signal amplitudes seem to make sense. However, as has been emphasized by a number of recent studies, there is a wide variety of different shaped fMRI signals during simple neuropsychological tests, that is with different temporal profiles to that of the box-car like signals which occur over wide swathes of cortex (see Figure 1.1 and colour version, Plate 1, between pp. 232 and 233).¹⁰² It is clear that just measuring the ‘amplitude’ of such different temporal profiles is an inadequate way of characterizing and comparing them.

      Figure 1.1 Significant activations over the whole brain revealed following averaging BOLD fMRI signals over 100 neuropsychological tests on a subject. (A) axial view of a map of the significant signal changes through the entire cortex to a simple motor response to a visual decision neuropsychological test, described in the text. (B) corresponding sagittal view of the map. (C) time course of the BOLD fMRI signals corresponding to coloured regions in the brain.

Source: Gonzalez-Castillo et al., 2012

Furthermore, there is no objective basis for accepting some shapes and rejecting others. Many of the fMRI determinations of the spatial distribution of activations of the cortex during neuropsychological tests are based on box-car temporal profiles and so assume that only these are relevant when defining the term ‘activation’. This assumption is unlikely to be correct and neglects important information regarding cortical activity accompanying a neuropsychological test. A plausible explanation for the large deviations of the fMRI signals from a box-car shape has recently been offered in terms of their originating from different extents of impulse activity in the region of interest conditional on temporal changes in the amount of inhibitory and excitatory activity there.¹⁰³ This being so, all shapes of the fMRI signal provide important information concerning the integrative activity in a given region.

       The amplitude of BOLD signals over the cortex of single subjects during a neuropsychological test and on-going cortical activity

The threshold at which a particular fMRI signal is to be accepted for determining the sites over the cortex involved in a neuropsychological test depends on both the signal-to-noise ratio, as well as the amplitude of the signal taken to be of the box-car variety. However, it has been known for some time that the amplitude of the signal, taken as a measure of the transient activity during a neuropsychological test, is conditional on the activity of the part of the cortex of interest

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