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Inhibition and functional magnetic resonance imaging
International Congress Series 1235 (2002) 213–222
Inhibition and functional magnetic resonance imaging Petra Ritter*, Arno Villringer Division of Neuroimaging, Department of Neurology, Neurologische Klinik, Charite´, Schumannstraße 20-21, 10117 Berlin, Germany
Abstract This review summarizes our current knowledge on how inhibitory phenomena are reflected in the functional magnetic resonance imaging (fMRI) signal. It is well-established that activity-related changes of brain metabolism and blood flow are dominated by changes in synaptic activity. Both excitatory and inhibitory synaptic activities are associated with increased metabolic demands. The amount of energy consumption associated with inhibition vs. excitation is reflected in metabolism- and blood flow-related neuroimaging signals such as the blood oxygen level-dependent (BOLD) contrast; the relationship between the different ‘‘signals’’, however, may not be linear. The influence on these signals depends on the number of active inhibiting synapses, the duration of inhibition and the degree of propagation within subsequent neuronal circuits. The relative influence of inhibition as compared to excitation on the metabolism/blood flow may also vary in different neuronal circuits. Inhibition leads to locally decreased discharge activity, which does not have a significant effect on the cerebral blood flow (CBF)/BOLD images. However, inhibition may also result in suppression of complex neuronal circuits, leading to a decrease in excitatory as well as inhibitory synaptic activity, and therewith, to a decreased metabolism and blood flow within those complex neuronal networks. The available fMRI data indicate that, depending on the abovementioned factors, inhibition may be reflected in positive, negative or no BOLD-signal at all. Thus, the BOLD-signal is ambiguous with respect to the underlying electrophysiological event. In the future, combining fMRI with electrophysiological methods will strengthen neuroimaging studies. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Functional magnetic resonance imaging; Blood oxygen level-dependent (BOLD); Metabolism; BOLD-signal
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Corresponding author. E-mail addresses: [email protected] (P. Ritter), [email protected] (A. Villringer).
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1. Introduction Several neuroimaging techniques assess neuronal activation indirectly after translation by neurovascular and neuro-metabolic coupling into a physiologic (vascular or metabolic) signal, which can be measured by the respective technique. The blood oxygen level-dependent (BOLD) and functional magnetic resonance imaging (fMRI) techniques are currently the most widely used methods for indirect mapping of neuronal activity. The BOLD-signal has an inverse relationship to changes in the local deoxyhemoglobin concentration, which result from changes in the local cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF) and cerebral blood volume (CBV) associated with neuronal activity. In ‘‘activated’’ brain areas, the BOLD-signal intensity increases within a few seconds after the onset of stimulation as a consequence of an increase in the regional CBF, exceeding the increase in oxygen utilization. After the termination of the stimuli, the signal decays in several seconds. It should be emphasized, however, that the term ‘‘activation’’ is only defined by the behavior of the BOLD-signal and is not a priori equivalent with any event (e.g., action potential, excitatory or inhibitory synaptic activity, etc.) occurring on a neuronal level. If the underlying situation is characterized by an increase in synaptic activity and an increased neuronal firing rate, then there is general consensus that this is reflected in a BOLD-signal increase, i.e., ‘‘activation’’. However, there are other situations in which these neuronal events are not in ‘‘synchrony’’. An increase in synaptic activity may also be due to an increase in excitatory (as in the case above) or inhibitory activity. In the latter case, synaptic activity and local firing rate of the neurons may actually diverge [1]. It is discussed controversially, whether the decreased neuronal activity of certain brain areas resulting from the inhibition leads to a drop in the BOLD-signal intensity below the baseline, or to an increase of the BOLD-signal intensity (similar to activation) due to an increase in energy metabolism, or whether it cannot be detected at all by functional neuroimaging methods due to negligible effects on local brain metabolism.
2. Spikes vs. synaptic potentials—what causes gross metabolic changes? In order to allow the predictions of the respective effects of neuronal spikes and of neuronal synaptic activity on regional brain metabolism, knowledge of the ratio between the energy requirements of both types of neuronal activity is critical. The complex reactions surrounding synaptic activity including transmitter cycling, transmitter –receptor reactions, second messenger activities (in contrast to the only reestablishment of ion equilibrium during discharge activity), as well as the mitochondrial distribution within a neuron, suggest synaptic activity to be the greater energy consumer. These hypotheses are supported by several studies, e.g., [14C]-2-deoxyglucose (2-DG) distribution [2] matched the distribution of the activated synapses and not the distribution of the discharging postsynaptic membrane, and during the stimulation of the excitatory afferents of the nucleus laminaris of a chick [3]. It follows that local changes in glucose consumption are not evidence of changes in local neuronal discharge activity, but instead evidence of alterations in synaptic activity.
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3. Glucose metabolism during excitatory and inhibitory activity Inhibitory postsynaptic potentials are caused by energy-requiring mechanisms. Using 2DG labeling increased glucose metabolism during the inhibition of the hippocampal pyramidal cells induced by low frequency stimulation of the fornix in rats and has been shown in Ref. [4]. Increased glucose uptake occurred particularly in the stratum pyramidale, which contains a dense plexus of inhibitory interneuronal terminals upon pyramidal cells. Another group also employing [14C]-2-DG labeling investigated glucose metabolism of: (1) synaptic activity in the absence of postsynaptic cell discharge (active inhibitory synapses); (2) cell discharge in the absence of synaptic activity. Also, they addressed the question whether increased glucose metabolism is caused predominantly by cell discharge or by synaptic activity [3]. It is well known from neuroanatomical experiments that lateral superior olives (LSOs) in the brainstem auditory system receive each of the afferents from both ears. According to electrophysiological, pharmacological and anatomical reports, afferents from the ipsilateral ear are excitatory, and those from the contralateral ear are inhibitory. After the destruction of the left cochlea in cats, auditory stimulation did result in heavy 2-DG labeling in the left as well as in the inhibited right LSO. In order to estimate the degree of 2-DG labeling contributed by the discharging membrane, the medial superior olive (MSO) in cats was stimulated antidromically, avoiding synaptic activity. No significant 2-DG labeling was produced. However, microphotodensitometry indicated that antidromic stimulation of the MSO did result in a slightly elevated glucose metabolism, too small to be assessed by the untrained eye. Finally, the group found that synaptic activity dominated the changes in glucose metabolism, and that discharges of neuronal membranes are not sufficient by themselves to produce obvious 2-DG labeling. To show this, researchers took advantage of the bipolar structure of the nucleus laminaris in the chicks. The nucleus laminaris is composed of two dendritic cells with a dorsoventral orientation. One set of afferents (from the ipsilateral ear) predominantly ends on the dorsal dendrites of the somata, the other set of afferents (from the contralateral ear) predominantly ends on the ventral dendrites. Exciting the nucleus laminaris yielded a dorsoventral asymmetry of 2-DG labeling, depending on whether it was stimulated via one set of afferents or the other.
4. Changes in cerebral metabolism vs. changes in cerebral blood flow Can data on changes that occur in cerebral metabolism (e.g., glucose consumption and oxygen consumption) be linked to the changes in the cerebral blood flow and in the BOLDsignal. Ever since the landmark reports by Fox and Raichle [5,6] on a ‘‘focal’’ uncoupling during transient changes in brain activity, this issue has been discussed controversially. In those studies, a large mismatch between the changes in oxygen consumption and the cerebral blood flow during increased brain activity had been reported. Whereas many other groups have confirmed the finding of a mismatch between CMRO2 and CBF, a consensus is now emerging that this mismatch is quantitative, not qualitative, i.e., there seems to be a tight coupling between the blood flow and metabolism; however, this coupling is not linear.
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A mathematical model for the delivery of oxygen to the brain [7] predicts that disproportionately large changes in the blood flow are required to support small changes in the cerebral metabolic rate of oxygen (CMRO2). In fact, the very nature of the positive BOLDsignal during ‘‘activation’’ studies is a consequence of this mismatch between CBF (more precisely, it is the blood flow velocity that matters) and oxygen use. This model also predicts a higher oxygen extraction fraction for decreases in flow. Accordingly, a negative BOLD response during ‘‘deactivation’’ induced by saccades in the striate visual cortex [8] has been reported, indicating a similar type of mismatch between flow and oxygen delivery with decreased neuronal activity. In conclusion, in healthy brain tissue, it can be expected that increases in brain metabolism (glucose consumption and oxygen consumption) are associated with increases in the local blood flow and local BOLD-signal. The quantitative relationship between these physiological parameters, however, awaits further investigation. Thus, in situations of inhibition, which are associated with an increase in metabolism, increases in blood flow and the BOLD-signal are to be expected. In an experimental study on the cerebellum, Mathiesen et al. [1] have shown nicely how the inhibitory synaptic activity is associated with a local increase in the cerebral blood flow.
5. Efficiency of excitatory and inhibitory synapses Excitatory and inhibitory synapses have distinct ultrastructures [9]. Two common morphological types, referred to as Gray type I (excitatory) and type II (inhibitory), differ in the width of the synaptic cleft, the presynaptic active zone and the shape of the synaptic vesicles. The synapses containing round vesicles, which are typical for excitatory synapses, are about five times as frequent as those with flat vesicles, typical for inhibitory synapses in area 17 of the cat [10]. A single hippocampal CA1 pyramidal cell receives around 30,000 excitatory and 1700 inhibitory inputs [11]. The highly convergent excitation arriving onto the distal dendrites of the pyramidal cells is controlled primarily by proximally located inhibition. The smaller number and higher efficiency [12] of inhibitory as compared to excitatory synapses may result in a lower metabolic demand during inhibition. Since few inhibitory synapses can inhibit large neuronal populations [13,14], such inhibited regions should have a low net regional CBF and regional cerebral metabolism. Due to less excitatory input from the inhibited regions, there might also be a decrease in metabolism in the projection areas.
6. Functional neuroimaging of inhibition 6.1. ‘‘Activation’’ of cerebral structures is accompanied by ‘‘deactivations’’ of other structures The results of a positron emission tomography (PET) study employing vibratory stimulation of the right hand indicated that the stimulation-induced increases of the
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regional CBF and CMRO2 in the left SI, left SII, left retroinsular field (RI), left anterior parietal cortex, left MI and left SMA are associated with regional decreases of CBF and CMRO2 in the superior parietal cortex bilaterally (main decrease was adjacent to left SI), paralimbic association areas and the left globus pallidus [15]. The regional changes were balanced, so that the mean global CBF and CMRO2 did not change when compared with the rest. During the specific tasks, deactivations of areas belonging to the nonrelevant sensory modality have been shown, e.g., decreases in CBF in the visual cortex during somatosensory tasks [16], and decreased CBF in the auditory and prefrontal regions during a visual task [17]. Thus, inhibition may be an essential component of the selective attentional processes playing a complementary role to task-specific activations. 6.2. Transcallosal and cortico –cortical motor system inhibition Three effects of transcranial magnetic stimulation (TMS) are well-known: (1) cortico – spinally excitatory contralateral tonic motor response mediated by large pyramidal cells and postexcitatory inhibition of these pyramidal cells [18,19]; (2) transcallosal inhibition of the contralateral motor cortex [20 –22]; (3) paired-pulse cortico – cortical facilitation at interstimulus intervals (ISI) of 6 – 20 ms (subthreshold conditioning stimulus) and 10 –40 ms (suprathreshold conditioning stimulus) and inhibition at ISI of 1 – 4 ms/40– 200 ms (sub/suprathreshold conditioning stimulus) [23,24]. These phenomena provide experimentally and neurophysiologically well-defined mechanisms inducing cortico – cortically mediated inhibitory and excitatory effects, which can be evaluated by neuroimaging methods like PET or BOLD-sensitive fMRI. Based on the findings described above, a recent study employing positron emission tomography (PET) and transcranial magnetic stimulation (TMS) of the left primary motor cortex (M1) evaluated the correlation between the local CBF and contralateral motorevoked potentials (MEPs) induced by paired-pulse stimuli (subthreshold conditioning stimulus, suprathreshold test stimulus), with ISIs of 3 and 12 ms [25]. A significant positive correlation was observed between the CBF changes (activation) in the left M1 and in the amount of suppression, as well as facilitation of the electromyographic (EMG) response for both ISIs. As the CBF changes in the left M1 for 3 and 12 ms, ISIs did not overlap, supporting the hypotheses that early inhibition and late facilitation arise from separate pools of cortical interneurons [23]. By using a combination of transcranial stimulation (TES) and fMRI as recently established by our group [26,27], we have recently shown that TES-stimulation of the motor cortex on one hemisphere (associated with transcallosal inhibition) leads to a BOLD – fMRI signal intensity increase in the somatomotor cortex of the other (presumably inhibited) hemisphere ([28] (Abstract) and unpublished results). Another physiological setting, in which transcallosal inhibition has been reported, is in finger/thumb tapping. Using this paradigm, a decrease of the BOLD-signal in the ipsilateral (presumably inhibited) sensorimotor cortex has been reported [29]. One intriguing interpretation of these diverging findings is that they are due to the different forms of transcallosal inhibition in the two settings. Studies in which electrophysiological recordings are performed simultaneously to the fMRI are needed to further clarify these points.
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6.3. Motor system inhibition by go/no-go task Employing a go/no-go auditory reaction time paradigm, simultaneously TMS-induced MEPs in the bilateral extensor pollicis brevis muscles were evaluated [30]. After the no-go tones, bilateral inhibition occurred at a time corresponding to the mean reaction time to the go tones. Using the go/no-go paradigm in combination with the event-related fMRI, it has recently been shown that there is no significant change in the BOLD-signal intensity from the baseline for the no-go task in M1 [31]. Based on these results, Waldvogel et al. [31] drew the conclusion that ‘‘when blood flow is increased, it is very likely that this represents predominant excitatory synaptic activity’’. 6.4. ‘Saccadic suppression’—inhibition of the primary visual cortex during saccades ‘Saccadic suppression’—the phenomenon of an elevated visual threshold associated with voluntary saccadic eye movement—has been quantitatively demonstrated by both psychophysical and electrophysiological techniques. The absence of any alteration in LGN cell activity during directionally specific inhibition of the striate visual cortex neurons, was recorded by microelectrodes in ence´phale isole´ monkeys, with a short latency of inhibition of only 20– 30 ms (the latency of the first component (P3a), the human visual-evoked response (VER) is approximately 40 ms). This supports the concept of a central mechanism (corollary discharge) playing a significant role in saccadic suppression [32]. Several facts suggest the superior colliculus (SC) to be a generator of corollary discharge [33 – 35]. Other possible sources for corollary discharge are the frontal cortical eye fields, which fire in association with eye movements [36]. With the use of PET, changes in regional CBF during the execution of saccades with varying frequencies (40 – 140 saccades per minute) were measured in complete darkness [37]. With increasing numbers of saccades, the regional CBF increased in the frontal eye field, the superior colliculus and the cerebellar vermis. In parallel, the regional CBF decreased (in comparison to the baseline) in the striate cortex, the adjacent extrastriate cortex and the parietal cortex, indicating a decrease in the net amount of synaptic neurotransmission. In accordance with these results, the regional BOLD decreases measured by fMRI and the regional increases of [deoxyhemoglobin] measured by near infrared spectroscopy (NIRS)—both indicating deactivation—in the primary and adjacent secondary visual areas have been shown [8]. 6.5. A model for deactivation: reversal of the common stimulus design The majority of the MR mapping studies employed paradigms that led to ‘‘brain activation’’, implying a change from low degree neuronal activity to a high degree of neuronal activity. In the BOLD – fMRI, ‘‘activation’’ simply refers to a positive BOLD effect. A general practice is the analysis of the switches in neuronal activity between arbitrary steady-state conditions and functional states. In a BOLD –fMRI study, ‘‘activation’’ (BOLD –fMRI signal increase) and ‘‘deactivation’’ (BOLD fMRI signal decrease) in the human visual cortex were accomplished by
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reversing the order of the baseline/stimulation condition [38]. All activation protocols employed a gray light stimulus as the baseline condition and a checkerboard stimulus as the activation condition. All the deactivation protocols employed the checkerboard as a baseline condition (corresponding to sustained visual stimulation). The steady-state conditions were established by presenting the ‘‘baseline stimulus’’ for 60 – 120 s. Decreased neuronal activity resulted in an initial 5% drop in the BOLD-signal corresponding to the poststimulus undershoot, followed by a small 1.5 –2% increase up to a new steady-state in sustained ‘‘deactivation’’. Furthermore, the activation paradigm induced a 4.5 –5% BOLD-signal increase and a poststimulus 1.5– 2% undershoot. These results from the PET and fMRI studies indicate that deactivation following inhibition might be regarded as less activation due to a decrease in neuronal synaptic activity.
7. Conclusions—inhibition can result in ‘‘activation’’ or ‘‘deactivation’’ The activity-related changes of brain metabolism and the blood flow are dominated by changes in synaptic activity. Both excitatory and inhibitory synaptic activities are associated with increased metabolic demands, increased blood flow and the BOLD-signal, and the quantitative relationship between these parameters is probably nonlinear. The difference in energy consumption associated with inhibition vs. excitation is probably reflected in metabolism- and blood flow-related neuroimaging signals such as the BOLD contrast. The influence on these signals depends on the number of active inhibiting synapses, the duration of inhibition and the degree of propagation within subsequent neuronal circuits. The relative influence of inhibition as compared to excitation on metabolism/blood flow may also vary in the different neuronal circuits. Inhibition leads to locally decreased discharge activity, which does not have a significant effect on the CBF/BOLD images. However, inhibition may also result in the suppression of the complex neuronal circuits, leading to a decrease in excitatory as well as inhibitory synaptic activity, and therewith, to decreased metabolism and blood flow within those complex neuronal networks. These considerations may explain why in the abovementioned TMS study, cortico – cortical inhibition is associated with increased CBF [25], whereas the fMRI –BOLD-signal decreases during transcallosal inhibition [29], which indicates a decrease in the CBF. Thus, inhibitory events may be associated with ‘‘activation’’ as well as ‘‘deactivation’’. The BOLD-signal is thus ambiguous with respect to the underlying neuronal events. The addition of electrophysiological techniques such as TMS to neuroimaging protocols may be useful in order to elucidate the functional status of the cerebral tissue under investigation.
8. On-Site Discussion Question: (Heiss) I found your reports of results of transcallosal inhibition very interesting. Collateral and transcallosal inhibition is very important for the development of lateralized function, e.g., for dominance of speech in the left hemisphere. Do you have any data showing disinhibition of collateral or transcallosal inhibition playing a role in
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compensation for lesions in primary centers? This might be important for recovery from motor deficit or aphasia after stroke. I will discuss some of these effects in my presentation. Answer: (Villinger) I agree that this may be very interesting to study; however, so far, we do not have our own data on this issue. Comment: (Hyder) (1) The kind of work being done for an excitatory event and inhibition event is similar at the pre-synaptic terminal (e.g., docking of vesicles, excytosis, vesicular release of transmitter). Since it is work being done, energy is being consumed for both events. Therefore, an energy-based imaging modality (e.g., BOLD) may not be able to dissociate between these two types of events. (2) So the correlation between spiking activity and BOLD found by Hees et al. and Heeger et al. (please see Nat. Neurosci. papers from 2000) will be only true for specific cases. The more likely correlation is to be found between synaptic activity and BOLD (e.g., Hyder et al. (Society for Neuroscience 2001) or Logothetis et al. (Society for Neuroscience 2001). Question: (Dirnagl) Should we call ‘‘saccadic suppression’’ deactivation (which implies an active process) or just ‘‘decrease of activity’’? Answer: (Villinger) In the case of saccadic depression, the decrease of fMRI signal (‘‘deactivation’’) probably corresponds to a decrease of neuronal activity. This relationship, however, may not necessarily hold in all situations. Question: (Gjedde) What makes you so sure that an increased BOLD-signal reflects increased (neuronal) work? Answer: (Villinger) We know this indirectly. In several instances where increased blood flow has been measured, it is known that glucose consumption increases. Question: (Iadecola) In response to Dr. Gjedde’s question, stimulation of the cerebellar parallel fiber increases glucose utilization locally. Concerning the inhibition effects on CBF, we must keep in mind that the withdrawal of vasodilator cannot be the sole mechanism of coupling of CBF to neural activity. Arteriolar diameter is determined by both constrictor and vasodilator influences—constrictor effects may predominate during inhibition. Answer: (Villinger) Your are right, Costantino. References [1] C. Mathiesen, K. Caesar, N. Akgoren, M. Lauritzen, Modification of activity-dependent increases of cerebral blood flow by excitatory synaptic activity and spikes in rat cerebellar cortex, J. Physiol. 512 (1998) 555 – 566. [2] L. Sokoloff, M. Reivich, C. Kennedy, M.H. Des Rosiers, C.S. Patlak, K.D. Pettigrew, O. Sakurada, M. Shinohara, The [C-14]deoxyglucose method for measurements of the local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat, J. Neurochem. 28 (1977) 897 – 916. [3] R.J. Nudo, R.B. Masterton, Stimulation-induced [14C]2-deoxyglucose labeling of synaptic activity in the central auditory system, J. Comp. Neurol. 245 (1986) 553 – 565.
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Inhibition and functional magnetic resonance imaging Petra Ritter*, Arno Villringer Division of Neuroimaging, Department of Neurology, Neurologische Klinik, Charite´, Schumannstraße 20-21, 10117 Berlin, Germany
Abstract This review summarizes our current knowledge on how inhibitory phenomena are reflected in the functional magnetic resonance imaging (fMRI) signal. It is well-established that activity-related changes of brain metabolism and blood flow are dominated by changes in synaptic activity. Both excitatory and inhibitory synaptic activities are associated with increased metabolic demands. The amount of energy consumption associated with inhibition vs. excitation is reflected in metabolism- and blood flow-related neuroimaging signals such as the blood oxygen level-dependent (BOLD) contrast; the relationship between the different ‘‘signals’’, however, may not be linear. The influence on these signals depends on the number of active inhibiting synapses, the duration of inhibition and the degree of propagation within subsequent neuronal circuits. The relative influence of inhibition as compared to excitation on the metabolism/blood flow may also vary in different neuronal circuits. Inhibition leads to locally decreased discharge activity, which does not have a significant effect on the cerebral blood flow (CBF)/BOLD images. However, inhibition may also result in suppression of complex neuronal circuits, leading to a decrease in excitatory as well as inhibitory synaptic activity, and therewith, to a decreased metabolism and blood flow within those complex neuronal networks. The available fMRI data indicate that, depending on the abovementioned factors, inhibition may be reflected in positive, negative or no BOLD-signal at all. Thus, the BOLD-signal is ambiguous with respect to the underlying electrophysiological event. In the future, combining fMRI with electrophysiological methods will strengthen neuroimaging studies. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Functional magnetic resonance imaging; Blood oxygen level-dependent (BOLD); Metabolism; BOLD-signal
*
Corresponding author. E-mail addresses: [email protected] (P. Ritter), [email protected] (A. Villringer).
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1. Introduction Several neuroimaging techniques assess neuronal activation indirectly after translation by neurovascular and neuro-metabolic coupling into a physiologic (vascular or metabolic) signal, which can be measured by the respective technique. The blood oxygen level-dependent (BOLD) and functional magnetic resonance imaging (fMRI) techniques are currently the most widely used methods for indirect mapping of neuronal activity. The BOLD-signal has an inverse relationship to changes in the local deoxyhemoglobin concentration, which result from changes in the local cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF) and cerebral blood volume (CBV) associated with neuronal activity. In ‘‘activated’’ brain areas, the BOLD-signal intensity increases within a few seconds after the onset of stimulation as a consequence of an increase in the regional CBF, exceeding the increase in oxygen utilization. After the termination of the stimuli, the signal decays in several seconds. It should be emphasized, however, that the term ‘‘activation’’ is only defined by the behavior of the BOLD-signal and is not a priori equivalent with any event (e.g., action potential, excitatory or inhibitory synaptic activity, etc.) occurring on a neuronal level. If the underlying situation is characterized by an increase in synaptic activity and an increased neuronal firing rate, then there is general consensus that this is reflected in a BOLD-signal increase, i.e., ‘‘activation’’. However, there are other situations in which these neuronal events are not in ‘‘synchrony’’. An increase in synaptic activity may also be due to an increase in excitatory (as in the case above) or inhibitory activity. In the latter case, synaptic activity and local firing rate of the neurons may actually diverge [1]. It is discussed controversially, whether the decreased neuronal activity of certain brain areas resulting from the inhibition leads to a drop in the BOLD-signal intensity below the baseline, or to an increase of the BOLD-signal intensity (similar to activation) due to an increase in energy metabolism, or whether it cannot be detected at all by functional neuroimaging methods due to negligible effects on local brain metabolism.
2. Spikes vs. synaptic potentials—what causes gross metabolic changes? In order to allow the predictions of the respective effects of neuronal spikes and of neuronal synaptic activity on regional brain metabolism, knowledge of the ratio between the energy requirements of both types of neuronal activity is critical. The complex reactions surrounding synaptic activity including transmitter cycling, transmitter –receptor reactions, second messenger activities (in contrast to the only reestablishment of ion equilibrium during discharge activity), as well as the mitochondrial distribution within a neuron, suggest synaptic activity to be the greater energy consumer. These hypotheses are supported by several studies, e.g., [14C]-2-deoxyglucose (2-DG) distribution [2] matched the distribution of the activated synapses and not the distribution of the discharging postsynaptic membrane, and during the stimulation of the excitatory afferents of the nucleus laminaris of a chick [3]. It follows that local changes in glucose consumption are not evidence of changes in local neuronal discharge activity, but instead evidence of alterations in synaptic activity.
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3. Glucose metabolism during excitatory and inhibitory activity Inhibitory postsynaptic potentials are caused by energy-requiring mechanisms. Using 2DG labeling increased glucose metabolism during the inhibition of the hippocampal pyramidal cells induced by low frequency stimulation of the fornix in rats and has been shown in Ref. [4]. Increased glucose uptake occurred particularly in the stratum pyramidale, which contains a dense plexus of inhibitory interneuronal terminals upon pyramidal cells. Another group also employing [14C]-2-DG labeling investigated glucose metabolism of: (1) synaptic activity in the absence of postsynaptic cell discharge (active inhibitory synapses); (2) cell discharge in the absence of synaptic activity. Also, they addressed the question whether increased glucose metabolism is caused predominantly by cell discharge or by synaptic activity [3]. It is well known from neuroanatomical experiments that lateral superior olives (LSOs) in the brainstem auditory system receive each of the afferents from both ears. According to electrophysiological, pharmacological and anatomical reports, afferents from the ipsilateral ear are excitatory, and those from the contralateral ear are inhibitory. After the destruction of the left cochlea in cats, auditory stimulation did result in heavy 2-DG labeling in the left as well as in the inhibited right LSO. In order to estimate the degree of 2-DG labeling contributed by the discharging membrane, the medial superior olive (MSO) in cats was stimulated antidromically, avoiding synaptic activity. No significant 2-DG labeling was produced. However, microphotodensitometry indicated that antidromic stimulation of the MSO did result in a slightly elevated glucose metabolism, too small to be assessed by the untrained eye. Finally, the group found that synaptic activity dominated the changes in glucose metabolism, and that discharges of neuronal membranes are not sufficient by themselves to produce obvious 2-DG labeling. To show this, researchers took advantage of the bipolar structure of the nucleus laminaris in the chicks. The nucleus laminaris is composed of two dendritic cells with a dorsoventral orientation. One set of afferents (from the ipsilateral ear) predominantly ends on the dorsal dendrites of the somata, the other set of afferents (from the contralateral ear) predominantly ends on the ventral dendrites. Exciting the nucleus laminaris yielded a dorsoventral asymmetry of 2-DG labeling, depending on whether it was stimulated via one set of afferents or the other.
4. Changes in cerebral metabolism vs. changes in cerebral blood flow Can data on changes that occur in cerebral metabolism (e.g., glucose consumption and oxygen consumption) be linked to the changes in the cerebral blood flow and in the BOLDsignal. Ever since the landmark reports by Fox and Raichle [5,6] on a ‘‘focal’’ uncoupling during transient changes in brain activity, this issue has been discussed controversially. In those studies, a large mismatch between the changes in oxygen consumption and the cerebral blood flow during increased brain activity had been reported. Whereas many other groups have confirmed the finding of a mismatch between CMRO2 and CBF, a consensus is now emerging that this mismatch is quantitative, not qualitative, i.e., there seems to be a tight coupling between the blood flow and metabolism; however, this coupling is not linear.
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A mathematical model for the delivery of oxygen to the brain [7] predicts that disproportionately large changes in the blood flow are required to support small changes in the cerebral metabolic rate of oxygen (CMRO2). In fact, the very nature of the positive BOLDsignal during ‘‘activation’’ studies is a consequence of this mismatch between CBF (more precisely, it is the blood flow velocity that matters) and oxygen use. This model also predicts a higher oxygen extraction fraction for decreases in flow. Accordingly, a negative BOLD response during ‘‘deactivation’’ induced by saccades in the striate visual cortex [8] has been reported, indicating a similar type of mismatch between flow and oxygen delivery with decreased neuronal activity. In conclusion, in healthy brain tissue, it can be expected that increases in brain metabolism (glucose consumption and oxygen consumption) are associated with increases in the local blood flow and local BOLD-signal. The quantitative relationship between these physiological parameters, however, awaits further investigation. Thus, in situations of inhibition, which are associated with an increase in metabolism, increases in blood flow and the BOLD-signal are to be expected. In an experimental study on the cerebellum, Mathiesen et al. [1] have shown nicely how the inhibitory synaptic activity is associated with a local increase in the cerebral blood flow.
5. Efficiency of excitatory and inhibitory synapses Excitatory and inhibitory synapses have distinct ultrastructures [9]. Two common morphological types, referred to as Gray type I (excitatory) and type II (inhibitory), differ in the width of the synaptic cleft, the presynaptic active zone and the shape of the synaptic vesicles. The synapses containing round vesicles, which are typical for excitatory synapses, are about five times as frequent as those with flat vesicles, typical for inhibitory synapses in area 17 of the cat [10]. A single hippocampal CA1 pyramidal cell receives around 30,000 excitatory and 1700 inhibitory inputs [11]. The highly convergent excitation arriving onto the distal dendrites of the pyramidal cells is controlled primarily by proximally located inhibition. The smaller number and higher efficiency [12] of inhibitory as compared to excitatory synapses may result in a lower metabolic demand during inhibition. Since few inhibitory synapses can inhibit large neuronal populations [13,14], such inhibited regions should have a low net regional CBF and regional cerebral metabolism. Due to less excitatory input from the inhibited regions, there might also be a decrease in metabolism in the projection areas.
6. Functional neuroimaging of inhibition 6.1. ‘‘Activation’’ of cerebral structures is accompanied by ‘‘deactivations’’ of other structures The results of a positron emission tomography (PET) study employing vibratory stimulation of the right hand indicated that the stimulation-induced increases of the
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regional CBF and CMRO2 in the left SI, left SII, left retroinsular field (RI), left anterior parietal cortex, left MI and left SMA are associated with regional decreases of CBF and CMRO2 in the superior parietal cortex bilaterally (main decrease was adjacent to left SI), paralimbic association areas and the left globus pallidus [15]. The regional changes were balanced, so that the mean global CBF and CMRO2 did not change when compared with the rest. During the specific tasks, deactivations of areas belonging to the nonrelevant sensory modality have been shown, e.g., decreases in CBF in the visual cortex during somatosensory tasks [16], and decreased CBF in the auditory and prefrontal regions during a visual task [17]. Thus, inhibition may be an essential component of the selective attentional processes playing a complementary role to task-specific activations. 6.2. Transcallosal and cortico –cortical motor system inhibition Three effects of transcranial magnetic stimulation (TMS) are well-known: (1) cortico – spinally excitatory contralateral tonic motor response mediated by large pyramidal cells and postexcitatory inhibition of these pyramidal cells [18,19]; (2) transcallosal inhibition of the contralateral motor cortex [20 –22]; (3) paired-pulse cortico – cortical facilitation at interstimulus intervals (ISI) of 6 – 20 ms (subthreshold conditioning stimulus) and 10 –40 ms (suprathreshold conditioning stimulus) and inhibition at ISI of 1 – 4 ms/40– 200 ms (sub/suprathreshold conditioning stimulus) [23,24]. These phenomena provide experimentally and neurophysiologically well-defined mechanisms inducing cortico – cortically mediated inhibitory and excitatory effects, which can be evaluated by neuroimaging methods like PET or BOLD-sensitive fMRI. Based on the findings described above, a recent study employing positron emission tomography (PET) and transcranial magnetic stimulation (TMS) of the left primary motor cortex (M1) evaluated the correlation between the local CBF and contralateral motorevoked potentials (MEPs) induced by paired-pulse stimuli (subthreshold conditioning stimulus, suprathreshold test stimulus), with ISIs of 3 and 12 ms [25]. A significant positive correlation was observed between the CBF changes (activation) in the left M1 and in the amount of suppression, as well as facilitation of the electromyographic (EMG) response for both ISIs. As the CBF changes in the left M1 for 3 and 12 ms, ISIs did not overlap, supporting the hypotheses that early inhibition and late facilitation arise from separate pools of cortical interneurons [23]. By using a combination of transcranial stimulation (TES) and fMRI as recently established by our group [26,27], we have recently shown that TES-stimulation of the motor cortex on one hemisphere (associated with transcallosal inhibition) leads to a BOLD – fMRI signal intensity increase in the somatomotor cortex of the other (presumably inhibited) hemisphere ([28] (Abstract) and unpublished results). Another physiological setting, in which transcallosal inhibition has been reported, is in finger/thumb tapping. Using this paradigm, a decrease of the BOLD-signal in the ipsilateral (presumably inhibited) sensorimotor cortex has been reported [29]. One intriguing interpretation of these diverging findings is that they are due to the different forms of transcallosal inhibition in the two settings. Studies in which electrophysiological recordings are performed simultaneously to the fMRI are needed to further clarify these points.
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6.3. Motor system inhibition by go/no-go task Employing a go/no-go auditory reaction time paradigm, simultaneously TMS-induced MEPs in the bilateral extensor pollicis brevis muscles were evaluated [30]. After the no-go tones, bilateral inhibition occurred at a time corresponding to the mean reaction time to the go tones. Using the go/no-go paradigm in combination with the event-related fMRI, it has recently been shown that there is no significant change in the BOLD-signal intensity from the baseline for the no-go task in M1 [31]. Based on these results, Waldvogel et al. [31] drew the conclusion that ‘‘when blood flow is increased, it is very likely that this represents predominant excitatory synaptic activity’’. 6.4. ‘Saccadic suppression’—inhibition of the primary visual cortex during saccades ‘Saccadic suppression’—the phenomenon of an elevated visual threshold associated with voluntary saccadic eye movement—has been quantitatively demonstrated by both psychophysical and electrophysiological techniques. The absence of any alteration in LGN cell activity during directionally specific inhibition of the striate visual cortex neurons, was recorded by microelectrodes in ence´phale isole´ monkeys, with a short latency of inhibition of only 20– 30 ms (the latency of the first component (P3a), the human visual-evoked response (VER) is approximately 40 ms). This supports the concept of a central mechanism (corollary discharge) playing a significant role in saccadic suppression [32]. Several facts suggest the superior colliculus (SC) to be a generator of corollary discharge [33 – 35]. Other possible sources for corollary discharge are the frontal cortical eye fields, which fire in association with eye movements [36]. With the use of PET, changes in regional CBF during the execution of saccades with varying frequencies (40 – 140 saccades per minute) were measured in complete darkness [37]. With increasing numbers of saccades, the regional CBF increased in the frontal eye field, the superior colliculus and the cerebellar vermis. In parallel, the regional CBF decreased (in comparison to the baseline) in the striate cortex, the adjacent extrastriate cortex and the parietal cortex, indicating a decrease in the net amount of synaptic neurotransmission. In accordance with these results, the regional BOLD decreases measured by fMRI and the regional increases of [deoxyhemoglobin] measured by near infrared spectroscopy (NIRS)—both indicating deactivation—in the primary and adjacent secondary visual areas have been shown [8]. 6.5. A model for deactivation: reversal of the common stimulus design The majority of the MR mapping studies employed paradigms that led to ‘‘brain activation’’, implying a change from low degree neuronal activity to a high degree of neuronal activity. In the BOLD – fMRI, ‘‘activation’’ simply refers to a positive BOLD effect. A general practice is the analysis of the switches in neuronal activity between arbitrary steady-state conditions and functional states. In a BOLD –fMRI study, ‘‘activation’’ (BOLD –fMRI signal increase) and ‘‘deactivation’’ (BOLD fMRI signal decrease) in the human visual cortex were accomplished by
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reversing the order of the baseline/stimulation condition [38]. All activation protocols employed a gray light stimulus as the baseline condition and a checkerboard stimulus as the activation condition. All the deactivation protocols employed the checkerboard as a baseline condition (corresponding to sustained visual stimulation). The steady-state conditions were established by presenting the ‘‘baseline stimulus’’ for 60 – 120 s. Decreased neuronal activity resulted in an initial 5% drop in the BOLD-signal corresponding to the poststimulus undershoot, followed by a small 1.5 –2% increase up to a new steady-state in sustained ‘‘deactivation’’. Furthermore, the activation paradigm induced a 4.5 –5% BOLD-signal increase and a poststimulus 1.5– 2% undershoot. These results from the PET and fMRI studies indicate that deactivation following inhibition might be regarded as less activation due to a decrease in neuronal synaptic activity.
7. Conclusions—inhibition can result in ‘‘activation’’ or ‘‘deactivation’’ The activity-related changes of brain metabolism and the blood flow are dominated by changes in synaptic activity. Both excitatory and inhibitory synaptic activities are associated with increased metabolic demands, increased blood flow and the BOLD-signal, and the quantitative relationship between these parameters is probably nonlinear. The difference in energy consumption associated with inhibition vs. excitation is probably reflected in metabolism- and blood flow-related neuroimaging signals such as the BOLD contrast. The influence on these signals depends on the number of active inhibiting synapses, the duration of inhibition and the degree of propagation within subsequent neuronal circuits. The relative influence of inhibition as compared to excitation on metabolism/blood flow may also vary in the different neuronal circuits. Inhibition leads to locally decreased discharge activity, which does not have a significant effect on the CBF/BOLD images. However, inhibition may also result in the suppression of the complex neuronal circuits, leading to a decrease in excitatory as well as inhibitory synaptic activity, and therewith, to decreased metabolism and blood flow within those complex neuronal networks. These considerations may explain why in the abovementioned TMS study, cortico – cortical inhibition is associated with increased CBF [25], whereas the fMRI –BOLD-signal decreases during transcallosal inhibition [29], which indicates a decrease in the CBF. Thus, inhibitory events may be associated with ‘‘activation’’ as well as ‘‘deactivation’’. The BOLD-signal is thus ambiguous with respect to the underlying neuronal events. The addition of electrophysiological techniques such as TMS to neuroimaging protocols may be useful in order to elucidate the functional status of the cerebral tissue under investigation.
8. On-Site Discussion Question: (Heiss) I found your reports of results of transcallosal inhibition very interesting. Collateral and transcallosal inhibition is very important for the development of lateralized function, e.g., for dominance of speech in the left hemisphere. Do you have any data showing disinhibition of collateral or transcallosal inhibition playing a role in
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compensation for lesions in primary centers? This might be important for recovery from motor deficit or aphasia after stroke. I will discuss some of these effects in my presentation. Answer: (Villinger) I agree that this may be very interesting to study; however, so far, we do not have our own data on this issue. Comment: (Hyder) (1) The kind of work being done for an excitatory event and inhibition event is similar at the pre-synaptic terminal (e.g., docking of vesicles, excytosis, vesicular release of transmitter). Since it is work being done, energy is being consumed for both events. Therefore, an energy-based imaging modality (e.g., BOLD) may not be able to dissociate between these two types of events. (2) So the correlation between spiking activity and BOLD found by Hees et al. and Heeger et al. (please see Nat. Neurosci. papers from 2000) will be only true for specific cases. The more likely correlation is to be found between synaptic activity and BOLD (e.g., Hyder et al. (Society for Neuroscience 2001) or Logothetis et al. (Society for Neuroscience 2001). Question: (Dirnagl) Should we call ‘‘saccadic suppression’’ deactivation (which implies an active process) or just ‘‘decrease of activity’’? Answer: (Villinger) In the case of saccadic depression, the decrease of fMRI signal (‘‘deactivation’’) probably corresponds to a decrease of neuronal activity. This relationship, however, may not necessarily hold in all situations. Question: (Gjedde) What makes you so sure that an increased BOLD-signal reflects increased (neuronal) work? Answer: (Villinger) We know this indirectly. In several instances where increased blood flow has been measured, it is known that glucose consumption increases. Question: (Iadecola) In response to Dr. Gjedde’s question, stimulation of the cerebellar parallel fiber increases glucose utilization locally. Concerning the inhibition effects on CBF, we must keep in mind that the withdrawal of vasodilator cannot be the sole mechanism of coupling of CBF to neural activity. Arteriolar diameter is determined by both constrictor and vasodilator influences—constrictor effects may predominate during inhibition. Answer: (Villinger) Your are right, Costantino. References [1] C. Mathiesen, K. Caesar, N. Akgoren, M. Lauritzen, Modification of activity-dependent increases of cerebral blood flow by excitatory synaptic activity and spikes in rat cerebellar cortex, J. Physiol. 512 (1998) 555 – 566. [2] L. Sokoloff, M. Reivich, C. Kennedy, M.H. Des Rosiers, C.S. Patlak, K.D. Pettigrew, O. Sakurada, M. Shinohara, The [C-14]deoxyglucose method for measurements of the local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat, J. Neurochem. 28 (1977) 897 – 916. [3] R.J. Nudo, R.B. Masterton, Stimulation-induced [14C]2-deoxyglucose labeling of synaptic activity in the central auditory system, J. Comp. Neurol. 245 (1986) 553 – 565.
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