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Perception affects the brain’s metabolic response to sensory stimulation

20 Sep 2021-bioRxiv (Cold Spring Harbor Laboratory)-
TL;DR: In this paper, perceived and unperceived chromatic flickering stimuli designed to have similar neurovascular responses as measured by blood oxygenation level dependent functional MRI (BOLD-fMRI) in primary visual cortex (V1) were found to have markedly different neurometabolic responses.
Abstract: Processing of incoming sensory stimulation triggers an increase of cerebral perfusion and blood oxygenation (neurovascular response) as well as an alteration of the metabolic neurochemical profile (neurometabolic response). Here we show that perceived and unperceived isoluminant chromatic flickering stimuli designed to have similar neurovascular responses as measured by blood oxygenation level dependent functional MRI (BOLD-fMRI) in primary visual cortex (V1) have markedly different neurometabolic responses as measured by functional MRS. In particular, a significant regional buildup of lactate, an index of aerobic glycolysis, and glutamate, an index of malate-aspartate shuttle, occurred in V1 only when the flickering is perceived, without any relation with behavioral or physiological variables. Wheras the BOLD-fMRI signal in V1, a proxy for input to V1, was insensitive to flickering perception by design, the BOLD-fMRI signal in secondary visual areas was larger during perceived than unperceived flickering indicating increased output from V1. These results indicate that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1, and that 1H-fMRS provides unique information about local input/output balance that is not measured by BOLD-fMRI.

Summary (1 min read)

Significance statement: 34

  • Visual perception has a measurable metabolic effect in the primary visual cortex (V1).
  • In agreement with 70 these arguments, it has been repeatedly reported that invisible visual flickering is still able to 71 activate V1 even without any perceptual effects (23), as revealed by in vivo electrophysiology in 72 non-human primates (16) as well as behavioral evidence (24) and BOLD fMRI (25) in humans.
  • Overall, the only correlated signals that survived 225 Page 18 of 38 in the difference spectrum between PF and UF were lactate and glutamate, which strongly supports 226 the significance of the concentration changes based on LCModel quantifications.
  • Together with the results that the authors report 300 here, these observations suggest that lactate and glutamate, and hence aerobic glycolysis, are both 301 Page 22 of 38 sensitive to cortical processing (e.g., input/output or excitation/inhibition balance) rather than the 302 targeted neuronal population.
  • Each subject underwent 1 fMRI and 2 fMRS runs (10 439 minutes apart, without moving the subject from inside the scanner); the order of PF and UF 440 conditions was counterbalanced within each subject, and the initial stimulation type was 441 randomized between subjects.

NOTE

  • Following eLife style suggestions, Supplementary figures are merged to main text as “Figure supplements” and linked to main figures as indicated by the title of each supplementary figure 2 Figure 1 - figure supplement 1 Left: average heatmap of eyes position (across subjects) during the different sessions.
  • 4 Figure 1 - figure supplement 3 Left: task performance in terms of response delay was not statistically different across conditions (One-Way ANOVA, p>0.09).
  • There was no correlation between task performance and mean pupil diameter (r2<0.08, p>0.49), also known as Right.
  • 5 Figure 2 - figure supplement 1 From Left to Right: intensity map of EPI images acquired with the surface coil normalized to MNI template, superimposed to different ROIs (in white): BA17 (i.e., V1), BA18, BA19, and the average spectroscopic voxel (1H-fMRS VOI).

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Page 1 of 38
Perception affects the brains metabolic response to sensory
stimulation
Short title: Cortical metabolic response to visual perception
Mauro DiNuzzo
1
, Silvia Mangia
2,§
, Marta Moraschi
3
, Daniele Mascali
1,4
, Gisela E. Hagberg
5
,
Federico Giove
1,6,*
1
Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi, 00184 Rome, Italy
2
Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota,
Minneapolis, MN 55455, USA
3
Unità Operativa di Radioterapia Oncologica, Università Campus Bio-Medico, 00128 Rome,
Italy
4
Dipartimento di Neuroscienze, Imaging e Scienze Cliniche, Università Gabriele DAnnunzio,
66100 Chieti, Italy
5
HighField Magnetic Resonance, Max Planck Institute for Biological Cybernetics and
Biomedical Magnetic Resonance, University Hospital Tübingen, 72076 Tübingen, Germany
6
Fondazione Santa Lucia IRCCS, 00179 Rome, Italy
§
These authors contributed equally to this work.
* correspondence to:
Federico Giove, Ph.D.
Magnetic Resonance for Brain Investigation Laboratory
c/o Fondazione Santa Lucia
Via Ardeatina 354, 00179 Rome, Italy
Phone: +39 06 51501157
mail: federico.giove@cref.it
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 20, 2021. ; https://doi.org/10.1101/2021.09.17.460759doi: bioRxiv preprint

Page 2 of 38
Author contributions 1
Conceptualization and Methodology: MDN, SM, GEH and FG. Investigation: MDN, DM, MM 2
and FG. Data curation and Formal analysis: MDN, DM, MM and FG. Writing original draft: 3
MDN, SM and FG. Writing – review and editing: All authors. Supervision: FG. 4
Competing interests 5
The authors declare no competing financial interests. 6
7
Keywords: central visual system • visual perception • isoluminant chromatic flickering • human 8
brain metabolism lactate BOLD fMRI single voxel
1
H-fMRS 9
Abstract word count: 190 10
Word count: about 5400 (excluding abstract, references and figure legends). 11
Number of Tables: 3 12
Number of figures: 4 13
References count: 95 14
Supplementary Information: 5 Figures (as supplements to main text figures), 1 Movie. 15
16
Article type: Research Article 17
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 20, 2021. ; https://doi.org/10.1101/2021.09.17.460759doi: bioRxiv preprint

Page 3 of 38
Authors Contact Information 18
Mauro DiNuzzo
ORCiD: https://orcid.org/0000-0003-0181-5597
email: mauro.dinuzzo@neuroenergetics.org
Silvia Mangia
ORCiD: https://orcid.org/0000-0001-6341-4516
email: mangia@umn.edu
Marta Moraschi
ORCiD: https://orcid.org/0000-0003-4789-6636
email: martamoras@gmail.com
Daniele Mascali
ORCiD: https://orcid.org/0000-0003-1269-6060
email: daniele.mascali@unich.it
Gisela E. Hagberg
ORCiD: https://orcid.org/0000-0003-2176-7086
email: gisela.hagberg@tuebingen.mpg.de
Federico Giove
ORCiD: https://orcid.org/0000-0002-6934-3146
email: federico.giove@cref.it
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 20, 2021. ; https://doi.org/10.1101/2021.09.17.460759doi: bioRxiv preprint

Page 4 of 38
Abstract
Processing of incoming sensory stimulation triggers an increase of cerebral perfusion and blood 19
oxygenation (neurovascular response) as well as an alteration of the metabolic neurochemical 20
profile (neurometabolic response). Here we show that perceived and unperceived isoluminant 21
chromatic flickering stimuli designed to have similar neurovascular responses as measured by 22
blood oxygenation level dependent functional MRI (BOLD-fMRI) in primary visual cortex (V1) 23
have markedly different neurometabolic responses as measured by functional MRS. In particular, 24
a significant regional buildup of lactate, an index of aerobic glycolysis, and glutamate, an index of 25
malate-aspartate shuttle, occurred in V1 only when the flickering is perceived, without any relation 26
with behavioral or physiological variables. Wheras the BOLD-fMRI signal in V1, a proxy for input 27
to V1, was insensitive to flickering perception by design, the BOLD-fMRI signal in secondary 28
visual areas was larger during perceived than unperceived flickering indicating increased output 29
from V1. These results indicate that the upregulation of energy metabolism induced by visual 30
stimulation depends on the type of information processing taking place in V1, and that 1H-fMRS 31
provides unique information about local input/output balance that is not measured by BOLD-32
fMRI. 33
Significance statement: 34
Visual perception has a measurable metabolic effect in the primary visual cortex (V1). Here we 35
show that the upregulation of energy metabolism induced by isoluminant chromatic flickering 36
depends on subjective visual perception. Within V1, perceived and unperceived stimuli that are 37
contrast-matched to elicit similar blood-oxygenation level-dependent fMRI response are 38
associated with clearly distinct neurochemical profiles. Specifically, regional accumulations of 39
lactate (an index of aerobic glycolysis) and glutamate (an index of malate-aspartate shuttle) only 40
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 20, 2021. ; https://doi.org/10.1101/2021.09.17.460759doi: bioRxiv preprint

Page 5 of 38
develop during perceived stimuli, together with a larger activation of secondary visual areas. Our 41
results imply a dissociation between metabolic and functional response, and indicate that that the 42
upregulation of energy metabolism induced by visual stimulation depends on the type of 43
information processing taking place in V1. 44
.CC-BY 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted September 20, 2021. ; https://doi.org/10.1101/2021.09.17.460759doi: bioRxiv preprint

References
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10,002 citations

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TL;DR: The results suggest the need for greater care in dealing with subject motion, and the need to critically revisit previous rs-fcMRI work that may not have adequately controlled for effects of transient subject movements.

6,411 citations

Journal ArticleDOI
Nikos K. Logothetis1, J Pauls1, Mark Augath1, T Trinath1, Axel Oeltermann1 
12 Jul 2001-Nature
TL;DR: These findings suggest that the BOLD contrast mechanism reflects the input and intracortical processing of a given area rather than its spiking output, and that LFPs yield a better estimate of BOLD responses than the multi-unit responses.
Abstract: Functional magnetic resonance imaging (fMRI) is widely used to study the operational organization of the human brain, but the exact relationship between the measured fMRI signal and the underlying neural activity is unclear. Here we present simultaneous intracortical recordings of neural signals and fMRI responses. We compared local field potentials (LFPs), single- and multi-unit spiking activity with highly spatio-temporally resolved blood-oxygen-level-dependent (BOLD) fMRI responses from the visual cortex of monkeys. The largest magnitude changes were observed in LFPs, which at recording sites characterized by transient responses were the only signal that significantly correlated with the haemodynamic response. Linear systems analysis on a trialby-trial basis showed that the impulse response of the neurovascular system is both animal- and site-specific, and that LFPs yield a better estimate of BOLD responses than the multi-unit responses. These findings suggest that the BOLD contrast mechanism reflects the input and intracortical processing of a given area rather than its spiking output.

6,140 citations

Journal ArticleDOI
TL;DR: In this paper, a series of images were acquired continuously with the same imaging pulse sequence (either gradient echo or spin-echo inversion recovery) during task activation, and a significant increase in signal intensity (paired t test; P less than 0.001) of 1.8% +/- 0.9% was observed in the primary visual cortex (V1) of seven normal volunteers.
Abstract: Neuronal activity causes local changes in cerebral blood flow, blood volume, and blood oxygenation. Magnetic resonance imaging (MRI) techniques sensitive to changes in cerebral blood flow and blood oxygenation were developed by high-speed echo planar imaging. These techniques were used to obtain completely noninvasive tomographic maps of human brain activity, by using visual and motor stimulus paradigms. Changes in blood oxygenation were detected by using a gradient echo (GE) imaging sequence sensitive to the paramagnetic state of deoxygenated hemoglobin. Blood flow changes were evaluated by a spin-echo inversion recovery (IR), tissue relaxation parameter T1-sensitive pulse sequence. A series of images were acquired continuously with the same imaging pulse sequence (either GE or IR) during task activation. Cine display of subtraction images (activated minus baseline) directly demonstrates activity-induced changes in brain MR signal observed at a temporal resolution of seconds. During 8-Hz patterned-flash photic stimulation, a significant increase in signal intensity (paired t test; P less than 0.001) of 1.8% +/- 0.8% (GE) and 1.8% +/- 0.9% (IR) was observed in the primary visual cortex (V1) of seven normal volunteers. The mean rise-time constant of the signal change was 4.4 +/- 2.2 s for the GE images and 8.9 +/- 2.8 s for the IR images. The stimulation frequency dependence of visual activation agrees with previous positron emission tomography observations, with the largest MR signal response occurring at 8 Hz. Similar signal changes were observed within the human primary motor cortex (M1) during a hand squeezing task and in animal models of increased blood flow by hypercapnia. By using intrinsic blood-tissue contrast, functional MRI opens a spatial-temporal window onto individual brain physiology.

4,138 citations

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CC-BY 4. 0 International license available under a ( which was not certified by peer review ) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.