Available online at www.sciencedirect.com Current Opinion in ScienceDirect Biomedical Engineering A suite of neurophotonic tools to underpin the contribution of internal brain states in fMRI Philipp Mächler1,2, Thomas Broggini2, Celine Mateo2, Martin Thunemann1, Natalie Fomin-Thunemann1, Patrick R. Doran1, Ikbal Sencan3, Kivilcim Kilic1, Michèle Desjardins4, Hana Uhlirova5, Mohammad A. Yaseen3,6, David A. Boas1, Andreas A. Linninger7, Massimo Vergassola2,8, Xin Yu3, Laura D. Lewis1, Jonathan R. Polimeni3, Bruce R. Rosen3, Sava Sakadzi c3, Richard B. Buxton9, Martin Lauritzen10,11, David Kleinfeld2,12 and Anna Devor1,3 Abstract Recent developments in optical microscopy, applicable for Current Opinion in Biomedical Engineering 2021, 18:100273 large-scale and longitudinal imaging of cortical activity in behaving animals, open unprecedented opportunities to gain a This review comes from a themed issue on Neural Engineering: Brain-computer interface and functional brain imaging deeper understanding of neurovascular and neurometabolic coupling during different brain states. Future studies will Edited by Bin He and Zhongming Liu leverage these tools to deliver foundational knowledge about Received 22 November 2020, revised 19 January 2021, accepted 29 brain state-dependent regulation of cerebral blood flow and January 2021 metabolism, as well as regulation as a function of brain Available online xxx maturation and aging. This knowledge is of critical importance https://doi.org/10.1016/j.cobme.2021.100273 to interpret hemodynamic signals observed with functional 2468-4511/© 2021 Elsevier Inc. All rights reserved. magnetic resonance imaging (fMRI). Keywords Addresses Neuromodulation, Optical imaging, Hemodynamic, CMRO2, Glycolysis. 1 Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA 2 Department of Physics, University of California San Diego, La Jolla, Introduction CA, 92093, USA Advancing our ability to accurately infer microscopic 3 Athinoula A. Martinos Center for Biomedical Imaging, Department of details underlying noninvasive imaging signals requires Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, 02129, USA direct measurement and manipulation of concrete, 4 Département de Physique, de Génie Physique et D’Optique, cellular level physiological parameters. These measure- Université Laval, Québec, QC, G1V 0A6, Canada ments are only available in model organisms such as 5 Institute of Scientific Instruments of the Czech Academy of Science, mice. Recent progress in large-scale microscopic imag- Brno, Czech Republic ing technology and the development of genetically 6 Department of Bioengineering, Northeastern University, Boston, MA, 02115, USA encoded optical probes have enabled chronic imaging in 7 Department of Bioengineering, University of Illinois at Chicago, awake behaving mice. This opens the door for longitu- Chicago, IL, 60607, USA dinal studies of brain neuronal, vascular, and metabolic 8 Département de Physique de L’Ecole Normale Supérieure, 75005, function across specific behavioral states that differ in Paris, France the processing capacity of cortical neuronal circuits. 9 Department of Radiology, University of California San Diego, La Jolla, CA, 92037, USA Here, we highlight several novel neurophotonics tools in 10 Department of Neuroscience and Pharmacology, University of the context of specific neuroscience problems that have Copenhagen, Copenhagen, N 2200, Denmark moved within reach of the greater research community. 11 Department of Clinical Neurophysiology, Glostrup Hospital, Glostrup, 2600, Denmark 12 Section on Neurobiology, University of California San Diego, La Spontaneous large-scale cortical activity Jolla, CA, 92093, USA and physiological underpinning of resting- state fMRI Corresponding author: Devor, Anna ([email protected]) www.sciencedirect.com Current Opinion in Biomedical Engineering 2021, 18:100273 2 Neural Engineering: Brain-computer interface and functional brain imaging The puzzling phenomenon of spontaneous large- differ in the attentional capability and processing ca- scale cortical activity pacity of cortical circuits [44,45]. Spontaneous large-scale neuronal activity, and activity that far extends beyond the boundaries of receptive Although state-dependent neurovascular coupling re- fields from punctate stimulation, is a long-recognized mains largely unexplored, arousal states, including rapid aspect of neuronal dynamics that has received eye movement (REM) and nonrapid eye movement renewed attention in light of its potential impact on (NREM) sleep, have been shown to strongly modulate neurocomputation [1e3]. While large-scale patterns of hemodynamic signals in mice that naturally fall asleep brain activity have been described since the earliest days during imaging [46]. This finding is in agreement with of electrophysiological measurements with awake ani- the known vasoactive role of neuromodulatory trans- mals, a striking advance occurred with the advent of mitters that can act on vascular receptors [47] in addi- Blood Oxygenation Level-Dependent (BOLD) func- tion to the modulating activity of neuronal circuits. tional Magnetic Resonance Imaging (fMRI) in resting Pharmacological activation of these receptors, including human subjects close to two decades ago (reviewed in those selectively expressed in microvessels, was Ref. [4]). These fMRI studies revealed large-scale, demonstrated to affect cerebral blood flow (CBF) and coherent fluctuations of the fMRI signal that the BOLD signal [48]. resemble the known pattern of functionally engaged cortical regions [5e8]. The BOLD signal reflects he- Electrophysiologically, brain states of attention, arousal, modynamics and O2 metabolism rather than neuronal and vigilance are manifested by ‘desynchronized’ activity per se [9,10]; therefore, the possibility that these cortical local field potential (LFP), where the power of spatial patterns of temporally coordinated hemodynamic low-frequency rhythmicity (<30 Hz) decrements and fluctuations, dubbed ‘resting-state’ networks, reflect the power of high frequencies or g-band rhythmicity spontaneous neuronal activity was initially met with (w30e90 Hz) increases [49]. The power of the g-band skepticism; however, today, a large body of experimental oscillations cofluctuates in brain regions with a shared evidence demonstrates that these signals are signifi- function. In resting mice, the state of arousal fluctuates cantly, albeit incompletely driven by neuronal activity in continuously on the scale of tens of seconds; this sup- rodents, nonhuman primates, and humans [11e26]. ports the idea that ultraslow (w0.1 Hz) fluctuations in the g-band power may be reflecting internal brain state In mice, recent technological advances now allow dynamics [50]. chronic imaging of the entire dorsal part of the cortex. These advances include large field-of-view or multi- Recently, using optical imaging methods, Mateo et al. region two-photon microscopes [27e30], mesoscopic [12] have demonstrated in an awake mouse study that single-photon imagers [13,31], and novel techniques to these ultra-slow frequency fluctuations in the g-band produce large cranial windows [32,33]. Combined with power, that is, variations around 0.1 Hz, will entrain the þ genetically encoded calcium (Ca2 ) indicators of dynamics of vasomotion in pial arterioles. This coupled neuronal activity [34], which record a trace of neuronal the slowly varying amplitude of the ongoing g-band spiking, these tools obtain a glimpse of the large-scale rhythm to the resting-state fMRI signal [12](Figure 1). spontaneous neuronal activity that contributes to This finding is apparently at odds with a recent study in resting-state hemodynamic fluctuations [11,13e16]. awake monkeys showing that pharmacological inactiva- tion of the basal forebrain, a center for cholinergic Large-scale cortical neuronal activity and ascending innervation, selectively diminished only spatially very neuromodulation broad hemodynamic correlations within the affected One possibility for the generation of spontaneous large- hemisphere, while finer scale correlations remained scale neuronal activity is that the dynamics reflect a [39]; however, the effect of inactivation depended on continuous ‘handshaking’ of synaptically connected the level of arousal and suggests possible engagement of brain regions [4]; however, some of the observed co- other neuromodulation systems, including intrinsic varying areas are not directly anatomically connected, cholinergic neurons in the cortex [51], to compensate such as the primary visual cortex across the two hemi- for cholinergic ‘denervation’. spheres. An alternative explanation for this neuronal activity is common inputs [35], which include ascending The activity of specific neuromodulatory afferents in the neuromodulation [4,36e38], such as cholinergic pro- cerebral cortex can now be directly measured, in real jections from the basal forebrain [39], adrenergic pro- time in animals, with sensitive optical probes for the jections from the locus coeruleus [40,41], dopaminergic respective neurotransmitters [52], including acetylcho- projections from the ventral tegmental area and the line [53,54], norepinephrine [55], dopamine [55,56], substantia nigra [42], and serotonergic projections from and serotonin [57]. This formidable advance in molec- the raphe nuclei [43]. These neuromodulatory systems ular engineering offers direct sensing of these neuro- work in parallel to generate internal brain states that transmitters’