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Origins of 1/f-like tissue oxygenation fluctuations in the murine cortex

['Qingguang Zhang', 'Center For Neural Engineering', 'Department Of Engineering Science', 'Mechanics', 'The Pennsylvania State University', 'University Park', 'Pennsylvania', 'United States Of America', 'Kyle W. Gheres', 'Graduate Program In Molecular Cellular']
Date: None

The concentration of oxygen in the brain spontaneously fluctuates, and the distribution of power in these fluctuations has a 1/f-like spectra, where the power present at low frequencies of the power spectrum is orders of magnitude higher than at higher frequencies. Though these oscillations have been interpreted as being driven by neural activity, the origin of these 1/f-like oscillations is not well understood. Here, to gain insight of the origin of the 1/f-like oxygen fluctuations, we investigated the dynamics of tissue oxygenation and neural activity in awake behaving mice. We found that oxygen signal recorded from the cortex of mice had 1/f-like spectra. However, band-limited power in the local field potential did not show corresponding 1/f-like fluctuations. When local neural activity was suppressed, the 1/f-like fluctuations in oxygen concentration persisted. Two-photon measurements of erythrocyte spacing fluctuations and mathematical modeling show that stochastic fluctuations in erythrocyte flow could underlie 1/f-like dynamics in oxygenation. These results suggest that the discrete nature of erythrocytes and their irregular flow, rather than fluctuations in neural activity, could drive 1/f-like fluctuations in tissue oxygenation.

Funding: This work was supported by the National Institutes of Health grant R01NS078168 to P.J.D., and the National Institutes of Health grant R01NS108407 “Understanding cellular architecture of the neurovascular unit and its function in the whole mouse brain” to Dr. Yongsoo Kim (Department of Neural and Behavioral Sciences, College of Medicine, The Pennsylvania State University). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

To understand the relationship between neural activity and 1/f-like oxygen tension oscillations in the brain, we used oxygen polarography to directly measure brain tissue oxygenation in different cortical regions and layers in awake mice. We find that in unanesthetized, head-fixed mice, (1) cortical oxygenation showed 1/f-like power spectra that are similar across cortical regions and layers; (2) the BLP of LFP activity did not show 1/f-like power spectra; (3) there was significant coherence and correlation between neural activity and tissue oxygenation, but both were small; (4) silencing neural activity did not stop 1/f-like fluctuations in brain oxygenation; and (5) simulations of erythrocyte flow, taking into account the statistics of erythrocyte spacing, showed that the irregular nature of erythrocyte spacing can generate 1/f-like dynamics in tissue oxygenation. Our results suggest that the driver of 1/f-like oxygenation fluctuations is nonneuronal in origin and could be due to fluctuations in RBC flux through the capillary network.

As 1/f-like oxygen fluctuations are found in other organs besides the brain [ 1 , 2 ], their origin may not be neural and could come from vascular process. Blood flow and arterial diameter show fluctuations in a similar frequency range as oxygen fluctuations [ 3 ]. Additionally, as oxygen is carried by red blood cells (RBCs), fluctuations in the flux of RBCs can drive erythrocyte-associated transients (EATs) in oxygen in the tissue [ 76 – 92 ], and fluctuations in flux of these changes in local oxygenation in the cortex [ 93 – 97 ]. Stalls, brief stoppages in blood flow through capillaries, happen sporadically and continuously in the cortex due to transient blockage of blood flow by leukocytes [ 98 – 103 ], which are known to greatly increase vascular resistance [ 104 ]. These blockages likely drive changes in tissue oxygenation [ 105 ], and increased frequency of these stalls has been linked to neurodegenerative disorders [ 98 , 99 , 105 ].

Though there are many studies investigating the relationship between neural activity and vasodilation, there is a paucity of studies simultaneously measuring neural activity and oxygen changes [ 63 – 66 ], with only a handful looking in awake animals [ 8 , 20 , 67 ]. Whether 1/f-like dynamics in brain oxygenation are driven by neural activity bears on the interpretation of hemodynamic imaging. Several fMRI studies have suggested that 1/f-like dynamics exist in human BOLD signals [ 68 – 71 ], and the 1/f-like fluctuations in brain hemodynamics have been interpreted as being driven by 1/f-like fluctuations in neural activity [ 72 , 73 ]. However, recordings of the LFP in both humans [ 74 ] and nonhuman primates [ 75 ] do not seem to show 1/f dynamics in band-limited power (BLP).

There have been speculations that the ultraslow (<1 Hz) electrical signals are the neural correlate of brain hemodynamics [ 49 – 51 ], but frequencies below 1 Hz in the LFPs are of a nonneuronal origin (see [ 36 ] for review; [ 52 – 57 ]). Because the electrical potential of the blood is negative relative to that of the cerebral spinal fluid [ 52 , 53 ], changes in the blood volume in the brain will generate ultraslow potentials. The dilation of arterioles (occurs over seconds) and veins (occurs over tens of seconds) in awake animals’ brain [ 58 – 60 ] will generate changes (<1 Hz) in the LFP [ 54 – 57 ]. The nonneuronal origin of <1 Hz electrical signals has been shown with manipulations that dilate or constrict blood vessels independent of changes in neural activity, such as CO 2 inhalation [ 55 – 57 , 61 ], head tilt, and Valsalva maneuver [ 54 ]. Additionally, most amplifiers have circuitry setup to reject these very low frequencies [ 62 ], so unless the recording setup is specifically designed to measure at DC frequencies, signals <1 Hz are not of a physiological origin.

Brain tissue oxygenation is determined by the balance between the oxygen supplied by the blood and the oxygen consumed by mitochondria in neurons, astrocytes, and mural cells of the brain parenchyma. Both of these processes could contribute to fluctuations in oxygenation. Increases in brain neural activity are usually accompanied by vasodilation and increased blood flow/volume that leads to increases in oxygenation [ 22 ]. The resulting change in oxygenation will involve an interplay of factors, with the increase in blood flow usually, but not always, driving an oxygen increase [ 20 ]. The linkage of oxygenation to neural activity is widely used to infer neural activity noninvasively using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) [ 23 ]; however, there are many examples of neural and vascular signals departing from this relationship [ 24 – 29 ]. Converging evidence from a large body of studies in both rodents and primates have shown that power in the gamma band (nominally 40 to 100 Hz) of the local field potential (LFP) is most closely related to the vasodilation that leads to increased blood volume and flow [ 30 – 36 ]. Spiking activity has similar correlations to blood volume as gamma-band LFP power [ 30 , 37 , 38 ], while the correlations for other bands of the LFP are much lower [ 30 , 31 , 34 ]. The signal in the LFP is the sum of population activity within the spatial area spanned by the electrodes [ 39 ]. Its precise relations to underlying neuronal activity is complex [ 40 ], but the LFP is primarily driven by synaptic currents generated by the interaction between pyramidal neurons and parvalbumin-positive interneurons [ 41 – 43 ]. The synaptic currents that drive the LFP are largely generated by local spiking, not from input from other areas, as localized increase in pyramidal neuron activity (generated with optogenetic or chemogenetic approaches) causes large increases in gamma-band power [ 41 , 42 , 44 ], and suppression of local neural activity drives large decreases in gamma-band power [ 44 ]. Given the interrelatedness of gamma-band oscillations and local neuronal spiking, it is not surprising that in the awake animal, increases in local spiking and gamma-band power tend to be strongly correlated [ 45 – 48 ].

Fluctuations in oxygen tension are ubiquitous throughout the body and are found in muscle tissue and tumors [ 1 ], in the retina [ 2 , 3 ], in the carotid artery [ 4 ], and in the cortex [ 5 – 12 ]. Despite their ubiquity, relatively little is understood about the origin of these oxygen fluctuations. While some of these fluctuations are driven by fluctuations in respiration, such as the breathing rate and intensity [ 4 , 13 – 20 ], fluctuations in oxygen concentration are present covering a wide range of frequency, not just at the respiration frequency, with most of the power concentrated at lower (<0.1 Hz) frequencies [ 1 , 2 , 5 , 7 – 9 ]. The power spectrum of oxygen concentrations in many tissues shows a “1/f-like” behavior, that is, the power at any given frequency f is proportional to 1/f β , where the exponent β is usually between 1 and 2 [ 8 ]. The hallmark of 1/f-like signals is that the power at lower frequencies is much larger than at higher frequencies, producing signals with rapid, small oscillations riding on top of much larger, but slower fluctuations. We refer to these oscillations as being 1/f-like because they are only characterized within a limited frequency region (here, ≥0.01 Hz and ≤1 Hz). While many biological processes have been shown to exhibit 1/f-like dynamics, a process can only be said to be 1/f if there are data over at least 2 orders of magnitude in both the abscissa and ordinate [ 21 ], a criterion that only a few studies meet [ 8 ]. In contrast, white noise has a constant power across frequencies, which when fitted with a power law gives a β close to 0 ( S1 Fig , panel A). In both cases, there can be “extra” spectral power concentrated in a single band, leading to a “bump” in the spectrum ( S1 Fig , panels B and D). Measurements of brain tissue oxygenation in primates show a clear, statistically robust 1/f-like power spectra, with an additional peak near 0.1 Hz [ 8 ].

Results

We measured tissue oxygenation signals and neural activity from the somatosensory and frontal cortices of awake behaving mice head fixed on a spherical treadmill [20,24,30,106]. We recorded laminar neural activity with linear multisite probes in 7 mice, laminar oxygenation using polarographic electrodes in 37 mice, and simultaneous neural activity, respiration, and oxygen measurements in 9 mice. Additionally, 9 mice were used to measure RBCs spacing in capillaries using two-photon laser scanning microscopy (2PLSM). We reported results for “rest,” which only include data from periods of time when the animal was not locomoting, or for all data, which include periods of locomotion and rest. We did this because unanesthetized mice engage in spontaneous movement frequently, and these spontaneous movements are large drivers of neural activity and hemodynamic signals [30,36,107–109]. Specifically, cutaneous sensation during locomotion drives large increases in neural activity in the forelimb/hindlimb (FL/HL) region [20,24,110,111]. The increase in neural activity drives localized increases in blood flow, which is not due to systemic factors [20,112]. Neural and oxygen measurements were made in the frontal cortex (FC) and in the FL/HL region of the somatosensory cortex (identified by cytochrome oxidase staining [113]). All power spectra and frequency-domain analyses were done using multitaper techniques [114], which minimize spectral leakage, using the Chronux toolbox (http://chronux.org/). In addition, we applied a time-domain analysis method, detrended fluctuation analysis (DFA) [115], which complements the frequency-domain approach, to rigorously test the 1/f-like dynamics in various signals. Portions of this dataset have been published previously [20]. In this previous report, we found that locomotion significantly and globally increases cerebral oxygenation, in brain regions involved in locomotion, as well as in the FC and the olfactory bulb. The oxygenation increase persists when neural activity and functional hyperemia are blocked, occurred both in the tissue and in arteries feeding the brain, and is tightly correlated with respiration rate and the phase of respiration cycle.

[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001298

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