Detecting activity-evoked pH changes in human brain

Abstract

Localized pH changes have been suggested to occur in the brain during normal function. However, the existence of such pH changes has also been questioned. Lack of methods for noninvasively measuring pH with high spatial and temporal resolution has limited insight into this issue. Here we report that a magnetic resonance imaging (MRI) strategy, T 1 relaxation in the rotating frame (T 1 ρ), is sufficiently sensitive to detect widespread pH changes in the mouse and human brain evoked by systemically manipulating carbon dioxide or bicarbonate. Moreover, T 1 ρ detected a localized acidosis in the human visual cortex induced by a flashing checkerboard. Lactate measurements and pH-sensitive 31 P spectroscopy at the same site also identified a localized acidosis. Consistent with the established role for pH in blood flow recruitment, T 1 ρ correlated with blood oxygenation level-dependent contrast commonly used in functional MRI. However, T 1 ρ was not directly sensitive to blood oxygen content. These observations indicate that localized pH fluctuations occur in the human brain during normal function. Furthermore, they suggest a unique functional imaging strategy based on pH that is independent of traditional functional MRI contrast mechanisms. T o what degree pH changes during normal brain function is unclear (1). However, neuronal activity could cause transient, localized pH changes via several mechanisms. Increased neuronal activity enhances carbohydrate metabolism producing the pHlowering by-products lactic acid and CO 2 (2). Activity-evoked HCO 3 − transport can alter pH (3). Local field potentials produced by ion fluxes could change pH (4). In addition, acidic synaptic vesicles release protons during neurotransmission (5). Such dynamic pH fluctuations have the potential to dramatically alter physiology and behavior through a number of pH-sensitive receptors and channels (6). Acid-sensing ion channels, for example, play critical roles in synaptic plasticity, learning, memory, pain, and neurodegeneration (7-10). Superimposed on activity-dependent brain pH changes and the potential physiological effects are several buffering systems. Principal among these is the CO 2 /HCO 3 − system. In a reversible reaction, CO 2 combines with water to form carbonic acid, which readily dissociates into HCO 3 − and H + . Raising HCO 3− shifts the equilibrium away from H + and increases pH. Conversely, raising CO 2 shifts the equilibrium toward H + , thereby lowering pH. The ability to measure these pH changes in the functioning brain is key for gaining insight into this poorly understood dimension of CNS physiology and pathophysiology.Routinely measuring pH in the brain would require novel noninvasive methods. Traditionally, 31 P spectroscopy has been used to estimate brain pH (11); however, 31 P is limited by poor spatial resolution (typically 10-to 30-cm 3 volumes), long acquisition times (often 5-10 min for a single measurement), and the need for special hardware not typically available on clinical scanners. Recently, 1 H MRI pulse...

Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase

“…The present findings suggest that this pH-normalizing effect of reperfusion may explain, in part, why superoxide production is greater in reperfused than nonreperfused ischemic brain, and why both NOX2 inhibitors and NMDA receptor antagonists are better neuroprotective agents in reperfused brain than nonreperfused brain (41)(42)(43). The degree of intracellular acidification shown here to influence neuronal superoxide production is within the range induced by physiological brain activity (28,44). Intracellular pH changes may thereby also influence the normal, physiological intercellular signaling mediated by neuronal superoxide production (45).…”

Neuronal hyperactivity causes Na+/H+ exchanger-induced extracellular acidification at active synapses

“…While pH affects neural activity, neural activity causes pH alterations that vary in location and time (Chen and Chesler, 1992;Dulla et al, 2005;Makani and Chesler, 2007). Local pH changes occur in the brain during normal function (Chesler and Kaila, 1992;Magnotta et al, 2012), and neuronal firing causes both intracellular and extracellular pH shifts (Chesler, 2003;Chesler and Kaila, 1992;Kim and Trussell, 2009;Trapp et al, 1996). Rapid changes in intracellular pH have been observed at Drosophila nerve terminals during high-frequency in vivo activity (Caldwell et al, 2013;Rossano et al, 2013), while in the mammalian CNS, intense and synchronous activity of neural networks is accompanied by an initial alkalinization followed by a slower wave of acidification of the extracellular environment (DeVries, 2001;Du et al, 2014).…”

Relationship altered between functional T1ρ and BOLD signals in bipolar disorder

“…An alternative fMRI approach to BOLD was recently proposed based on T1 relaxation in the rotating frame (T1ρ), called functional T1 ρ mapping (fT1ρ) (Jin & Kim, 2013; Johnson, Heo, Thedens, Wemmie, & Magnotta, 2014; Magnotta et al., 2012). This technique aims to quantitatively map the spin‐lock–based T1ρ relaxation time temporally and is sensitive to chemical exchange of protons between water and amide, hydroxyl, and/or amine groups (Jin, Autio, Obata, & Kim, 2011).…”

“…It has previously been shown that both BOLD and fT1ρ signals reflect functional activity in vivo (Hulvershorn et al., 2005; Jin & Kim, 2013; Magnotta et al., 2012), however, it remains unclear how these two imaging methods relate to each other (Magnotta et al., 2014). In this exploratory study, we investigated the relationship between BOLD and fT1ρ activation in response to a flashing checkerboard stimulus in participants with bipolar disorder and in matched healthy controls.…”