Decades of research have highlighted the amygdala’s influential role in fear. Surprisingly, we found that inhalation of 35% CO2 evoked not only fear, but also panic attacks, in three rare patients with bilateral amygdala damage. These results indicate that the amygdala is not required for fear and panic, and make an important distinction between fear triggered by external threats from the environment versus fear triggered internally by CO2.

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...

Abnormal metabolism has been reported in bipolar disorder, however these studies have been limited to specific regions of the brain. To investigate whole-brain changes potentially associated with these processes, we applied a magnetic resonance imaging technique novel to psychiatric research, quantitative mapping of T1 relaxation in the rotating frame (T1ρ). This method is sensitive to proton chemical exchange, which is affected by pH, metabolite concentrations, and cellular density with high spatial resolution relative to alternative techniques such as magnetic resonance spectroscopy and positron emission tomography. Study participants included 15 patients with bipolar I disorder in the euthymic state and 25 normal controls balanced for age and gender. T1ρ maps were generated and compared between the bipolar and control groups using voxel-wise and regional analyses. T1ρ values were found to be elevated in the cerebral white matter and cerebellum in the bipolar group. However, volumes of these areas were normal as measured by high-resolution T1- and T2-weighted magnetic resonance imaging. Interestingly, the cerebellar T1ρ abnormalities were normalized in participants receiving lithium treatment. These findings are consistent with metabolic or microstructural abnormalities in bipolar disorder and draw attention to roles of the cerebral white matter and cerebellum. This study highlights the potential utility of high-resolution T1ρ mapping in psychiatric research.

The data suggest greater activity-evoked T1ρ changes in the visual cortex and anterior cingulate cortex of panic disorder participants. These observations are consistent with a pH dysregulation in panic disorder. In addition, our data suggest that T1ρ imaging may provide information about panic disorder that is distinct from conventional BOLD imaging and may reflect abnormalities in pH and/or brain metabolism.

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