Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety.

Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate. Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain regions underlies primates' capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex, a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.

Task-related BOLD responses and resting-state functional connectivity during physiological clamping of end-tidal CO(2).

Carbon dioxide (CO(2)), a potent vasodilator, is known to have a significant impact on the blood-oxygen level dependent (BOLD) signal. With the growing interest in studying synchronized BOLD fluctuations during the resting state, the extent to which the apparent synchrony is due to variations in the end-tidal pressure of CO(2) (PETCO(2)) is an important consideration. CO(2)-related fluctuations in BOLD signal may also represent a potential confound when studying task-related responses, especially if breathing depth and rate are affected by the task. While previous studies of the above issues have explored retrospective correction of BOLD fluctuations related to arterial PCO(2), here we demonstrate an alternative approach based on physiological clamping of the arterial CO(2) level to a near-constant value. We present data comparing resting-state functional connectivity within the default-mode-network (DMN), as well as task-related BOLD responses, acquired in two conditions in each subject: 1) while subject's PETCO(2) was allowed to vary spontaneously; and 2) while controlling subject's PETCO(2) within a narrow range. Strong task-related responses and areas of maximal signal correlation in the DMN were not significantly altered by suppressing fluctuations in PETCO(2). Controlling PETCO(2) did, however, improve the performance of retrospective physiological noise correction techniques, allowing detection of additional regions of task-related response and resting-state connectivity in highly vascularized regions such as occipital cortex. While these results serve to further rule out systemic physiological fluctuations as a significant source of apparent resting-state network connectivity, they also demonstrate that fluctuations in arterial CO(2) are one of the factors limiting sensitivity in task-based and resting-state fMRI, particularly in regions of high vascular density. This must be considered when comparing subject groups who might exhibit differences in respiratory physiology or breathing patterns.

Localization of the cortical response to smiling using new imaging paradigms with functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) can serve to localize activity in the cerebral cortex. The present study was performed to develop a quantitative means of describing the cortical location activated during voluntary smiling in multiple subjects and to determine whether this location is specific to smiling when compared with other motor tasks. Five human subjects were instructed to smile or to tap the fingers of both hands. Both tasks were performed in a blocked-trial paradigm that consisted of alternating 15-second blocks of a repetitive motor task and 15 seconds of rest. Smiling was also performed as an event-related paradigm in which the subject smiled briefly once every 15 seconds for 20 repetitions that were combined to produce an average response to a single smile. A series of 300 images was acquired using an echo-planar imaging sequence (24-cm field of view; 5-mm slice thickness; repetition time/echo time, 1000/27.2 msec). Each subject's three-dimensional brain images were transformed to Talairach coordinates by stretching or compressing the brain images to fit the standard brain as defined in the Talairach atlas. This allowed data from five subjects to be combined for a numeric description. Functional activation maps acquired by use of the event-related paradigm contained significantly fewer motion artifacts than maps acquired with the blocked-trial paradigm, allowing better visualization of functionally active areas. Three-dimensional Talairach coordinates to describe the locations of peak cortical activity after smiling and finger tapping were established. These coordinates were consistent among subjects. During smiling, statistically significant activation was seen in the motor cortex, primarily along the precentral sulcus; this was inferior and anterior to the region that was associated with finger tapping. This study demonstrates that motion artifacts associated with traditional blocked-trial fMRI protocols can be overcome by employing an event-related paradigm to obtain an average response from a single smile. With the implementation of new imaging paradigms with fMRI, an area of the cerebral cortex has been identified that is specifically activated during voluntary smiling, and remains consistent among subjects. Quantification of fMRI data represents a powerful tool by which to study the cortical response to motor activity and to monitor possible alteration in this activity after injury or surgery. When combined with biofeedback therapy, this technique may help to improve the outcome of facial reanimation procedures in the future.

Spatial heterogeneity of the nonlinear dynamics in the FMRI BOLD response.

Recent studies of blood oxygenation level dependent (BOLD) signal responses averaged over a region of interest have demonstrated that the response is nonlinear with respect to stimulus duration. Specifically, shorter duration stimuli produce signal changes larger than expected from a linear system. The focus of this study is to characterize the spatial heterogeneity of this nonlinear effect. A series of MR images of the visual and motor cortexes were acquired during visual stimulation and finger tapping, respectively, at five different stimulus durations (SD). The nonlinearity was assessed by fitting ideal linear responses to the responses at each SD. This amplitude, which is constant for different SD in a linear system, was normalized by the amplitude of the response to a blocked design, thus describing the amount by which the stimulus is larger than predicted from a linear extrapolation of the response to the long duration stimulus. The amplitude of the BOLD response showed a nonlinear behavior that varied considerably and consistently over space, ranging from almost linear to 10 times larger than a linear prediction at short SD. In the motor cortex different nonlinear behavior was found in the primary and supplementary motor cortexes.

Event-related fMRI of tasks involving brief motion.

The assessment of brain function by blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) for tasks involving motion near the field of view is compromised by artifacts arising from the motion. The aim of this study is to demonstrate that these artifacts can be reduced by acquiring the average response from a brief stimulus (a "single-trial," or "event-related," paradigm) as opposed to alternating blocks of repeated task with rest (a "block-trial" paradigm). The basis of this technique is that the NMR signal changes from neuronal activation are delayed relative to the motion due to a slow hemodynamic response. By acquiring the average response from a brief stimulus, motion-induced signal changes occur prior to neuronal activation-induced signal changes, and the two can thus be distinguished. This technique is applied to the tasks of speaking out loud, swallowing, jaw clenching, and tongue movement. Functional activation maps derived from the single-trial paradigm contain significantly less artifact than functional activation maps derived from a more traditional block-trial paradigm.

Identification and characterization of cerebral cortical response to esophageal mucosal acid exposure and distention.

BACKGROUND & AIMS: Esophageal acid exposure is a common occurrence in healthy individuals and patients with esophagitis. Clinically, perception of this exposure ranges from no perception to severe heartburn and chest pain. Cerebral cortical response to esophageal mucosal contact to acid has not been systematically studied. The aim of this study was to elucidate cerebral cortical response to esophageal acid exposure in normal individuals by functional magnetic resonance imaging (FMRI). METHODS: We studied 10 normal healthy volunteers. Cortical FMRI response to 10 minutes of intraesophageal perfusion of 0.1N HCl (1 mL/min) was determined, and the results were compared with those of saline infusion and balloon distention. RESULTS: Acid perfusion did not induce heartburn or chest pain but increased FMRI signal intensity by 6.7% +/- 2.0% over the preperfusion values. No increase was detected for saline infusion. FMRI signal intensity to balloon distention was similar to that of acid perfusion. Activation latency, activation to peak, and the deactivation periods for response to acid perfusion were significantly longer than those of balloon distention (P < 0.05). CONCLUSIONS: Contact of esophageal mucosa with acid, before inducing heartburn, evokes a cerebral cortical response detectable by FMRI. Temporal characteristics of this response are significantly different from those induced by esophageal balloon distention.

Magnetic field changes in the human brain due to swallowing or speaking.

Variations in the magnetic field in the human brain caused by the processes of swallowing or speaking are measured. In both processes, motion of the pharyngeal muscles, especially the tongue and jaw, alter the susceptibility-induced magnetic field distribution at the brain slice being imaged. This leads to image warping, compromising the analysis of a time series of images, such as in functional magnetic resonance imaging (fMRI). These dynamic changes are assessed by acquiring a time series of images using a gradient-echo asymmetric-spin-echo sequence (GREASE), a technique in which two images are acquired for each excitation--one during the gradient echo, and one during the latter part of the spin echo. The NMR phase difference between the two images is a measure of the magnetic field distribution. A series of brain images, acquired with this sequence while the subject either swallows or speaks, indicated negative magnetic field changes of up to 0.087 ppm in the inferior region of the brain for both speaking and swallowing, and in some speech, additional positive changes of up to 0.056 ppm in the frontal region of the brain were indicated.

Functional MRI of brain activation induced by scanner acoustic noise.

A method is introduced by which brain activation caused by the acoustic noise associated with echo planar imaging (EPI) is mapped. Two types of time series were compared. The first time series, considered the "task," involved applying only EPI gradients for 20 s without the application of RF pulses, then, without pause, starting image collection. The second, considered the "control," involved typical sequential image acquisition without the prior gradient pulses. Subtraction of the first 5 s of the two time series revealed signal enhancement mainly in the primary auditory cortex. The technique was validated using a motor cortex task that mimicked the hypothesized scanner noise induced activation.

Effect of motion outside the field of view on functional MR.

PURPOSE: To evaluate the effect of objects moving outside the field of view on functional MR imaging. METHODS: Echo-Planar image sequences were acquired in the sagittal plane of a stationary phantom or of the head of a volunteer subject while a second phantom was moved periodically outside the field of view. The signal intensity changes in each pixel within the field of view were measured. RESULTS: Movement of the phantom outside the field of view produced signal intensity changes in the field of view that equaled or exceeded typical functional activation without the latency that characterizes activation. The greatest changes occurred at the bottom and top edges in the phantom and at the interfaces in the head. CONCLUSION: If temporally correlated with the performance of a task, movement of objects or tissues outside the field of view may produce artifactual changes in signal intensity. The artifactual signal intensity changes were characterized by their location, greater magnitude, and more rapid rise to maximum than seen with typical "activation."