Reliable non-invasive measurement of human neurochemistry using proton spectroscopy with an anatomically defined amygdala-specific voxel.

Given the central role of the amygdala in fear perception and expression and its likely abnormality in affective disorders and autism, there is great demand for a technique to measure differences in neurochemistry of the human amygdala. Unfortunately, it is also a technically complex target for magnetic resonance spectroscopy (MRS) due to a small volume, high field inhomogeneity and a shared boundary with hippocampus, which can undergo opposite changes in response to stress. We attempted to achieve reliable PRESS-localized single-voxel MRS at 3T of the isolated human amygdala by using anatomy to guide voxel size and location. We present data from 106 amygdala-MRS sessions from 58 volunteers aged 10 to 52 years, including two tests of one-week stability and a feasibility study in an adolescent sample. Our main outcomes were indices of spectral quality, repeated measurement variability (within- and between-subject standard deviations), and sensitivity to stable individual differences measured by intra-class correlation (ICC). We present metrics of amygdala-MRS reliability for n-acetyl-aspartate, creatine, choline, myo-Inositol, and glutamate+glutamine (Glx). We found that scan quality suffers an age-related difference in field homogeneity and modified our protocol to compensate. We further identified an effect of anatomical inclusion near the endorhinal sulcus, a region of high synaptic density, that contributes up to 29% of within-subject variability across 4 sessions (n=14). Remaining variability in line width but not signal-to-noise also detracts from reliability. Statistical correction for partial inclusion of these strong neurochemical gradients decreases n-acetyl-aspartate reliability from an intraclass correlation of 0.84 to 0.56 for 7-minute acquisitions. This suggests that systematic differences in anatomical inclusion can contribute greatly to apparent neurochemical concentrations and could produce false group differences in experimental studies. Precise, anatomically-based prescriptions that avoid age-related sources of inhomogeneity and use longer scan times may permit study of individual differences in neurochemistry throughout development in this late-maturing structure.

Simultaneous acquisition of corrugator electromyography and functional magnetic resonance imaging: a new method for objectively measuring affect and neural activity concurrently.

The development of functional neuroimaging of emotion holds the promise to enhance our understanding of the biological bases of affect and improve our knowledge of psychiatric diseases. However, up to this point, researchers have been unable to objectively, continuously and unobtrusively measure the intensity and dynamics of affect concurrently with functional magnetic resonance imaging (fMRI). This has hindered the development and generalizability of our field. Facial electromyography (EMG) is an objective, reliable, valid, sensitive, and unobtrusive measure of emotion. Here, we report the successful development of a method for simultaneously acquiring fMRI and facial EMG. The ability to simultaneously acquire brain activity and facial physiology will allow affective neuroscientists to address theoretical, psychiatric, and individual difference questions in a more rigorous and generalizable way.

Fear is fast in phobic individuals: amygdala activation in response to fear-relevant stimuli.

BACKGROUND: Two core characteristics of pathologic fear are its rapid onset and resistance to cognitive regulation. We hypothesized that activation of the amygdala early in the presentation of fear-relevant visual stimuli would distinguish phobics from nonphobics. METHODS: Chronometry of amygdala activation to phobia-relevant pictures was assessed in 13 spider phobics and 14 nonphobics using functional magnetic resonance imaging (fMRI). RESULTS: Blood oxygen level-dependent (BOLD) responses in the amygdala early in picture processing consistently differentiated between phobic and nonphobic subjects, as well as between phobogenic and nonphobogenic stimuli among phobics. Furthermore, amygdalar BOLD responses associated with timing but not magnitude of activation predicted affective responses to phobogenic stimuli. Computational modeling procedures were used to identify patterns of neural activation in the amygdala that could yield the observed BOLD data. These data suggest that phobic responses were characterized by strong but brief amygdala responses, whereas nonphobic responses were weaker and more sustained. CONCLUSIONS: Results are discussed in the context of the amygdala's role in rapid threat detection and the vigilance-avoidance hypothesis of anxiety. These data highlight the importance of examining the neural substrates of the immediate impact of phobogenic stimuli for understanding pathological fear.

Amygdalar interhemispheric functional connectivity differs between the non-depressed and depressed human brain.

The amygdalae are important, if not critical, brain regions for many affective, attentional and memorial processes, and dysfunction of the amygdalae has been a consistent finding in the study of clinical depression. Theoretical models of the functional neuroanatomy of both normal and psychopathological affective processes which posit cortical hemispheric specialization of functions have been supported by both lesion and functional neuroimaging studies in humans. Results from human neuroimaging studies in support of amygdalar hemispheric specialization are inconsistent. However, recent results from human lesion studies are consistent with hemispheric specialization. An important, yet largely ignored, feature of the amygdalae in the primate brain--derived from both neuroanatomical and electrophysiological data--is that there are virtually no direct interhemispheric connections via the anterior commissure (AC). This feature stands in stark contrast to that of the rodent brain wherein virtually all amygdalar nuclei have direct interhemispheric connections. We propose this feature of the primate brain, in particular the human brain, is a result of influences from frontocortical hemispheric specialization which have developed over the course of primate brain evolution. Results consistent with this notion were obtained by examining the nature of human amygdalar interhemispheric connectivity using both functional magnetic resonance imaging (FMRI) and positron emission tomography (PET). We found modest evidence of amygdalar interhemispheric functional connectivity in the non-depressed brain, whereas there was strong evidence of functional connectivity in the depressed brain. We interpret and discuss the nature of this connectivity in the depressed brain in the context of dysfunctional frontocortical-amygdalar interactions which accompany clinical depression.

The neural substrates of affective processing in depressed patients treated with venlafaxine.

OBJECTIVE: The purpose of this study was to use functional magnetic resonance imaging (fMRI) to probe the neural circuitry associated with reactivity to negative and positive affective stimuli in patients with major depressive disorder before treatment and after 2 and 8 weeks of treatment with venlafaxine. Relations between baseline neural activation and response to treatment were also evaluated. METHOD: Patients with major depressive disorder (N=12) and healthy comparison subjects (N=5) were scanned on three occasions, during which trials of alternating blocks of affective and neutral pictorial visual stimuli were presented. Symptoms were evaluated at each testing occasion, and both groups completed self-report measures of mood. Statistical parametric mapping was used to examine the fMRI data with a focus on the group-by-time interactions. RESULTS: Patients showed a significant reduction in depressive symptoms with treatment. Group-by-time interactions in response to the negative versus neutral stimuli were found in the left insular cortex and the left anterior cingulate. At baseline, both groups showed bilateral activation in the visual cortices, lateral prefrontal cortex, and amygdala in response to the negative versus neutral stimuli, with patients showing greater activation in the visual cortex and less activation in the left lateral prefrontal cortex. Patients with greater relative anterior cingulate activation at baseline in response to the negative versus neutral stimuli showed the most robust treatment response. CONCLUSIONS: The findings underscore the importance of the neural circuitry activated by negative affect in depression and indicate that components of this circuitry can be changed within 2 weeks of treatment with antidepressant medication.