Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder.

Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala-calcarine (P=0.01) and amygdala-thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala-ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.

Electromyography as a recording system for eyeblink conditioning with functional magnetic resonance imaging.

This study was designed to develop a suitable method of recording eyeblink responses while conducting functional magnetic resonance imaging (fMRI). Given the complexity of this behavioral setup outside of the magnet, this study sought to adapt and further optimize an approach to eyeblink conditioning that would be suitable for conducting event-related fMRI experiments. This method involved the acquisition of electromyographic (EMG) signals from the orbicularis oculi of the right eye, which were subsequently amplified and converted into an optical signal outside of the head coil. This optical signal was converted back into an electrical signal once outside the magnet room. Electromyography (EMG)-detected eyeblinks were used to measure responses in a delay eyeblink conditioning paradigm. Our results indicate that: (1) electromyography is a sensitive method for the detection of eyeblinks during fMRI; (2) minimal interactions or artifacts of the EMG signal were created from the magnetic resonance pulse sequence; and (3) no electromyography-related artifacts were detected in the magnetic resonance images. Furthermore, an analysis of the functional data showed areas of activation that have previously been shown in positron emission tomography studies of human eyeblink conditioning. Our results support the strength of this behavioral setup as a suitable method to be used in association with fMRI.

Impact of signal-to-noise on functional MRI of the human amygdala.

The impact of signal-to-noise (SNR) on fMRI of the amygdala was investigated during a picture encoding task. The SNR value required to observe reliable activation was determined by computer simulations. Blood oxygen level-dependent (BOLD) sensitivity maps were generated to indicate brain regions with sufficient SNR to test the statistical hypotheses. The results showed that the medial aspect of the amygdala had insufficient SNR to detect a 1% peak BOLD signal change for a t-test comparison in a majority of subjects. None of these subjects showed activation in regions with unacceptable SNR values, indicating a low false positive rate. Furthermore, hemispheric asymmetries in the BOLD sensitivity maps mirrored asymmetries in the activation patterns. Impoverished SNR was also found in the basal forebrain and orbitofrontal cortex. These findings emphasize the importance of considering SNR when interpreting fMRI results in the limbic forebrain.

Hunger selectively modulates corticolimbic activation to food stimuli in humans.

Functional magnetic resonance imaging (fMRI) was used to determine whether visual responses to food in the human amygdala and related corticolimbic structures would be selectively altered by changes in states of hunger. Participants viewed images of motivationally relevant (food) and motivationally irrelevant (tool) objects while undergoing fMRI in alternately hungry and satiated conditions. Food-related visual stimuli elicited greater responses in the amygdala, parahippocampal gyrus. and anterior fusiform gyrus when participants were in a hungry state relative to a satiated state. The state-dependent activation of these brain structures did not generalize to the motivationally irrelevant objects. These results support the hypothesis that the amygdala and associated inferotemporal regions are involved in the integration of subjective interoceptive states with relevant sensory cues processed along the ventral visual stream.

Emotional curiosity: modulation of visuospatial attention by arousal is preserved in aging and early-stage Alzheimer's disease.

Previous studies have shown that Alzheimer's disease, even in its early stages, decreases novelty-seeking behaviors (curiosity) and impairs the shifting of spatial attention to extrapersonal targets. In this study, early-stage probable Alzheimer's disease patients (PRAD) and young and aging controls were shown pairs of visual scenes, some of which contained emotionally-arousing material, while eye movements were recorded under free viewing conditions. In all three subject groups, emotionally-arousing scenes attracted more viewing time and also became the preferential target of the initial visual orientation. Our findings suggest that the arousing properties of sensory stimuli may overcome some of the AD-related impairments in the distribution of attention to extrapersonal targets. These results may have implications for interventions aimed at improving the cognitive symptoms of PRAD.

Impact of signal-to-noise on functional MRI.

Functional magnetic resonance imaging (fMRI) has recently been adopted as an investigational tool in the field of neuroscience. The signal changes induced by brain activations are small ( approximately 1-2%) at 1.5T. Therefore, the signal-to-noise ratio (SNR) of the time series used to calculate the functional maps is critical. In this study, the minimum SNR required to detect an expected MR signal change is determined using computer simulations for typical fMRI experimental designs. These SNR results are independent of manufacturer, site environment, field strength, coil type, or type of cognitive task used. Sensitivity maps depicting the minimum detectable signal change can be constructed. These sensitivity maps can be used as a mask of the activation map to help remove false positive activations as well as identify regions of the brain where it is not possible to confidently reject the null hypothesis due to a low SNR.

Real-time monitoring of eye movements using infrared video-oculography during functional magnetic resonance imaging of the frontal eye fields.

Monitoring eye movements is a critical aspect of experimental design for studies of spatial attention and visual perception. However, obtaining online eye-movement recordings has been technologically difficult during functional magnetic resonance (MR) imaging studies. Previous approaches to monitoring eye movements either have distorted the MR images or have shown MR-related interference in the recordings. We report a technique using long-range infrared video-oculography to record eye movements without causing artifacts in the MR images. Analysis of the MR signal from a phantom obtained with the eye-movement equipment turned on or off confirmed the absence of significant additional noise in the MR time series. Eye movements of three subjects were monitored while they performed tasks of covert and overt shifts of spatial attention. Activation of the frontal eye fields during the covert task was seen even when the eye-movement recordings demonstrated no significant difference in saccadic eye movements between the baseline and the active conditions.

Neuroanatomic overlap of working memory and spatial attention networks: a functional MRI comparison within subjects.

Frontal and posterior parietal activations have been reported in numerous studies of working memory and visuospatial attention. To directly compare the brain regions engaged by these two cognitive functions, the same set of subjects consecutively participated in tasks of working memory and spatial attention while undergoing functional MRI (fMRI). The working memory task required the subject to maintain an on-line representation of foveally displayed letters against a background of distracters. The spatial attention task required the subject to shift visual attention covertly in response to a centrally presented directional cue. The spatial attention task had no working memory requirement, and the working memory task had no covert spatial attention requirement. Subjects' ability to maintain central fixation was confirmed outside the MRI scanner using infrared oculography. According to cognitive conjunction analysis, the set of activations common to both tasks included the intraparietal sulcus, ventral precentral sulcus, supplementary motor area, frontal eye fields, thalamus, cerebellum, left temporal neocortex, and right insula. Double-subtraction analyses yielded additional activations attributable to verbal working memory in premotor cortex, left inferior prefrontal cortex, right inferior parietal lobule, precuneus, and right cerebellum. Additional activations attributable to covert spatial attention included the occipitotemporal junction and extrastriate cortex. The use of two different tasks in the same set of subjects allowed us to provide an unequivocal demonstration that the neural networks subserving spatial attention and working memory intersect at several frontoparietal sites. These findings support the view that major cognitive domains are represented by partially overlapping large-scale neural networks. The presence of this overlap also suggests that spatial attention and working memory share common cognitive features related to the dynamic shifting of attentional resources.

A large-scale distributed network for covert spatial attention: further anatomical delineation based on stringent behavioural and cognitive controls.

Functional MRI was used to examine cerebral activations in 12 subjects while they performed a spatial attention task. This study applied more stringent behavioural and cognitive controls than previously used for similar experiments: (i) subjects were included only if they showed evidence of attentional shifts while performing the task in the magnet; (ii) the experimental task and baseline condition were designed to eliminate the contributions of motor output, visual fixation, inhibition of eye movements, working memory and the conditional (no-go) component of responding. Activations were seen in all three hypothesized cortical epicentres forming a network for spatial attention: the lateral premotor cortex (frontal eye fields), the posterior parietal cortex and the cingulate cortex. Subcortical activations were seen in the basal ganglia and the thalamus. Although the task required attention to be equally shifted to the left and to the right, eight of 10 subjects showed a greater area of activation in the right parietal cortex, consistent with the specialization of the right hemisphere for spatial attention. Other areas of significant activation included the posterior temporo-occipital cortex and the anterior insula. The temporo-occipital activation was within a region broadly defined as MT+ (where MT is the middle temporal area) which contains the human equivalent of area MT in the macaque monkey. This temporo-occipital area appears to constitute a major component of the functional network activated by this spatial attention task. Its activation may reflect the 'inferred' shift of the attentional focus across the visual scene.

The large-scale neural network for spatial attention displays multifunctional overlap but differential asymmetry.

Functional magnetic resonance imaging (fMRI) was used to determine the brain regions activated by two types of covert visuospatial attentional shifts: one based on exogenous spatial priming and the other on foveally presented cues which endogenously regulated the direction of spatial expectancy. Activations were seen in the cortical and subcortical components of a previously characterized attentional network, namely, the frontal eye fields, posterior parietal cortex, the cingulate gyrus, the putamen, and the thalamus. Additional activations occurred in the anterior insula, dorsolateral prefrontal cortex, temporo-occipital cortex in the middle and inferior temporal gyri, the supplementary motor area, and the cerebellum. Direct comparisons showed a nearly complete overlap in the location of activations resulting from the two tasks. However, the spatial priming task displayed a more pronounced rightward asymmetry of parietal activation, and a conjunction analysis showed that the area of posterior parietal cortex jointly activated by both tasks was more extensive in the right hemisphere. Furthermore, the posterior parietal and temporo-occipital activations were more pronounced in the task of endogenous attentional shifts. The results show that both exogenous (based on spatial priming) and endogenous (based on expectancy cueing) shifts of attention are subserved by a common network of cortical and subcortical regions. However, the differences between the two tasks, especially in the degree of rightward asymmetry, suggests that the pattern of activation within this network may show variations that reflect the specific attributes of the attentional task.

Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study.

Echoplanar functional magnetic resonance imaging (fMRI) was used in normal human subjects to investigate the role of the amygdala in conditioned fear acquisition and extinction. A simple discrimination procedure was employed in which activation to a visual cue predicting shock (CS+) was compared with activation to another cue presented alone (CS-). CS+ and CS- trial types were intermixed in a pseudorandom order. Functional images were acquired with an asymmetric spin echo pulse sequence from three coronal slices centered on the amygdala. Activation of the amygdala/periamygdaloid cortex was observed during conditioned fear acquisition and extinction. The extent of activation during acquisition was significantly correlated with autonomic indices of conditioning in individual subjects. Consistent with a recent electrophysiological recording study in the rat (Quirk et al., 1997), the profile of the amygdala response was temporally graded, although this dynamic was only statistically reliable during extinction. These results provide further evidence for the conservation of amygdala function across species and implicate an amygdalar contribution to both acquisition and extinction processes during associative emotional learning tasks.

Conditioning, awareness, and the hippocampus.

For the past 50 years, psychologists have wrestled with questions regarding the relationship between conscious awareness and human conditioned behavior. A recent proposal that the hippocampus mediates awareness during trace conditioning (Clark, Squire, Science 1998;280:77-81) has extended the awareness-conditioning debate to the neuroscience arena. In the following commentary, we raise specific theoretical and methodological issues regarding the Clark and Squire study and place their finding into a broader context. Throughout our discussion, we consider the difficulties in assessing subjective awareness, the importance of establishing necessary and sufficient conditions for cognitive mediation effects, the influence of conditioned response modality, and the nature of hippocampal requirements across conditioning protocols. It is clear that trace eyeblink conditioning is a hippocampal-dependent task, but whether awareness is a necessary component of trace conditioning is not definitively proven. We propose that future functional neuroimaging studies and behavioral experiments using on-line measures of awareness may help clarify the relationship among classical conditioning, awareness, and the hippocampus.

Memory for emotional words following unilateral temporal lobectomy.

We recently reported that patients who had received unilateral temporal lobectomy, including the amygdala and hippocampus, show impaired acquisition in a fear conditioning task (LaBar, LeDoux, Spencer, & Phelps, 1995), indicating a deficit in emotional memory. In the present paper, we examined performance of these patients on two verbal, emotional memory tasks in an effort to determine the extent of this deficit. In Experiment 1, subjects were asked to recall emotional and non-emotional words. In Experiment 2, subjects were asked to recall neutral words which were embedded in emotional and non-emotional sentence contexts. Both temporal lobectomy subjects and normal controls showed enhanced recall for emotional words (Experiment 1) and enhanced recall for neutral words embedded in emotional sentence contexts (Experiment 2). These results suggest that the deficit seen in emotional memory following unilateral temporal lobectomy is not a global deficit and may be limited to specific circumstances where emotion influences memory performance. Several hypotheses concerning the discrepancy between the present studies and the fear conditioning results (LaBar et al., 1995) are discussed.

"Willed action": a functional MRI study of the human prefrontal cortex during a sensorimotor task.

Functional MRI (fMRI) was used to examine human brain activity within the dorsolateral prefrontal cortex during a sensorimotor task that had been proposed to require selection between several responses, a cognitive concept termed "willed action" in a positron emission tomography (PET) study by Frith et al. [Frith, C. D., Friston, K., Liddle, P. F. & Frackowiak, R. S. J. (1991) Proc. R. Soc. London Ser. B 244, 241-246]. We repeated their sensorimotor task, in which the subject chooses to move either of two fingers after a stimulus, by fMRI experiments in a 2.1-T imaging spectrometer. Echo-planar images were acquired from four coronal slices in the prefrontal cortex from nine healthy subjects. Slices were 5 mm thick, centers separated by 7 mm, with nominal in-plane spatial resolution of 9.6 x 5.0 mm2 for mean data. Our mean results are in agreement with the PET results in that we saw similar bilateral activations. The present results are compared with our previously published fMRI study of a verbal fluency task, which had also been proposed by Frith et al. to elicit a "willed action" response. We find a clear separation of activation foci in the left dorsolateral prefrontal cortex for the sensorimotor (Brodmann area 46) and verbal fluency (Brodmann area 45) tasks. Hence, assigning a particular activated region to "willed action" is not supported by the fMRI data when examined closely because identical regions are not activated with different modalities. Similar modality linked activations can be observed in the original PET study but the greater resolution of the fMRI data makes the modality linkages more definite.

Partial disruption of fear conditioning in rats with unilateral amygdala damage: correspondence with unilateral temporal lobectomy in humans.

Conditioned fear in rats was assessed for the effects of pretraining amygdala lesions (unilateral vs. bilateral) across unconditioned stimulus (US) modalities (white noise vs. shock). In contrast to sham controls, unilateral amygdala lesions significantly reduced conditioned freezing responses, whereas bilateral amygdala lesions resulted in a nearly complete lack of freezing to both the conditioned stimulus (CS) and the context. The lesion effects were more pronounced for CS conditioning but were consistent across US modalities. It was concluded that white noise can serve as an effective US and that unilateral amygdala lesions attenuate but do not eliminate conditioned fear in rats. The results support our interpretation of a recent fear conditioning study in humans (K. S. LaBar, J. E. LeDoux, D. D. Spencer, & E. A. Phelps, 1995).

Impaired fear conditioning following unilateral temporal lobectomy in humans.

Classical fear conditioning was used in the present study as a model for investigating emotional learning and memory in human subjects with lesions to the medial temporal lobe. Animal studies have revealed a critical role for medial temporal lobe structures, particularly the amygdala, in simple and complex associative emotional responding. Whether these structures perform similar functions in humans is unknown. On both simple and conditional discrimination tasks, unilateral temporal lobectomy subjects showed impaired conditioned response acquisition relative to control subjects. This impairment could not be accounted for by deficits in nonassociative sensory or autonomic performance factors, or by differences in declarative memory for the experimental parameters. These results show that temporal lobe structures in humans, as in other mammals, are important components in an emotional memory network.