Background: Subclinical doses of propofol produce anterograde amnesia, characterized by an early failure of memory consolidation. It is unknown how propofol affects the amygdala-dependent emotional memory system, which modulates consolidation in the hippocampus in response to emotional arousal and neurohumoral stress. We present an event-related functional magnetic resonance imaging study of the effects of propofol on the emotional memory system in human subjects.Methods: Thirty-five healthy subjects were randomized to receive propofol, at an estimated brain concentration of 0.90 mu g ml(-1), or placebo. During drug infusion, emotionally arousing and neutral images were presented in a continuous recognition task, while blood-oxygen-level-dependent activation responses were acquired. After a drug-free interval of 2 h, subsequent memory for successfully encoded items was assessed. Imaging analysis was performed using statistical parametric mapping and behavioural analysis using signal detection models.Results: Propofol had no effect on the stereotypical amygdalar response to emotional arousal, but caused marked suppression of the hippocampal response. Propofol caused memory performance to become uncoupled from amygdalar activation, but it remained correlated with activation in the posterior hippocampus, which decreased in proportion to amnesia.Conclusions: Propofol is relatively ineffective at suppressing amygdalar activation at sedative doses, but abolishes emotional modulation and causes amnesia via mechanisms that commonly involve hyporesponsiveness of the hippocampus. These findings raise the possibility that amygdala-dependent fear systems may remain intact even when a patient has diminished memory of events. This may be of clinical importance in the perioperative development of fear-based psychopathologies, such as post-traumatic stress disorder.

Echo planar imaging (EPI) is used widely for neurological fMRI studies. However, in regions of magnetic field inhomogeneity - particularly near the nasal sinuses - EPI suffers from signal dropout. Z-shim methods are one approach to recover this lost signal, where a z gradient is employed prior to the EPI readout echo train to counter phase accumulation in the signal dropout region. Typically, two separate images of the same region are acquired under different z-shim gradient strengths, and then combined into a composite image. Single-shot z-shim methods give improved temporal resolution, but with a cost of longer echo trains, which increases geometric distortion. Here, we combine parallel MR imaging (pMRI) with a single-shot z-shim method to achieve short echo train lengths. We also employ temporal encoding to counter Nyquist ghost effects, which improves the pMRI calibration. We demonstrate the method with phantom images, and evaluate its suitability for fMRI applications.

Introduction: Neuroimaging methods that use gradient-echo EPI (e.g. BOLD fMRI) consistently suffer adverse effects from magnetic field inhomogeneity in regions close to nasal sinuses and ear canals. Magnetic susceptibility at air-tissue interfaces in these regions results in both geometric distortion and signal loss due to spin dephasing. Z-shim methods [1,2] are one approach to correct this signal loss, where a z gradient is applied across the slice to rephase the spins prior to data acquisition. Unfortunately, rephasing spins in one location will dephase spins in another. For this reason, z-shimming is typically achieved in two shots, with the final image formed by combining two z-shimmed images, each emphasizing signal regions that are “dark” in the complementary image. Single-shot z-shim methods, e.g. [3,4], are desirable in that temporal resolution is improved, often at a cost of longer EPI echo-trains, which increases geometric distortion. In this work, we seek to shorten the EPI echo train of the interleaved single-shot method of Gu, et al, [4] through the use of parallel MR imaging (pMRI). We also employ temporal encoding to mitigate the effect of Nyquist ghosts in the pMRI calibration [5]. Methods: We implemented an interleaved single-shot z-shim sequence by adding kz blips coincident in time with the standard EPI ky blips. An initial z-shim value of z1 is achieved by a z-gradient applied at the start of the echo train. The second z-shim value, z2, is achieved by setting the kz blips to be proportional to the difference, (z1 z2). Toggling the polarity of this gradient at each ky blip ensures that data acquired on positive readout gradients, +RO, is associated with z1, and data acquired on negative readout gradients, -RO, is associated with z2. With temporal encoding, the readout polarity and z-shim parameter settings are modulated to acquire four images: +RO z1, -RO z1, +RO z2, -RO z2, where {+,-}RO and z{1,2} refers to the first line of measured k-space. We employ the cycle shown in Table 1, so that data is acquired using alternating readouts {⋅⋅⋅,+RO,-RO,+RO,-RO,⋅⋅⋅} for both z-shim values. The first step in image reconstruction is to calibrate the pMRI reconstruction parameters. Here we employ GRAPPA [6] with a ‘2x5’ kernel. We interleave data from two frames, from data at (t-3) and (t-1), to yield images Sz1 and S z2, where the superscript/subscript refers to the readout gradient polarity and z-shim value, respectively. To improve the pMRI calibration [5], a second set of frames, from data at (t-2) and (t), are interleaved to generate images at the same zshim setting but of opposite readout polarity, e.g Sz1 and Sz2. Each pair of opposite polarity images at each z value are coherently combined to cancel residual Nyquist ghosts [7]. This calibration data is then used to generate GRAPPA reconstruction coefficients for each z value. To reconstruct the temporal series, the +RO and -RO data is separated at each time point. This induces a 2x acceleration in each set. As the z-shim value and readout polarity are correlated, using GRAPPA parameters associated with the z-value of each set maintains proper image contrast and weighting. After GRAPPA reconstruction and combination of the multi-coil images, the data acquired at each time frame yields two images, Iz1(t) and Iz2(t), one for each z-shim value. To form the final composite image, we employ a root-sum-of-squares combination of Iz1(t) and Iz2(t) [4]. Phantom data was acquired on a 3T GE (GE Healthcare Systems, Milwaukee, WI, USA) Signa scanner (EXCITE v15), using a standard 8-channel head coil. The ball phantom was suspended off the scanner table using a plastic holder ring. The interaction between the plastic ring and the ball was sufficient to introduce magnetic susceptibility artifacts near the points of contact. 32 time frames of data were acquired using both a new single-shot EPI sequence and a legacy double-shot sequence, both with temporal encoding. Results: Fig 1 shows a comparison between images acquired using both the single-shot and double-shot z-shim pulse sequences. The z-shim settings were chosen by observation, to demonstrate the method. In practice, an iterative optimization approach would be used to identify z1 and z2 for each slice. The images in Fig 1 show good agreement, although the single-shot z-shim images appear slightly darker. This is caused by a slight increase in EPI echo spacing, due to the fact that z-shim kz blips are slightly longer than the EPI ky phase-encoding blips. Fig 2 shows the temporal signal variance between (a) single-shot and (b) double-shot images. The single-shot series has notable artifacts near the susceptibility regions. In the double-shot images, these artifacts are effectively cancelled in a manner similar to GESTE [8]. When the temporal encoding order of Table 1 is employed, these artifacts alternate in polarity at the temporal Nyquist rate. Thus they can be suppressed through the use of a 95% bandpass UNFOLD filter [9], Fig 2(c), with slight temporal resolution loss (5%). Discussion: We have demonstrated that interleaved single-shot z-shim combined with pMRI can improve temporal resolution while maintaining the same echo train length (and geometric distortion) compared to double-shot z-shim methods. While temporal encoding dramatically improves the pMRI reconstruction quality, it also inadvertently introduced flickering artifacts near susceptibility regions. This can be mitigated with the use of UNFOLD, or by using temporal encoding only occasionally (e.g. during fMRI resting state periods). Acknowledgements: Supported in part by NIH R25 CA089017-08 Time point t-3 t-2 t-1 t ⋅⋅⋅ Odd ky line polarity (+) (+) (-) (-) ⋅⋅⋅ Even ky line polarity (-) (-) (+) (+) ⋅⋅⋅ Odd line z-shim value z1 z2 z2 z1 ⋅⋅⋅ Even line z-shim value z2 z1 z1 z2 ⋅⋅⋅ Table 1: four-cycle acquisition order

The Attentional Blink (AB) is a visual phenomenon demonstrating an apparent limit of the visual system's ability to process individual items in a rapid serial visual presentation (RSVP). The AB occurs when two items, the first (target) to be identified and the second (probe) to be detected, are presented among other stimuli in a RSVP. The AB describes the interval of time in which attention cannot be focused on the probe which thereby proceeds undetected. Previous research has demonstrated that an iconic happy face attenuates the AB (Mack et al, 2002). We chose to explore whether this finding was face specific or emotionally mediated. Methods: RSVP streams of face stimuli with similar emotional expressions were presented at a rate of 100/ms each to produce an AB. Ss were instructed to identify one of five blue shapes superimposed over one of the faces in the RSVP and detect a subsequent face probe presenting a different emotional expression. Conditions consisted of: 1) a smiling face probe among neutral expressions; 2) a frowning face probe among neutral expressions and; 3) a neutral expression face probe among smiling faces. Results: When Ss were asked solely to detect the probe, performance ranged between 90 & 100%. However when Ss were asked to both identify the target and detect the probe, the results demonstrated a monotonic AB with a lag effect (Awh et al, 2003) rather than the classic U-shaped AB function (Raymond et al, 1992) across all conditions. Notably, significant differences were found between detection rates of the happy face and sad face as compared to the neutral face (p Conclusions: The AB has been demonstrated reliably over numerous conditions using various stimuli. Our experiment differs from these studies in that both the distractors and probes comprised similar forms with different meaning. Our results point to the attenuation of the AB by emotion and offer additional support in the late selection processes mediating perception of the attentional blink.

Introduction: Human mitochondrial DNA (mtDNA) is a circular molecule of 16,569 base pairs encoding 37 genes. Previously we have sequenced the entire mitochondrial genome using 45 overlapping PCR fragments, a time-consuming and costly procedure. Recently affymetrix have updated their mitochondrial resequencing chip. The Mitochip v2 is an array based sequencing platform that offers the potential of rapid and high throughput analysis of mtDNA. Here, we sought to compare the effectiveness and accuracy of MitoChip v2 compared to cycle sequencing, by paired analysis of the mtDNA from 40 patients with suspected mtDNA disease. Methods: A cohort of 40 patients with clinical, histological or biochemical evidence of mitochondrial disease, but without a genetic diagnosis, was identified through referral to the National Commissioning Group Mitochondrial Genetics laboratories in London and Newcastle. Sequence analysis was undertaken by both methods described above, and the resulting data sets compared to determine the effectiveness of the Mitochip v2 in the identification of pathogenic mutations, and the frequency of false positives and false negatives. In addition, we aimed to identify any regions that were consistently mis-called by the Affymetrix software. Results and discussion: To date, 20 patients have been analysed using the Mitochip v2. Six known pathogenic mutations and four novel and potentially pathogenic mutations (2 probably pathogenic, 2 of uncertain status) have been identified. All changes were confirmed by cycle sequencing. 13 of these 20 Mitochips generated between one and three false positives; 19 of the 20 Mitochips contained up to four false negatives. This preliminary data suggests that the Mitochip v2 is a potentially useful tool in the identification of mtDNA mutations, but further analysis is needed to determine whether all types of mutation are detected by this method.

The human stress response consists of a complex, coordinated sequence of neural and physiological changes partly subserved by the hypothalamic-pituitary-adrenocortical (HPA) axis. Key limbic and frontal structures, involved in fear conditioning and its modulation, have been demonstrated to play a role in modulating the activity of the HPA axis, including amygdaloid and hippocampal formations, and ventromedial prefrontal cortex (vmPFC) regions, which exhibit excitatory (amygdala) and inhibitory (hippocampus; vmPFC) effects on the HPA axis. While HPA function and associated endocrine changes have been widely investigated, to date, little research has been conducted utilizing functional neuroimaging in the study of the HPA axis and associated frontolimbic function in response to traumatic material. 20 subjects present in New York on the day of the September 11th, 2001 World Trade Center attacks participated in an emotional visual scene paradigm consisting of the presentation of images of varying emotional qualities, including images of the World Trade Center attacks, while BOLD response was measured utilizing fMRI. Salivary cortisol samples were collected, immediately prior to and following the scanning session, with changes in cortisol values analyzed as a covariate of interest during key condition contrasts of World Trade Center attack images, New York city images, and low-level visual controls. Results suggest that those subjects with a relative cortisol rise in response to the paradigm demonstrated greater amygdalar and bilateral dorsal hippocampi activity, in the context of decreased vmPFC activity in key condition contrasts involving traumatic imagery. These findings help to bridge models of fear circuitry with models of stress response as indexed by relative cortisol levels.

Neurocircuitry models of panic disorder have hypothesized that the panic attack itself stems from loci in the brainstem including the ascending reticular system and respiratory and cardiovascular control centers. Voxel-based morphometry with acobian modulation was used to examine gray matter volume changes in 10 panic disorder patients and 23 healthy controls. The panic disorder patients had a relatively increased gray matter volume in the midbrain and rostral pons of the brainstem. Increased ventral hippocampal and decreased regional prefrontal cortex volumes were also noted at a lower significance threshold. This finding has implications for pathophysiologic models of panic disorder, and provides structural evidence for the role of the brainstem in neurocircuitry models of panic disorder.

Background: Previous neuroiniaging studies have demonstrated exaggerated amygdala response to negative stimuli in postraumatic stress disorder (PTSD). The time course of this amygdala response is largely unstudied and is relevant to questions of habituation and sensitization in PTSD exposure therapy.Methods: We applied blood oxygen level dependent functional magnetic resonance imaging and statistical parametric mapping to study amygdala responce to trauma-related and nontrauma-related emotional words in sexual/physical abuse PTSD and normal control subjects. We examined the time course of this responce by separate analysis of early and late epochs.Results: PTSD versus normal control subjects have a relatively increased initial amygdala response to trauma-relatcd negative, but not nontramna-related negative, versus neutral stimuli. Patients also fail to show the normal patterns of sensitization and habituation to different categories of negative stimuli. These findings correlate with measured PTSD symptom severity.Conclusions: Our results demonstrate differential time courses and specificity of amygdala response to emotional and control stimuli in PTSD and normal control subjects. This has implications for pathophysiologic models of PTSD and treatment response. The results also extend previous neuroimaging studies demonstrating relatively increased amygdala in PTSD and expand these results to a largely female patient population probed with emotionally valenced words.

Single‐shot interleaved z‐shim EPI (SSIZS‐EPI) was extended to a simultaneous perfusion and blood‐oxygenation‐level‐dependent (BOLD) imaging technique that reduces susceptibility‐induced signal loss while preserving rapid image acquisition. Experiments on human brains showed that images acquired with this technique had improved signal‐to‐noise ratio in the inferior prefrontal, meso‐, and lateral–temporal lobes compared with a conventional EPI. Perfusion maps obtained from the SSIZS‐EPI images at resting state illustrated substantial signal recovery in these brain areas. Perfusion and BOLD images collected with a sensorimotor paradigm demonstrated the feasibility of the technique to simultaneously measure cerebral blood flow and blood oxygenation signals associated with brain activation. Functional experiments with a neuropsychiatric paradigm showed increased brain activities in the periamygdalar regions in both perfusion and BOLD maps, consistent with a previous H215O PET study. The proposed technique, with its advantages of reducing susceptibility artifacts and fast scanning speed, would be useful for obtaining more reliable measurements of functional signals, particularly in the brain regions with field inhomogeneities. Magn Reson Med 53:1207–1211, 2005. Published 2005 Wiley‐Liss, Inc.

Functional magnetic resonance imaging in association with an instructed fear/anticipatory anxiety paradigm was used to explore sex differences in the human fear response. During anticipation of mild electrodermal stimulation, women, as compared with men, demonstrated increased activity in the subgenual anterior cingulate cortex and functionally related regions of the insula and brainstem. The subgenual anterior cingulate cortex is a region critical for emotional control implicated in the pathogenesis of psychiatric disease. Present findings suggest a contributory neural substrate for the greater susceptibility of women to anxiety and affective disorders, and emphasize the importance of considering participant sex when designing and interpreting functional neuroimaging studies.

Environmental sounds convey specific meanings and the neural circuitry for their recognition may have preceded language. To dissociate semantic mnemonic from sensory perceptual processing of non-verbal sound stimuli we systematically altered the inherent semantic properties of non-verbal sounds from natural and man-made sources while keeping their acoustic characteristics closely matched. We hypothesized that acoustic analysis of complex non-verbal sounds would be right lateralized in auditory cortex regardless of meaning content and that left hemisphere regions would be engaged when meaningful concept could be extracted. Using H(2)(15)O-PET imaging and SPM data analysis, we demonstrated that activation of the left superior temporal and left parahippocampal gyrus along with left inferior frontal regions was specifically associated with listening to meaningful sounds. In contrast, for both types of sounds, acoustic analysis was associated with activation of right auditory cortices. We conclude that left hemisphere brain regions are engaged when sounds are meaningful or intelligible.