Extended-amygdala intrinsic functional connectivity networks: A population study.

Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance-use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task-free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter-individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST-CeA intrinsic functional connectivity (iFC) was heritable and further examined co-heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST-CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co-heritability associations with our principal components either across the ICNs or for specific BST-Amygdala iFC. Possible differences in phenotype associations across task-free, task-based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well-established ExtA ICNs.

Whole brain 31 P MRSI at 7T with a dual-tuned receive array.

PURPOSE: The design and performance of a novel head coil setup for 31 P spectroscopy at ultra-high field strengths (7T) is presented. The described system supports measurements at both the 1 H and 31 P resonance frequencies. METHODS: The novel coil consists of 2, actively detunable, coaxial birdcage coils to give homogeneous transmit, combined with a double resonant 30 channel receive array. This allows for anatomical imaging combined with 31 P acquisitions over the whole head, without changing coils or disturbing the subject. A phosphate buffer phantom and 3 healthy volunteers were scanned with a pulse acquire CSI sequence using both the novel array coil and a conventional transceiver birdcage. Four different methods of combining the array channels were compared at 3 different levels of SNR. RESULTS: The novel coil setup delivers significantly increased 31 P SNR in the peripheral regions of the brain, reaching up to factor 8, while maintaining comparable performance relative to the birdcage in the center. CONCLUSIONS: The new system offers the potential to acquire whole brain 31 P MRSI with superior signal relative to the standard options.

Calcium channel blockade with nimodipine reverses MRI evidence of cerebral oedema following acute hypoxia.

Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema.

The BOLD response in primary motor cortex and supplementary motor area during kinesthetic motor imagery based graded fMRI neurofeedback.

There is increasing interest in exploring the use of functional MRI neurofeedback (fMRI-NF) as a therapeutic technique for a range of neurological conditions such as stroke and Parkinson's disease (PD). One main therapeutic potential of fMRI-NF is to enhance volitional control of damaged or dysfunctional neural nodes and networks via a closed-loop feedback model using mental imagery as the catalyst of self-regulation. The choice of target node/network and direction of regulation (increase or decrease activity) are central design considerations in fMRI-NF studies. Whilst it remains unclear whether the primary motor cortex (M1) can be activated during motor imagery, the supplementary motor area (SMA) has been robustly activated during motor imagery. Such differences in the regulation potential between primary and supplementary motor cortex are important because these areas can be differentially affected by a stroke or PD, and the choice of fMRI-NF target and grade of self-regulation of activity likely have substantial influence on the clinical effects and cost effectiveness of NF-based interventions. In this study we therefore investigated firstly whether healthy subjects would be able to achieve self-regulation of the hand-representation areas of M1 and the SMA using fMRI-NF training. There was a significant decrease in M1 neural activity during fMRI-NF, whereas SMA neural activity was increased, albeit not with the predicated graded effect. This study has important implications for fMRI-NF protocols that employ motor imagery to modulate activity in specific target regions of the brain and to determine how they may be tailored for neurorehabilitation.

The thalamus and brainstem act as key hubs in alterations of human brain network connectivity induced by mild propofol sedation.

Despite their routine use during surgical procedures, no consensus has yet been reached on the precise mechanisms by which hypnotic anesthetic agents produce their effects. Molecular, animal and human studies have suggested disruption of thalamocortical communication as a key component of anesthetic action at the brain systems level. Here, we used the anesthetic agent, propofol, to modulate consciousness and to evaluate differences in the interactions of remote neural networks during altered consciousness. We investigated the effects of propofol, at a dose that produced mild sedation without loss of consciousness, on spontaneous cerebral activity of 15 healthy volunteers using functional magnetic resonance imaging (fMRI), exploiting oscillations (<0.1 Hz) in blood oxygenation level-dependent signal across functionally connected brain regions. We considered the data as a graph, or complex network of nodes and links, and used eigenvector centrality (EC) to characterize brain network properties. The EC mapping of fMRI data in healthy humans under propofol mild sedation demonstrated a decrease of centrality of the thalamus versus an increase of centrality within the pons of the brainstem, highlighting the important role of these two structures in regulating consciousness. Specifically, the decrease of thalamus centrality results from its disconnection from a widespread set of cortical and subcortical regions, while the increase of brainstem centrality may be a consequence of its increased influence, in the mildly sedated state, over a few highly central cortical regions key to the default mode network such as the posterior and anterior cingulate cortices.

Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis.

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very different functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, independent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psychedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psilocybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenology and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

A multisensory investigation of the functional significance of the "pain matrix".

Functional neuroimaging studies in humans have shown that nociceptive stimuli elicit activity in a wide network of cortical areas commonly labeled as the "pain matrix" and thought to be preferentially involved in the perception of pain. Despite the fact that this "pain matrix" has been used extensively to build models of where and how nociception is processed in the human brain, convincing experimental evidence demonstrating that this network is specifically related to nociception is lacking. The aim of the present study was to determine whether there is at least a subset of the "pain matrix" that responds uniquely to nociceptive somatosensory stimulation. In a first experiment, we compared the fMRI brain responses elicited by a random sequence of brief nociceptive somatosensory, non-nociceptive somatosensory, auditory and visual stimuli, all presented within a similar attentional context. We found that the fMRI responses triggered by nociceptive stimuli can be largely explained by a combination of (1) multimodal neural activities (i.e., activities elicited by all stimuli regardless of sensory modality) and (2) somatosensory-specific but not nociceptive-specific neural activities (i.e., activities elicited by both nociceptive and non-nociceptive somatosensory stimuli). The magnitude of multimodal activities correlated significantly with the perceived saliency of the stimulus. In a second experiment, we compared these multimodal activities to the fMRI responses elicited by auditory stimuli presented using an oddball paradigm. We found that the spatial distribution of the responses elicited by novel non-target and novel target auditory stimuli resembled closely that of the multimodal responses identified in the first experiment. Taken together, these findings suggest that the largest part of the fMRI responses elicited by phasic nociceptive stimuli reflects non nociceptive-specific cognitive processes.

Coupling of simultaneously acquired electrophysiological and haemodynamic responses during visual stimulation.

We investigate the relationship between the temporal variation in the magnitude of occipital visual evoked potentials (VEPs) and of haemodynamic measures of brain activity obtained using both blood oxygenation level dependent (BOLD) and perfusion sensitive (ASL) functional magnetic resonance imaging (fMRI). Volunteers underwent a continuous BOLD fMRI scan and/or a continuous perfusion-sensitive (gradient and spin echo readout) ASL scan, during which 30 second blocks of contrast reversing visual stimuli (at 4 Hz) were interleaved with 30 second blocks of rest (visual fixation). Electroencephalography (EEG) and fMRI were simultaneously recorded and following EEG artefact cleaning, VEPs were averaged across the whole stimulation block (120 reversals, VEP(120)) and at a finer timescale (15 reversals, VEP(15)). Both BOLD and ASL time-series were linearly modelled to establish: (1) the mean response to visual stimulation, (2) transient responses at the start and end of each stimulation block, (3) the linear decrease between blocks, (4) the nonlinear between-block variation (covariation with VEP(120)), (5) the linear decrease within block and (6) the nonlinear variation within block (covariation with VEP(15)). VEPs demonstrated a significant linear time-dependent reduction in amplitude, both within and between blocks of stimulation. Consistent with the VEPs finding, both BOLD and perfusion measures showed significant linear time-dependent reductions in response amplitude between blocks. In addition, there were significant linear time-dependent within-block reductions in BOLD response as well as between-block variations positively correlating with VEP(120) (medial occipital and frontal) and within-block variations positively correlating with VEP(15) (occipital and thalamus). Both electrophysiological and haemodynamic (BOLD and ASL) measures of visual activity showed steady habituation through the experiment. Beyond this, the VEP measures were predictive of shorter timescale (3-30 second) localised variations in BOLD response engaging both occipital cortex and other regions such as anterior cingulate and parietal regions, implicating attentional processes in the modulation of the VEP signal.

EEG signatures of auditory activity correlate with simultaneously recorded fMRI responses in humans.

We recorded auditory-evoked potentials (AEPs) during simultaneous, continuous fMRI and identified trial-to-trial correlations between the amplitude of electrophysiological responses, characterised in the time domain and the time-frequency domain, and the hemodynamic BOLD response. Cortical AEPs were recorded from 30 EEG channels within the 3 T MRI scanner with and without the collection of simultaneous BOLD fMRI. Focussing on the Cz (vertex) EEG response, single-trial AEP responses were measured from time-domain waveforms. Furthermore, a novel method was used to characterise the single-trial AEP response within three regions of interest in the time-frequency domain (TF-ROIs). The latency and amplitude values of the N1 and P2 AEP peaks during fMRI scanning were not significantly different from the Control session (p>0.16). BOLD fMRI responses to the auditory stimulation were observed in bilateral secondary auditory cortices as well as in the right precentral and postcentral gyri, anterior cingulate cortex (ACC) and supplementary motor cortex (SMC). Significant single-trial correlations were observed with a voxel-wise analysis, between (1) the magnitude of the EEG TF-ROI1 (70-800 ms post-stimulus, 1-5 Hz) and the BOLD response in right primary (Heschl's gyrus) and secondary (STG, planum temporale) auditory cortex; and (2) the amplitude of the P2 peak and the BOLD response in left pre- and postcentral gyri, the ACC and SMC. No correlation was observed with single-trial N1 amplitude on a voxel-wise basis. An fMRI-ROI analysis of functionally-identified auditory responsive regions identified further single-trial correlations of BOLD and EEG responses. The TF amplitudes in TF-ROI1 and TF-ROI2 (20-400 ms post-stimulus, 5-15 Hz) were significantly correlated with the BOLD response in all bilateral auditory areas investigated (planum temporale, superior temporal gyrus and Heschl's gyrus). However the N1 and P2 peak amplitudes, occurring at similar latencies did not show a correlation in these regions. N1 and P2 peak amplitude did correlate with the BOLD response in bilateral precentral and postcentral gyri and the SMC. Additionally P2 and TF-ROI1 both correlated with the ACC. TF-ROI3 (400-900 ms post-stimulus, 4-10 Hz) correlations were only observed in the ACC and SMC. Across the group, the subject-mean N1 peak amplitude correlated with the BOLD response amplitude in the primary and secondary auditory cortices bilaterally, as well as the right precentral gyrus and SMC. We confirm that auditory-evoked EEG responses can be recorded during continuous and simultaneous fMRI. We have presented further evidence of an empirical single-trial coupling between the EEG and BOLD fMRI responses, and show that a time-frequency decomposition of EEG signals can yield additional BOLD fMRI correlates, predominantly in auditory cortices, beyond those found using the evoked response amplitude alone.

Determination of the human brainstem respiratory control network and its cortical connections in vivo using functional and structural imaging.

This study combined functional and structural magnetic resonance imaging techniques, optimized for the human brainstem, to investigate activity in brainstem respiratory control centres in a group of 12 healthy human volunteers. We stimulated respiration with carbon dioxide (CO(2)), and utilized novel methodology to separate its vascular from its neuronal effects upon the blood oxygen level dependent (BOLD) signal. In the brainstem we observed activity in the dorsal rostral pons (representing the Kölliker-Fuse/parabrachial (KF/PB) nuclei and locus coeruleus), the inferior ventral pons and the dorsal and lateral medulla. These areas of activation correspond to respiratory nuclei identified in recent rodent studies. Our results also reveal functional participation of the anteroventral (AV), ventral posterolateral (VPL) ventrolateral thalamic nuclei, and the posterior putamen in the response to CO(2) stimulation, suggesting that these centres may play a role in gating respiratory information to the cortex. As the functional imaging plane was limited to the brainstem and adjacent subcortical areas, we employed diffusion tractography to further investigate cortical connectivity of the thalamic activations. This revealed distinct connectivity profiles of these thalamic activations suggesting subdivision of the thalamus with regards to respiratory control. From these results we speculate that the thalamus plays an important role in integrating respiratory signals to and from the brainstem respiratory centres.

Lateralisation of nociceptive processing in the human brain: a functional magnetic resonance imaging study.

Nociceptive processing within the human brain takes place within two distinct and parallel systems: the lateral and medial pain systems. Current knowledge indicates that the lateral system is involved in processing the sensory-discriminative aspects of pain, and that the medial system is involved in processing the affective-motivational aspects of pain. Hemispheric differences in brain activation (lateralisation) during nociceptive processing were studied to further clarify the division of function between the lateral and medial pain systems. Hemispheric lateralisation was studied by applying painful CO(2) laser stimuli of 3-s duration sequentially to the left and right medial lower calves of five normal right-handed human subjects. The resultant brain activity was measured using 3-T functional magnetic resonance imaging, by determining significant changes in blood oxygen level dependent (BOLD) signal and applying a general linear modelling approach. Volumes of interest were defined for the primary and secondary somatosensory cortices (SI and SII), the insular cortex, and the thalamus, on individual subjects' high-resolution structural scans. Hemispheric lateralisation was quantified by comparing the level of activation between brain hemispheres within each volume of interest. In SII, no significant hemispheric difference in activation was detected. In the insula, activation was significantly greater in the left hemisphere than the right. In both SI and the thalamus, activation in response to painful stimulation was significantly greater in the hemisphere contralateral to the stimulus, which is consistent with these areas being involved in processing the sensory-discriminative aspects of pain.

An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging.

BACKGROUND: Anatomic sites within the brain, which activate in response to noxious stimuli, can be identified with the use of functional magnetic resonance imaging. The aim of this study was to determine whether the analgesic effects of ketamine could be imaged. METHODS: Ketamine was administered to eight healthy volunteers with use of a target-controlled infusion to three predicted plasma concentrations: 0 (saline), 50 (subanalgesic), and 200 ng/ml (analgesic, subanesthetic). Volunteers received noxious thermal stimuli and auditory stimuli and performed a motor task within a 3-T human brain imaging magnet. Activation of brain regions in response to noxious and auditory stimuli and during the motor task was compared with behavioral measures. RESULTS: The analgesic subanesthetic dose of ketamine significantly reduced the pain scores, and this matched a decrease in activity within brain regions that activate in response to noxious stimuli, in particular, the insular cortex and thalamus. A different pattern of activation was observed in response to an auditory task. In comparison, smaller behavioral and imaging changes were found for the motor paradigm. The lower dose of ketamine gave similar but smaller nonsignificant effects. CONCLUSION: The analgesic effect can be measured within a more global effect of ketamine as shown by auditory and motor tasks, and the analgesia produced by ketamine occurs with a smaller degree of cortical processing in pain-related regions.