Mild propofol sedation reduces frontal lobe and thalamic cerebral blood flow: An arterial spin labeling study

Mechanisms of anesthetic drug-induced sedation and unconsciousness are still incompletely understood. Functional neuroimaging modalities provide a window to study brain function changes during anesthesia allowing us to explore the sequence of neuro-physiological changes associated with anesthesia. Cerebral perfusion change under an assumption of intact neurovascular coupling is an indicator of change in large-scale neural activity. In this experiment, we have investigated resting state cerebral blood flow (CBF) changes in the human brain during mild sedation, with propofol. Arterial spin labeling (ASL) provides a non-invasive, reliable, and robust means of measuring cerebral blood flow (CBF) and can therefore be used to investigate central drug effects. Mild propofol sedation-related CBF changes were studied at rest (n = 15), in a 3 T MR scanner using a PICORE-QUIPSS II ASL technique. CBF was reduced in bilateral paracingulate cortex, premotor cortex, Broca’s areas, right superior frontal gyrus and also the thalamus. This cerebral perfusion study demonstrates that propofol induces suppression of key cortical (frontal lobe) and subcortical (thalamus) regions during mild sedation

Investigating the functional neuroanatomic basis of oscillatory brain activity in healthy individuals and in patients with schizophrenia

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Enhanced stimulus-induced gamma activity in humans during propofol-induced sedation.

Stimulus-induced gamma oscillations in the 30-80 Hz range have been implicated in a wide number of functions including visual processing, memory and attention. While occipital gamma-band oscillations can be pharmacologically modified in animal preparations, pharmacological modulation of stimulus-induced visual gamma oscillations has yet to be demonstrated in non-invasive human recordings. Here, in fifteen healthy humans volunteers, we probed the effects of the GABAA agonist and sedative propofol on stimulus-related gamma activity recorded with magnetoencephalography, using a simple visual grating stimulus designed to elicit gamma oscillations in the primary visual cortex. During propofol sedation as compared to the normal awake state, a significant 60% increase in stimulus-induced gamma amplitude was seen together with a 94% enhancement of stimulus-induced alpha suppression and a simultaneous reduction in the amplitude of the pattern-onset evoked response. These data demonstrate, that propofol-induced sedation is accompanied by increased stimulus-induced gamma activity providing a potential window into mechanisms of gamma-oscillation generation in humans

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

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

Trait related aberrant connectivity in clinically stable patients with schizophrenia:A seed based resting state fMRI study

Aberrant resting-state connectivity within and between the Default Mode Network, the Executive Control Network, and the Salience Network is well-established in schizophrenia. Meta-analyses have identified that bilateral lingual gyrus is as the only region showing hyperactivity in schizophrenia and there are reports of increased connectivity between the lingual gyrus and other brain regions in schizophrenia. It is not clear whether these abnormalities represent state or trait markers of the illness, i.e., if they are only present during the acute phase of the illness (state) or if they reflect a predisposition to schizophrenia (trait). In this study, we used a seed-based functional connectivity analysis to investigate brain networks in schizophrenia patients who are in the stable phase of their illness and assess functional connectivity using seeds in the lingual gyrus, the posterior cingulate, the right dorsolateral prefrontal cortex (dlPFC), the right anterior insula (rAI) and the right orbital frontoinsula. Twenty patients with schizophrenia in a stable phase of their illness (as defined by the course of illness and Signs and Symptoms of Psychotic Illness (SSPI) scores) and 20 age and sex-matched healthy controls underwent resting-state functional Magnetic Resonance Imaging (rs-fMRI). Data was analysed using the Data Processing Assistant for Resting-State fMRI Advanced Edition (DPARSFA) V3.1 (http://rfmri.org/DPARSF) and the statistical parametric mapping software 8 (SPM8). Compared with healthy controls, patients with schizophrenia showed increased connectivity between the left lingual gyrus and the middle frontal gyrus, and the cingulate cortex. Lingual gyrus hyper-connectivity may be a stable trait neuroimaging marker for schizophrenia. Our findings suggest that aberrant connectivity in major resting-state networks may not be present after the acute illness has stabilised. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11682-022-00731-9

Separating neural and vascular effects of caffeine using simultaneous EEG-FMRI: Differential effects of caffeine on cognitive and sensorimotor brain responses.

The effects of caffeine are mediated through its non-selective antagonistic effects on adenosine A1 and A2A adenosine receptors resulting in increased neuronal activity but also vasoconstriction in the brain. Caffeine, therefore, can modify BOLD FMRI signal responses through both its neural and its vascular effects depending on receptor distributions in different brain regions. In this study we aim to distinguish neural and vascular influences of a single dose of caffeine in measurements of task-related brain activity using simultaneous EEG–FMRI. We chose to compare low-level visual and motor (paced finger tapping) tasks with a cognitive (auditory oddball) task, with the expectation that caffeine would differentially affect brain responses in relation to these tasks. To avoid the influence of chronic caffeine intake, we examined the effect of 250 mg of oral caffeine on 14 non and infrequent caffeine consumers in a double-blind placebo-controlled cross-over study. Our results show that the task-related BOLD signal change in visual and primary motor cortex was significantly reduced by caffeine, while the amplitude and latency of visual evoked potentials over occipital cortex remained unaltered. However, during the auditory oddball task (target versus non-target stimuli) caffeine significantly increased the BOLD signal in frontal cortex. Correspondingly, there was also a significant effect of caffeine in reducing the target evoked response potential (P300) latency in the oddball task and this was associated with a positive potential over frontal cortex. Behavioural data showed that caffeine also improved performance in the oddball task with a significantly reduced number of missed responses. Our results are consistent with earlier studies demonstrating altered flow-metabolism coupling after caffeine administration in the context of our observation of a generalised caffeine-induced reduction in cerebral blood flow demonstrated by arterial spin labelling (19% over grey matter). We were able to identify vascular effects and hence altered neurovascular coupling through the alteration of low-level task FMRI responses in the face of a preserved visual evoked potential. However, our data also suggest a cognitive effect of caffeine through its positive effect on the frontal BOLD signal consistent with the shortening of oddball EEG response latency. The combined use of EEG–FMRI is a promising methodology for investigating alterations in brain function in drug and disease studies where neurovascular coupling may be altered on a regional basis

Pulsed arterial spin labeling perfusion imaging at 3 T:estimating the number of subjects required in common designs of clinical trials

Pulsed arterial spin labeling (PASL) is an increasingly common technique for noninvasively measuring cerebral blood flow (CBF) and has previously been shown to have good repeatability. It is likely to find a place in clinical trials and in particular the investigation of pharmaceutical agents active in the central nervous system. We aimed to estimate the sample sizes necessary to detect regional changes in CBF in common types of clinical trial design including (a) between groups, (b) a two-period crossover and (3) within-session single dosing. Whole brain CBF data were acquired at 3 T in two independent groups of healthy volunteers at rest; one of the groups underwent a repeat scan. Using these data, we were able to estimate between-groups, between-session and within-session variability along with regional mean estimates of CBF. We assessed the number of PASL tag–control image pairs that was needed to provide stable regional estimates of CBF and variability of regional CBF across groups. Forty tag–control image pairs, which take approximately 3 min to acquire using a single inversion label delay time, were adequate for providing stable CBF estimates at the group level. Power calculations based on the variance estimates of regional CBF measurements suggest that comparatively small cohorts are adequate. For example, detecting a 15% change in CBF, depending on the region of interest, requires from 7–15 subjects per group in a crossover design, 6–10 subjects in a within-session design and 20–41 subjects in a between-groups design. Such sample sizes make feasible the use of such CBF measurements in clinical trials of drugs

Summary of total (evoked plus induced) amplitude differences in the experiment.

<p>a) Grand-averaged source localisation of gamma oscillations (40–80 Hz) for awake and sedated states respectively. Units are <i>t</i> statistics. The peak source location for the gamma band was at MNI co-ordinate [15–95 7] for awake and [17 97 1] for sedated (adjacent SAM voxels). b) Grand-averaged time-frequency spectrograms showing source-level oscillatory amplitude (evoked+induced) changes following visual stimulation with a grating patch (stimulus onset at time = 0) during awaked and sedated states. Spectrograms are displayed as percentage change from the pre-stimulus baseline and were computed for frequencies from 5 up to 150 Hz but truncated here to 100 Hz for visualisation purposes. c) Envelopes of oscillatory amplitude for the gamma (40–80 Hz) and alpha (8–15 Hz) bands respectively. Time-periods with significant differences between the awake and sedated states are indicated with a black bar (*<i>p</i><.05, **<i>p</i><.01, ***<i>p</i><.001, shaded areas represent SEM).</p

Summary of evoked amplitude differences in the experiment.

<p>a) Grand-averaged time-frequency spectrograms showing source-level oscillatory amplitude changes for the evoked response. b) Evoked amplitude spectra for the 0–0.2 s time period. c) Source-level time-averaged evoked responses for awake and sedated states. Significant differences were seen in the amplitude of the M100 and M150 responses (*<i>p</i><.05, **<i>p</i><.01, ***<i>p</i><.001, shaded areas represent SEM).</p