Functional connectivity predicts changes in attention observed across minutes, days, and months.

The ability to sustain attention differs across people and changes within a single person over time. Although recent work has demonstrated that patterns of functional brain connectivity predict individual differences in sustained attention, whether these same patterns capture fluctuations in attention within individuals remains unclear. Here, across five independent studies, we demonstrate that the sustained attention connectome-based predictive model (CPM), a validated model of sustained attention function, generalizes to predict attentional state from data collected across minutes, days, weeks, and months. Furthermore, the sustained attention CPM is sensitive to within-subject state changes induced by propofol as well as sevoflurane, such that individuals show functional connectivity signatures of stronger attentional states when awake than when under deep sedation and light anesthesia. Together, these results demonstrate that fluctuations in attentional state reflect variability in the same functional connectivity patterns that predict individual differences in sustained attention.

Multi-modal analysis of functional connectivity and cerebral blood flow reveals shared and unique effects of propofol in large-scale brain networks.

Anesthesia-induced changes in functional connectivity and cerebral blow flow (CBF) in large-scale brain networks have emerged as key markers of reduced consciousness. However, studies of functional connectivity disagree on which large-scale networks are altered or preserved during anesthesia, making it difficult to find a consensus amount studies. Additionally, pharmacological alterations in CBF could amplify or occlude changes in connectivity due to the shared variance between CBF and connectivity. Here, we used data-driven connectivity methods and multi-modal imaging to investigate shared and unique neural correlates of reduced consciousness for connectivity in large-scale brain networks. Rs-fMRI and CBF data were collected from the same subjects during an awake and deep sedation condition induced by propofol. We measured whole-brain connectivity using the intrinsic connectivity distribution (ICD), a method not reliant on pre-defined seed regions, networks of interest, or connectivity thresholds. The shared and unique variance between connectivity and CBF were investigated. Finally, to account for shared variance, we present a novel extension to ICD that incorporates cerebral blood flow (CBF) as a scaling factor in the calculation of global connectivity, labeled CBF-adjusted ICD). We observed altered connectivity in multiple large-scale brain networks including the default mode (DMN), salience, visual, and motor networks and reduced CBF in the DMN, frontoparietal network, and thalamus. Regional connectivity and CBF were significantly correlated during both the awake and propofol condition. Nevertheless changes in connectivity and CBF between the awake and deep sedation condition were only significantly correlated in a subsystem of the DMN, suggesting that, while there is significant shared variance between the modalities, changes due to propofol are relatively unique. Similar, but less significant, results were observed in the CBF-adjusted ICD analysis, providing additional evidence that connectivity differences were not fully explained by CBF. In conclusion, these results provide further evidence of alterations in large-scale brain networks are associated with reduced consciousness and suggest that different modalities capture unique aspects of these large scale changes.

fMRI and Anesthesia.

BOLD activation studies discussed vary in the anesthetic agent studied (propofol, sevoflurane, and isoflurane), the concentration of the anesthetic (mostly under 0.5MAC or equivalent doses), and the activation paradigm/functional activation. The data analysis technique also differs between the studies. Notwithstanding these variations, the results can be summarized as follows: Higher order association cortices are more sensitive to anesthesia. Higher order regions processing language and semantics (regions in the frontal cortex) are affected at a lower concentration of anesthetic as compared with regions processing auditory stimuli. Whereas primary visual activation regions in the visual cortex and the thalamus are less sensitive, higher order visual spatial attention regions in the parietal cortex are more sensitive to anesthesia. In most studies, the loss of consciousness (no response to call) is achieved at or below 0.5MAC of anesthesia.

Functional Connectivity and Anesthesia.

Various anesthetic agents at various concentrations have been studied as described above. The analysis techniques for the BOLD fMRI data are also institution and investigator dependent. Despite this variability there seems to be some common patterns in the connectivity effect of various anesthetics/sedatives when the endpoint is LOC. Anesthesia in lower doses does not affect lower-order sensory/motor networks. Anesthetic agents primarily affect cortico-cortical and within-network connectivity. Higher-order networks (such as DMN, ECN, and the salience) are more sensitive to anesthesia.38 Salience network (the term "salience" meaning dominant, important) coordinates the function of the DMN and ECN network. The communication and information processing between the lowerorder networks and the higher-order networks (related to association cortices) is disrupted by anesthesia, leading to LOC. Connectivity in the precuneus, PCC, and posterior inferior parietal cortex (3 regions that are among the most active regions in the awake state) decreases with LOC.

NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia.

Glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain's global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate's role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.

Connectivity.

PURPOSE OF REVIEW: Connectivity is a technique that uses functional MRI (fMRI) to explore global brain function in healthy and diseased states. Connectivity is now being studied as a part of global brain function in major national and international studies. It is, therefore, timely to review its relevance to anaesthesia. RECENT FINDINGS: Dynamic connectivity in the brain, which transcends anatomical boundaries, links functionally related regions. Clinical manifestations in neuropsychiatric diseases such has Alzheimer's disease and schizophrenia can be explained on the basis of altered connectivity patterns in the brain. Anaesthetic agents primarily disrupt long-range networks and affect the higher order networks linked to cognition causing cognitive unbinding in the brain. Lower-order, basic sensorimotor networks are less sensitive. Normal ageing causes alterations in connectivity that affects the default mode network (DMN) and certain other networks, which in turn impair fluidic measures of brain function such as reaction time, dual task performance and executive function in elderly. SUMMARY: Higher mental function related networks such as the DMN, the executive control network and salience are more sensitive to anaesthesia. In geriatric patients, the DMN is impaired, which affects cognition. Hence, the combined effect of age and anaesthesia in elderly on mental function can cause significant postoperative cognitive impairment.

Functional MRI and pain.

PURPOSE OF REVIEW: This article reviews the current state of knowledge in functional MRI (fMRI) research related to pain with primary focus on clinical studies. RECENT FINDINGS: With fMRI, the subjective effects of pain (sensory, affect, emotion, and motor components) can be objectively imaged. Although the conventional fMRI technique has been the isolation of regions in the brain transmitting and modulating pain, functional connectivity measurement can identify functionally linked regions associated with pain processing. The primary and secondary somatosensory cortex (S1 and S2), anterior cingulate cortex (ACC), and insula are the four regions (part of pain matrix) consistently activated in pain states. Functional connectivity between the prefrontal cortex (PFC), ACC, and insula correlates well with clinical pain measures. The dorsal medial PFC to insula connectivity can identify patients prone to persistent back pain. Default mode network (DMN) to insula connectivity is associated with spontaneous pain in fibromyalgia patients. In addition, the DMN encompasses the PFC. Techniques for fMRI analysis, templates, and standards for identifying the functional networks in the brain are evolving continuously. The activation pattern with analgesic agents seems to be specific to the class of drugs. SUMMARY: As we learn more about fMRI related to pain, functional connectivity patterns could emerge as biomarkers for specific pain conditions.

A whole-brain voxel based measure of intrinsic connectivity contrast reveals local changes in tissue connectivity with anesthetic without a priori assumptions on thresholds or regions of interest.

The analysis of spontaneous fluctuations of functional magnetic resonance imaging (fMRI) signals has recently gained attention as a powerful tool for investigating brain circuits in a non-invasive manner. Correlation-based connectivity analysis investigates the correlations of spontaneous fluctuations of the fMRI signal either between a single seed region of interest (ROI) and the rest of the brain or between multiple ROIs. To do this, a priori knowledge is required for defining the ROI(s) and without such knowledge functional connectivity fMRI cannot be used as an exploratory tool for investigating the functional organization of the brain and its modulation under different conditions. In this work we examine two indices that provide voxel based maps reflecting the intrinsic connectivity contrast (ICC) of individual tissue elements without the need for defining ROIs and hence require no a priori information or assumptions. These voxel based ICC measures can also be used to delineate regions of interest for further functional or network analyses. The indices were applied to the study of sevoflurane anesthesia-induced alterations in intrinsic connectivity. In concordance with previous studies, the results show that sevoflurane affects different brain circuits in a heterogeneous manner. In addition ICC analyses revealed changes in regions not previously identified using conventional ROI connectivity analyses, probably because of an inappropriate choice of the ROI in the earlier studies. This work highlights the importance of such voxel based connectivity methodology.

Functional connectivity and alterations in baseline brain state in humans.

This work examines the influence of changes in baseline activity on the intrinsic functional connectivity fMRI (fc-fMRI) in humans. Baseline brain activity was altered by inducing anesthesia (sevoflurane end-tidal concentration 1%) in human volunteers and fc-fMRI maps between the pre-anesthetized and anesthetized conditions were compared across different brain networks. We particularly focused on low-level sensory areas (primary somatosensory, visual, and auditory cortices), the thalamus, and pain (insula), memory (hippocampus) circuits, and the default mode network (DMN), the latter three to examine higher-order brain regions. The results indicate that, while fc-fMRI patterns did not significantly differ (p<0.005; 20-voxel cluster threshold) in sensory cortex and in the DMN between the pre- and anesthetized conditions, fc-fMRI in high-order cognitive regions (i.e. memory and pain circuits) was significantly altered by anesthesia. These findings provide further evidence that fc-fMRI reflects intrinsic brain properties, while also demonstrating that 0.5 MAC sevoflurane anesthesia preferentially modulates higher-order connections.

Spatial nonuniformity of the resting CBF and BOLD responses to sevoflurane: in vivo study of normal human subjects with magnetic resonance imaging.

Pulsed arterial spin labeling magnetic resonance imaging (MRI) was performed to investigate the local coupling between resting regional cerebral blood flow (rCBF) and BOLD (blood oxygen level dependent) signal changes in 22 normal human subjects during the administration of 0.25 MAC (minimum alveolar concentration) sevoflurane. Two states were compared with subjects at rest: anesthesia and no-anesthesia. Regions of both significantly increased and decreased resting-state rCBF were observed. Increases were limited primarily to subcortical structures and insula, whereas, decreases were observed primarily in neocortical regions. No significant change was found in global CBF (gCBF). By simultaneously measuring rCBF and BOLD, region-specific anesthetic effects on the coupling between rCBF and BOLD were identified. Multiple comparisons of the agent-induced rCBF and BOLD changes demonstrated significant (P < 0.05) spatial variability in rCBF-BOLD coupling. The slope of the linear regression line for AC, where rCBF was increased by sevoflurane, was markedly smaller than the slope for those ROIs where rCBF was decreased by sevoflurane, indicating a bigger change in BOLD per unit change in rCBF in regions where rCBF was increased by sevoflurane. These results suggest that it would be inaccurate to use a global quantitative model to describe coupling across all brain regions and in all anesthesia conditions. The observed spatial nonuniformity of rCBF and BOLD signal changes suggests that any interpretation of BOLD fMRI data in the presence of an anesthetic requires consideration of these insights.

Anesthetic effects on regional CBF, BOLD, and the coupling between task-induced changes in CBF and BOLD: an fMRI study in normal human subjects.

Functional MR imaging was performed in sixteen healthy human subjects measuring both regional cerebral blood flow (CBF) and blood oxygen level dependent (BOLD) signal when visual and auditory stimuli were presented to subjects in the presence or absence of anesthesia. During anesthesia, 0.25 mean alveolar concentration (MAC) sevoflurane was administrated. We found that low-dose sevoflurane decreased the task-induced changes in both BOLD and CBF. Within the visual and auditory regions of interest inspected, both baseline CBF and the task-induced changes in CBF decreased significantly during anesthesia. Low-dose sevoflurane significantly altered the task-induced CBF-BOLD coupling; for a unit change of CBF, a larger change in BOLD was observed in the anesthesia condition than in the anesthesia-free condition. Low-dose sevoflurane was also found to have significant impact on the spatial nonuniformity of the task-induced coupling. The alteration of task-induced CBF-BOLD coupling by low-dose sevoflurane introduces ambiguity to the direct interpretation of functional MRI (fMRI) data based on only one of the indirect measures-CBF or BOLD. Our observations also indicate that the manipulation of the brain with an anesthetic agent complicates the model-based quantitative interpretation of fMRI data, in which the relative task-induced changes in oxidative metabolism are calculated by means of a calibrated model given the relative changes in the indirect vascular measures, usually CBF and BOLD.

Vagus nerve stimulation therapy for seizures.

Of the 3 million patients with seizures in North America approximately 70% have effective seizure control with medications. In the group refractory to medical treatment only a minority fit the criteria for surgical therapy. Vagus nerve stimulation therapy seems to be a suitable nonpharmacologic therapy for reducing seizure frequency in these cases. It is a simple device with 2 electrodes and an anchor loop implanted on the midcervical portion of left vagus nerve and the impulse generator is implanted subcutaneously in the left infraclavicular region. The left vagus is the preferred site as the right vagus innervates the sinoatrial node and influences the heart rate. Data from laboratory studies suggest that it most probably works by increasing the release of norepinephrine in the locus ceruleus, which in turn increases the seizure threshold. More than 32,000 devices have been implanted since it was approved in 1997. There is class I evidence that vagus nerve stimulator reduces the frequency of seizures. In addition it also elevates the patients' mood-independent of seizure control. In one of the studies 50% reduction in seizure frequency was 37% in the first year and 44% in the second and third year. The side effects commonly reported are constriction in the throat, change in voice, and throat pain which most patients are able to tolerate and continue the use of the device. In conclusion VNS seems to be an effective nonpharmacologic therapy for medically refractory partial onset seizures.

Understanding anesthesia through functional imaging.

PURPOSE OF REVIEW: This review will highlight the recent functional magnetic resonance imaging, positron emission tomogram scan and connectivity studies in anesthesia and analgesia. RECENT FINDINGS: In regional cerebral blood flow (rCBF) studies with isoflurane and sevoflurane, there is a consistent pattern of rise in rCBF in the anterior cingulate cortex and insula while the thalamus, lingual cortex and cerebellum show a decrease in rCBF, in a dose range of 0.2-1 minimum alveolar concentration. Even 0.25 minimum alveolar concentration causes a predominant decrease of rCBF in the cortical regions and increase of rCBF in the subcortical regions. This minimum alveolar concentration level primarily affects the association cortices. Thalamus and thalamo-cortical pathways seem to be linked to the hypnotic effects of anesthesia and deep sedation. Connectivity studies also confirm this. The electroencephalogram equivalent of this appears to be a transition from 'alpha' wave activity to 'delta' wave activity. Anterior cingulate cortex, S1 and S2 are the regions consistently activated in acute pain. Remifentanil infusion in acute pain decreases the activation in pain perception regions while activating the pain modulation regions. In chronic pain states, prefrontal cortex and insula are activated whereas there is a decrease in activity in the thalamus. SUMMARY: Slowly, a pattern of neuronal activity reflecting hypnosis, analgesia, amnesia and reflex suppression seems to be emerging giving us a better insight into the central nervous system effects of anesthesia.

Sevoflurane 0.25 MAC preferentially affects higher order association areas: a functional magnetic resonance imaging study in volunteers.

BACKGROUND: Functional magnetic resonance imaging (fMRI) can objectively measure the subjective effects of anesthesia. Memory-related regions (association areas) are affected by subanesthetic doses of volatile anesthetics. In this study we measured the regional neuronal effects of 0.25 MAC sevoflurane in healthy volunteers and differentiated the effect between primary cortical regions and association areas. METHODS: The effect of 0.25 MAC sevoflurane on visual, auditory, and motor activation was studied in 16 ASA I volunteers. With fMRI (3 Tesla Siemens magnetom), regional cerebral blood flow (rCBF) was measured by the pulsed arterial spin labeling technique. Subjects inhaled a mixture of O2 and 0.25 MAC sevoflurane and standard ASA monitoring was performed. Visual, auditory, and motor activation tasks were used. rCBF was measured in the awake state and during inhalation of 0.25 MAC sevoflurane, without and with activation. The change in rCBF (deltaCBF) with 0.25 MAC Sevoflurane during baseline state and with activation was calculated in 11 regions of interest related to visual, auditory, and motor activation tasks. RESULTS: The change from baseline rCBF with 0.25 MAC sevoflurane was not statistically significant in the 11 regions of interest. With activation there was a significant increase in CBF in several regions. However, only in the primary and secondary visual cortices (V1, V2), thalamus, hippocampus, and supplementary motor area was the decrease in activation with 0.25 MAC sevoflurane statistically significant (P < 0.05). CONCLUSION: Memory-related regions (association areas) are affected by subanesthetic concentrations of volatile anesthetics. Using fMRI, this study showed that 0.25 MAC sevoflurane predominantly affects the primary visual cortex, the related association cortex, and certain other higher order association cortices.

Geriatric Pharmacology.

Aging involves changes in several physiologic processes that lead to decreased volumes of distribution, slowed metabolism, and increased end-organ sensitivity to anesthetics. These changes generally result in increased potency. Elderly patients require less anesthetic medication, but the true extent of reduction is underappreciated and less uniformly practiced. The impact of potential anesthetic drug overdosing on intermediate and long-term outcomes is not fully appreciated. It may be necessary to consider age as a continuous variable for anesthetic drug dosing in older patients rather than treating adult versus elderly patients. Further pharmacologic studies are required in people more than 85 years old.

The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity.

Preclinical research suggests that N-methyl-D-aspartate glutamate receptors (NMDA-Rs) have a crucial role in working memory (WM). In this study, we investigated the role of NMDA-Rs in the brain activation and connectivity that subserve WM. Because of its importance in WM, the lateral prefrontal cortex, particularly the dorsolateral prefrontal cortex and its connections, were the focus of analyses. Healthy participants (n=22) participated in a single functional magnetic resonance imaging session. They received saline and then the NMDA-R antagonist ketamine while performing a spatial WM task. Time-course analysis was used to compare lateral prefrontal activation during saline and ketamine administration. Seed-based functional connectivity analysis was used to compare dorsolateral prefrontal connectivity during the two conditions and global-based connectivity was used to test for laterality in these effects. Ketamine reduced accuracy on the spatial WM task and brain activation during the encoding and early maintenance (EEM) period of task trials. Decrements in task-related activation during EEM were related to performance deficits. Ketamine reduced connectivity in the DPFC network bilaterally, and region-specific reductions in connectivity were related to performance. These results support the hypothesis that NMDA-Rs are critical for WM. The knowledge gained may be helpful in understanding disorders that might involve glutamatergic deficits such as schizophrenia and developing better treatments.