Delineating the Trajectory of Cognitive Recovery From General Anesthesia in Older Adults: Design and Rationale of the TORIE (Trajectory of Recovery in the Elderly) Project.

BACKGROUND: Mechanistic aspects of cognitive recovery after anesthesia and surgery are not yet well characterized, but may be vital to distinguishing the contributions of anesthesia and surgery in cognitive complications common in the elderly such as delirium and postoperative cognitive dysfunction. This article describes the aims and methodological approach to the ongoing study, Trajectory of Recovery in the Elderly (TORIE), which focuses on the trajectory of cognitive recovery from general anesthesia. METHODS: The study design employs cognitive testing coupled with neuroimaging techniques such as functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labeling to characterize cognitive recovery from anesthesia and its biological correlates. Applying these techniques to a cohort of age-specified healthy volunteers 40-80 years of age, who are exposed to general anesthesia alone, in the absence of surgery, will assess cognitive and functional neural network recovery after anesthesia. Imaging data are acquired before, during, and immediately after anesthesia, as well as 1 and 7 days after. Detailed cognitive data are captured at the same time points as well as 30 days after anesthesia, and brief cognitive assessments are repeated at 6 and 12 months after anesthesia. RESULTS: The study is underway. Our primary hypothesis is that older adults may require significantly longer to achieve cognitive recovery, measured by Postoperative Quality of Recovery Scale cognitive domain, than younger adults in the immediate postanesthesia period, but all will fully recover to baseline levels within 30 days of anesthesia exposure. Imaging data will address systems neuroscience correlates of cognitive recovery from general anesthesia. CONCLUSIONS: The data acquired in this project will have both clinical and theoretical relevance regardless of the outcome by delineating the mechanism behind short-term recovery across the adult age lifespan, which will have major implications for our understanding of the effects of anesthetic drugs.

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.

Inflammatory bowel disease: MR- and SPECT/CT-based macrophage imaging for monitoring and evaluating disease activity in experimental mouse model--pilot study.

PURPOSE: To evaluate the feasibility of using magnetic resonance (MR) imaging and single photon emission computed tomography (SPECT)/computed tomography (CT) to visualize the in vivo recruitment of iron oxide-labeled macrophages and indium 111 ((111)In)-labeled macrophages in inflammatory bowel disease (IBD) and to monitor disease activity. MATERIALS AND METHODS: This study had institutional animal care and use committee approval. Twenty-seven C57/B6 mice with dextran sodium sulfate (DSS)-induced IBD and control mice were included. Peritoneal macrophages were harvested from seven thioglycollate-treated mice and were labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Macrophage iron content was determined by using inductively coupled plasma mass spectrometry. SPIO nanoparticle-labeled macrophages (5 × 10(6)) were intravenously administered. Mice with DSS-induced IBD (n = 8) and control mice (n = 6) were imaged with a 9.4-T MR imaging unit at 0, 5, and 24 hours after macrophage administration. Percentage normalized enhancement (NE) was calculated for the intestinal wall and liver 24 hours after injection. Six mice with IBD coinjected with SPIO nanoparticles and (111)In oxine-labeled macrophages were imaged with MR imaging and SPECT/CT after 24 hours. The pharmacokinetics and biodistribution of the implanted macrophages were determined. Correlation between percentage NE and IBD scores was calculated. RESULTS: Ex vivo mass spectrometry revealed strong SPIO nanoparticle uptake (7.4 pg iron per cell). R2* correlated with cell number (r = 0.9813, P < .05). Percentage NE correlated with both clinical (r = 0.924) and pathologic (r = 0.795) IBD score. Cell circulation half-life in the first and second phases was 0.32 hour and 10.2 hours, respectively. SPECT/CT showed that approximately 3% of the injected dose was present in the intestines 24 hours after injection; this was confirmed at MR imaging and histologic examination. Indium 111-labeled cells were present in all tissue associated with the reticuloendothelial system or mononuclear phagocyte system at 24 hours. CONCLUSION: SPIO nanoparticles and (111)In-labeled macrophages could be observed in vivo at MR imaging and SPECT/CT in mice with IBD. Percentage NE at MR imaging correlates with disease activity.

Diagnostic value of diffusion-weighted MR imaging in thyroid disease: application in differentiating benign from malignant disease.

BACKGROUND: Fine needle aspiration biopsy is usually performed to evaluate thyroid lesions. The purpose of this study was to evaluate the usefulness of diffusion weighted imaging to differentiate malignancy of thyroid lesions. METHODS: The study was approved by ethics committee of Shanghai Changzheng Hospital.Forty-two patients, 10 men and 32 women (range: 20-72 years, mean age 42.4 years) with thyroid lesions were included in the study. Routine neck MR and diffusion-weighted MR imaging was performed using multiple b-values. ADC values were computed for the different b-values. Histological results of the thyroidectomy samples were obtained for all the patients. ADC values of benign and malignant thyroid lesions were compared with the pathology results. Logistic regression analysis was used to detect independent parameters for differentiating benign and malignancy of lesions. RESULT: Based on the histology results there were 28 benign and 14 malignant cases. The difference of ADC value between benign and malignant thyroid lesions was significant for ADC values obtained using b-values of 0 and 300 s/mm(2) (p < 0.001). The ADC values were significantly higher in benign lesions (benign ADC: 2.37 ± 0.47 × 10-3 mm(2)/s vs. malignant: 1.49 ± 0.60 × 10-3 mm(2)/s). ADC values obtained with b-values of 0 and 300 mm(2)/s and max nodular diameter was regarded as the two most discriminative parameters for differentiating malignancy. Using the pathology results as a standard reference, area under ROC curve was found to be 0.876 for an ADC cutoff value of 2.17 × 10-3 mm(2)/s that corresponded to an acquisition with b-values of 0 and 300 mm(2)/s. CONCLUSION: Diffusion-weighted MR imaging is a promising non-invasive method to differentiate malignancy in thyroid lesions.

Investigation of hypoxia conditions using oxygen-enhanced magnetic resonance imaging measurements in glioma models.

The objective of this study was to determine whether using oxygen-enhanced magnetic resonance imaging (OE-MRI) to assess hypoxia is feasible and whether historical measurements, pO2 changes, and percentage of signal intensity changes (PSIC) are correlated in an animal model of glioma. A total of 25 Sprague-Dawley rats were used to establish C6 brain or subcutaneous glioma model. Nine rats with brain gliomas underwent OE-MRI followed by histopathologic analysis to assess microvessel density and hypoxia. Another 11 rats were underwent OE-MRI and were followed for a survival analysis. Time-T1-weighted MR signal intensity (SI) curves and PSIC maps were derived from the OE-MRI data. High-regions of interests (ROI-h; PSIC > 10%) and low-ROIs (ROI-l; PSIC < 10%) were defined on the PSIC maps. To validate the PSIC map for identifying tumor hypoxia, we subjected an additional 5 rats with subcutaneous glioma to OE-MRI and pO2 measurements. All tumors showed regional heterogeneity on the PSIC maps. For the brain tumors, the time-SI curves for the ROIs-h showed a greater increase in SI than those for the ROIs-l did. The percentage of tumor area with a low PSIC was significantly correlated with the percentage of hypoxia staining and necrosis (r =0.71; P<0.05). ROIs with a higher PSIC typically had more vessels (r=0.88; P<0.05). A significant difference in survival was shown (log-rank P = 0.035). The time-pO2 curves of the subcutaneous tumors were similar to the time-SI curves. PSIC was significantly correlated with pO2 changes (r =0.82; P<0.05). These findings suggest that OE-MRI measurements can be used to assess hypoxia in C6 glioma models. In these models, the PSIC value was correlated with survival, indicating that PSIC could serve as a prognostic marker for glioma.

Social stress induces neurovascular pathology promoting depression.

Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood-brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression.

Effects of Manganese Exposure on Olfactory Functions in Teenagers: A Pilot Study.

Long-term exposure to environmental manganese (Mn) affects not only attention and neuromotor functions but also olfactory functions of a pre-adolescent local population who have spent their whole life span in contaminated areas. In order to investigate the effect of such exposure at the level of the central nervous system we set up a pilot fMRI experiment pointing at differences of brain activities between a non-exposed population (nine subjects) and an exposed one (three subjects). We also measured the volume of the olfactory bulb as well as the identification of standard olfactory stimuli. Our results suggest that young subjects exposed to Mn exhibit a reduction of BOLD signal, subjective odor sensitivity and olfactory bulb volume. Moreover a region of interest SPM analysis showed a specifically reduced response of the limbic system in relation to Mn exposure, suggesting an alteration of the brain network dealing with emotional responses.

In vivo micro magnetic resonance imaging signal changes in scrapie infected mice.

Signal abnormalities on magnetic resonance imaging (MRI) T2-weighted images (T2WI) have been described in patients with Creutzfeldt-Jakob disease; however, the pathology underlying these findings remains to be fully described. We investigated the time-course of signal alterations in a murine model of prion disease using in vivo 9.4 Tesla micro magnetic resonance imaging (muMRI). The topography of muMRI signal changes was correlated with the accumulation of proteinase resistant PrP(Sc) in corresponding brain sections. Increased signal intensity on T2WI was observed in the septum and in the hippocampus of presymptomatic mice 120 days post infection (dpi). Mildly symptomatic animals (150 dpi) and animals with apparent neurological deficit (180 dpi) had a greater increase of signal intensity on T2WI in the septum and the hippocampus; in addition, abnormalities in the cortex and in the thalamus were found. Neuropathological evaluation demonstrated accumulation of PrP(Sc) and astrogliosis but only minimal or no spongiform changes in structures where abnormal signal was detected. These observations suggest that early pathological changes related to the accumulation of PrP(Sc) may be detectable in presymptomatic subjects using MRI systems with higher magnetic field strength.

Effects of hyperoxia on resting state functional magnetic resonance imaging.

We studied the effect of oxygen inhalation during resting state functional MRI scanning in healthy control individuals. We hypothesized that resting state networks would be modified under hyperoxic conditions. Thirty-four normal volunteers were recruited for this study. All participants were scanned twice: once while breathing atmospheric air and once under hyperoxic conditions in a randomized order. Hyperoxic conditions were produced by administering 100% O2. Blood oxygen level-dependent T2* scans were obtained for each of the scans. Resting state networks were extracted using independent component analysis. A paired t-test showed that the resting state networks scans (default mode network, attention network and executive network) acquired under hyperoxic conditions had significantly higher Z-scores than scans performed under atmospheric air. Spectral analysis of the time-course signal in these networks also showed a difference in the total power of low frequencies between the two conditions. These results were reversed in the visual network. Clinical or research applications of oxygen-enhanced MRI need to take into account the modularly effects that hyperoxia exerts on the networks resting state functional MRI.

Novel imaging strategies for assessment of cerebrovascular involvement.

There is an important correlation between vascular risk factors and nonspecific imaging findings in the brain such as white-matter hyperintensities. These vascular risk factors are also associated with dementia and lesser forms of cognitive impairment. One hypothesis is that these vascular risk factors lead to disruption of connective networks in the central nervous system that are supported by myelinated white-matter fibers, which in turn lead to deficits in functional signaling between various brain regions. Another possibility is an alteration of the neurovascular coupling due to vascular risk factors. This reduced functional signaling contributes to the cognitive deficits in persons harboring these vascular risk factors. Lifestyle changes may restore some of these functional deficits through brain plasticity. It is imperative that preclinical diagnostic techniques are developed to identify these early brain changes in persons harboring vascular risk factors, as such efforts may improve primary and secondary prevention efforts. Recently developed imaging techniques may provide objective imaging biomarkers to measure the structural and functional brain changes in persons with vascular risk factors and resulting subclinical atherosclerotic disease. This article reviews a few of these novel imaging techniques.

Regional gray matter correlates of vocational interests.

BACKGROUND: Previous studies have identified brain areas related to cognitive abilities and personality, respectively. In this exploratory study, we extend the application of modern neuroimaging techniques to another area of individual differences, vocational interests, and relate the results to an earlier study of cognitive abilities salient for vocations. FINDINGS: First, we examined the psychometric relationships between vocational interests and abilities in a large sample. The primary relationships between those domains were between Investigative (scientific) interests and general intelligence and between Realistic ("blue-collar") interests and spatial ability. Then, using MRI and voxel-based morphometry, we investigated the relationships between regional gray matter volume and vocational interests. Specific clusters of gray matter were found to be correlated with Investigative and Realistic interests. Overlap analyses indicated some common brain areas between the correlates of Investigative interests and general intelligence and between the correlates of Realistic interests and spatial ability. CONCLUSIONS: Two of six vocational-interest scales show substantial relationships with regional gray matter volume. The overlap between the brain correlates of these scales and cognitive-ability factors suggest there are relationships between individual differences in brain structure and vocations.

Oxygen-enhanced magnetic resonance imaging of the brain: a rodent model.

Oxygen-enhanced MRI has been shown to be a viable alternative to hyperpolarized gases for pulmonary imaging. The changes in the relaxation times due to hyperoxic conditions in the blood pool induced by inhalation of pure oxygen have produced sufficient signal changes for imaging applications. This is a safe and low-cost alternative for contrast-enhanced imaging. The application of oxygen-enhanced MRI in brain imaging has been much less studied. In this study, we investigated the changes in the relaxation times in the brain due to inhalation of pure oxygen in a rodent model. We also assessed the effects of reduced blood flow due to hyperoxic conditions. Despite the reduced blood flow, significant changes in T1, T2, and T2* relaxation times were detected. We conclude that oxygen-enhanced MRI can be used in rodent models of disease.

Diffuse Disconnectivity in tBi: a resting state fMri anD Dti stuDy.

Diffuse axonal injury is a common pathological consequence of Traumatic Brain Injury (TBI). Diffusion Tensor Imaging is an ideal technique to study white matter integrity using the Fractional Anisotropy (FA) index which is a measure of axonal integrity and coherence. There have been several reports showing reduced FA in individuals with TBI, which suggest demyelination or reduced fiber density in white matter tracts secondary to injury. Individuals with TBI are usually diagnosed with cognitive deficits such as reduced attention span, memory and executive function. In this study we sought to investigate correlations between brain functional networks, white matter integrity, and TBI severity in individuals with TBI ranging from mild to severe. A resting state functional magnetic resonance imaging protocol was used to study the default mode network in subjects at rest. FA values were decreased throughout all white matter tracts in the mild to severe TBI subjects. FA values were also negatively correlated with TBI injury severity ratings. The default mode network showed several brain regions in which connectivity measures were higher among individuals with TBI relative to control subjects. These findings suggest that, subsequent to TBI, the brain may undergo adaptation responses at the cellular level to compensate for functional impairment due to axonal injury.

Occupational solvent exposure and brain function: an fMRI study.

BACKGROUND: Deficits in cognitive function have been demonstrated among workers chronically exposed to solvents, but the neural basis for these deficits has not been shown. OBJECTIVES: We used functional magnetic resonance imaging (fMRI) to compare pathophysiological changes in brain function between solvent-exposed and control workers. METHODS: Painters, drywall tapers, and carpenters were recruited from the International Union of Painters and Allied Trades, District Council 9 in New York City and District Council 21 in Philadelphia, Pennsylvania, and from the Carpenters Union in New Jersey. Twenty-seven solvent-exposed and 27 control subjects of similar age, education, and occupational status completed the N-Back working memory test during fMRI. After controlling for confounders (age; lifetime marijuana, cocaine, and alcohol use; blood lead; symptoms of depression; verbal intelligence), voxelwise group analysis and regional activation levels were compared and then correlated with an index of lifetime solvent exposure. RESULTS: Solvent-exposed workers' performance on the N-Back was significantly worse than that of controls. Activation of the anterior cingulate, prefrontal, and parietal cortices--areas serving working memory function and attention--was also significantly lower for solvent-exposed workers relative to controls. After controlling for confounders, we observed a negative correlation between lifetime solvent exposure and activation in these same regions among the solvent-exposed workers. CONCLUSIONS: This study is one of the few to document neural structures affected by exposure to solvents. Our findings provide a biological mechanism for the neurobehavioral deficits in working memory and attention that have previously been reported by other groups studying the effects of chronic exposure to solvents. These imaging markers, which are consistent with the neurobehavioral measures in our subject population, are consistent with altered brain pathology caused by prolonged exposure to solvent mixtures during construction work.

The effects of hypertension and body mass index on diffusion tensor imaging in schizophrenia.

Recently, the negative effects of hypertension and elevated body mass index on cognitive functioning in schizophrenia have been reported (Friedman et al., 2010). Data suggests that cognitive changes in hypertensive patients from the general population may be mediated, in part, by white matter damage. Therefore, we performed diffusion tensor imaging (DTI) in the same subjects studied by Friedman et al. (2010) to investigate the effects of hypertension and elevated body mass index on the fractional anisotropy (FA) of several major white matter tracts. Significant interactions between a diagnosis of schizophrenia and hypertension on FA in several white matter regions were detected. Hypertension was associated with lower FA in the schizophrenic group and higher FA in the same tracts in the non-schizophrenic subjects. These results suggest hypertension-induced compensatory mechanisms in the brains of non-schizophrenic patients with hypertension which may be impaired in persons with schizophrenia.

Detection of Alzheimer's amyloid in transgenic mice using magnetic resonance microimaging.

The presence of amyloid-beta (Abeta) plaques in the brain is a hallmark pathological feature of Alzheimer's disease (AD). Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin-1 (APP/PS1), develop Abeta plaques similar to those in AD patients, and have been proposed as animal models in which to test experimental therapeutic approaches for the clearance of Abeta. However, at present there is no in vivo whole-brain imaging method to detect Abeta plaques in mice or men. A novel method is presented to detect Abeta plaques in the brains of transgenic mice by magnetic resonance microimaging (muMRI). This method uses Abeta1-40 peptide, known for its high binding affinity to Abeta, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). Intraarterial injection of magnetically labeled Abeta1-40, with mannitol to transiently open the blood-brain barrier (BBB), enabled the detection of many Abeta plaques. Furthermore, the numerical density of Abeta plaques detected by muMRI and by immunohistochemistry showed excellent correlation. This approach provides an in vivo method to detect Abeta in AD transgenic mice, and suggests that diagnostic MRI methods to detect Abeta in AD patients may ultimately be feasible.