An exploratory research report on brain mineralization in postoperative delirium and cognitive decline.

Delirium is a severe postoperative complication associated with poor overall and especially neurocognitive prognosis. Altered brain mineralization is found in neurodegenerative disorders but has not been studied in postoperative delirium and postoperative cognitive decline. We hypothesized that mineralization-related hypointensity in susceptibility-weighted magnetic resonance imaging (SWI) is associated with postoperative delirium and cognitive decline. In an exploratory, hypothesis-generating study, we analysed a subsample of cognitively healthy patients ≥65 years who underwent SWI before (N = 65) and 3 months after surgery (N = 33). We measured relative SWI intensities in the basal ganglia, hippocampus and posterior basal forebrain cholinergic system (pBFCS). A post hoc analysis of two pBFCS subregions (Ch4, Ch4p) was conducted. Patients were screened for delirium until the seventh postoperative day. Cognitive testing was performed before and 3 months after surgery. Fourteen patients developed delirium. After adjustment for age, sex, preoperative cognition and region volume, only pBFCS hypointensity was associated with delirium (regression coefficient [90% CI]: B = -15.3 [-31.6; -0.8]). After adjustments for surgery duration, age, sex and region volume, perioperative change in relative SWI intensities of the pBFCS was associated with cognitive decline 3 months after surgery at a trend level (B = 6.8 [-0.9; 14.1]), which was probably driven by a stronger association in subregion Ch4p (B = 9.3 [2.3; 16.2]). Brain mineralization, particularly in the cerebral cholinergic system, could be a pathomechanism in postoperative delirium and cognitive decline. Evidence from our studies is limited because of the small sample and a SWI dataset unfit for iron quantification, and the analyses presented here should be considered exploratory.

Structural disconnectivity in postoperative delirium: A perioperative two-center cohort study in older patients.

BACKGROUND: Structural disconnectivity was found to precede dementia. Global white matter abnormalities might also be associated with postoperative delirium (POD). METHODS: We recruited older patients (≥65 years) without dementia that were scheduled for major surgery. Diffusion kurtosis imaging metrics were obtained preoperatively, after 3 and 12 months postoperatively. We calculated fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK), and free water (FW). A structured and validated delirium assessment was performed twice daily. RESULTS: Of 325 patients, 53 patients developed POD (16.3%). Preoperative global MD (standardized beta 0.27 [95% confidence interval [CI] 0.21-0.32] p < 0.001) was higher in patients with POD. Preoperative global MK (-0.07 [95% CI -0.11 to (-0.04)] p < 0.001) and FA (0.07 [95% CI -0.10 to (-0.04)] p < 0.001) were lower. When correcting for baseline diffusion, postoperative MD was lower after 3 months (0.05 [95% CI -0.08 to (-0.03)] p < 0.001; n = 183) and higher after 12 months (0.28 [95% CI 0.20-0.35] p < 0.001; n = 45) among patients with POD. DISCUSSION: Preoperative structural disconnectivity was associated with POD. POD might lead to white matter depletion 3 and 12 months after surgery.

The Thalamus in Perioperative Neurocognitive Disorders.

Thalamus function and structure are known predictors of individual differences in the risk of age-related neurocognitive disorders (NCD), such as dementia. However, to date, little is known about their role in the perioperative setting. Here, we provide a narrative review of brain-imaging studies of preoperative and postoperative thalamus scanning parameters associated with risks of developing perioperative NCD, such as postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) during the postoperative phase. These findings are discussed in light of the concept of reserve capacity.

Presurgical Thalamus Volume in Postoperative Delirium: A Longitudinal Observational Cohort Study in Older Patients.

BACKGROUND: Previous studies suggest a role of the thalamus in cognitive function, while others implicate it as a central effect site of anesthetics. Yet, its role in postoperative neurocognition in the aging brain remains uncertain. We used presurgical thalamic volume as a functional indicator and determined its association with postoperative delirium (POD). METHODS: For this study, 301 older adults (aged ≥65) without dementia and scheduled for surgery were enrolled. Before surgery, participants underwent magnetic resonance imaging (MRI). Thalamus volume was segmented using Freesurfer (Version 5.3.). Participants were screened for POD twice a day until discharge or for a maximum of 7 days. POD was defined as a positive screening on ≥1 of 4 validated instruments: Richmond Agitation Sedation Scale (RASS), Nursing Delirium Screening Scale (Nu-DESC), Confusion Assessment Method (CAM), and Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) score. A logistic regression associated thalamus volume with POD with adjustment for age, global brain atrophy, and physical status according to the American Society of Anesthesiologists (ASA) classification. RESULTS: In this cohort, 44 participants (14.6%) were diagnosed with POD. Independently of age, global brain atrophy, and physical status score, a higher preoperative thalamus volume was associated with a reduced odds of POD (odds ratio per 1-cm3 increment; 0.73 [95% confidence interval (CI), 0.58-0.92]; P = .008). CONCLUSIONS: A larger thalamus volume was associated with reduced odds of POD. Thus, the thalamus marks a region of interest in POD in the aging brain. These findings may help to understand the neuronal basis of POD.

Ketamine effects on default mode network activity and vigilance: A randomized, placebo-controlled crossover simultaneous fMRI/EEG study.

In resting-state functional connectivity experiments, a steady state (of consciousness) is commonly supposed. However, recent research has shown that the resting state is a rather dynamic than a steady state. In particular, changes of vigilance appear to play a prominent role. Accordingly, it is critical to assess the state of vigilance when conducting pharmacodynamic studies with resting-state functional magnetic resonance imaging (fMRI) using drugs that are known to affect vigilance such as (subanesthetic) ketamine. In this study, we sought to clarify whether the previously described ketamine-induced prefrontal decrease of functional connectivity is related to diminished vigilance as assessed by electroencephalography (EEG). We conducted a randomized, double-blind, placebo-controlled crossover study with subanesthetic S-Ketamine in N = 24 healthy, young subjects by simultaneous acquisition of resting-state fMRI and EEG data. We conducted seed-based default mode network functional connectivity and EEG power spectrum analyses. After ketamine administration, decreased functional connectivity was found in medial prefrontal cortex whereas increased connectivities were observed in intraparietal cortices. In EEG, a shift of energy to slow (delta, theta) and fast (gamma) wave frequencies was seen in the ketamine condition. Frontal connectivity is negatively related to EEG gamma and theta activity while a positive relationship is found for parietal connectivity and EEG delta power. Our results suggest a direct relationship between ketamine-induced functional connectivity changes and the concomitant decrease of vigilance in EEG. The observed functional changes after ketamine administration may serve as surrogate end points and provide a neurophysiological framework, for example, for the antidepressant action of ketamine (trial name: 29JN1556, EudraCT Number: 2009-012399-28).

Averaging auditory evoked magnetoencephalographic and electroencephalographic responses: a critical discussion.

In the analysis of data from magnetoencephalography (MEG) and electroencephalography (EEG), it is common practice to arithmetically average event-related magnetic fields (ERFs) or event-related electric potentials (ERPs) across single trials and subsequently across subjects to obtain the so-called grand mean. Comparisons of grand means, e.g. between conditions, are then often performed by subtraction. These operations, and their statistical evaluation with parametric tests such as ANOVA, tacitly rely on the assumption that the data follow the additive model, have a normal distribution, and have a homogeneous variance. This may be true for single trials, but these conditions are rarely met when ERFs/ERPs are compared between subjects, meaning that the additive model is seldom the correct model for computing grand mean waveforms. Here, we summarize some of our recent work and present new evidence, from auditory-evoked MEG and EEG results, that the non-normal distributions and the heteroscedasticity observed instead result because ERFs/ERPs follow a mixed model with additive and multiplicative components. For peak amplitudes, such as the auditory M100 and N100, the multiplicative component dominates. These findings emphasize that the common practice of simply subtracting arithmetic means of auditory-evoked ERFs or ERPs is problematic without prior adequate transformation of the data. Application of the area sinus hyperbolicus (asinh) transform to data following the mixed model transforms them into the requested additive model with its normal distribution and homogeneous variance. We therefore advise checking the data for compliance with the additive model and using the asinh transform if required.

Perioperative Levels of IL8 and IL18, but not IL6, are Associated with Nucleus Basalis Magnocellularis Atrophy Three Months after Surgery.

Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in circulation as well as the perioperative change in interleukin levels are associated with increased postoperative atrophy in the Nucleus basalis magnocellularis (of Meynert, NBM) which is the major source of cortical acetylcholine. We analyzed data from the BioCog cohort which included patients ≥ 65 years presenting for elective major surgery (≥ 60min). Blood samples were taken before surgery and on the first postoperative day. Magnetic resonance imaging of the brain and neuropsychological assessments were conducted before surgery and after three months follow-up. We used linear regression analysis to determine the association of three interleukins (IL6, IL8 and IL18) with NBM atrophy (in % volume change from baseline before surgery to follow-up), as well as to examine the associations of NBM atrophy and volume with postoperative cognitive ability and perioperative cognitive change. Receiver-operating curves were used to determine the prognostic value of preoperative interleukin levels. For IL8 (N = 97) and IL18 (N = 217), but not IL6 (N = 240), we observed significant associations of higher postoperative IL levels at the first postoperative day with higher NBM atrophy at three months after surgery. Subsequent analyses suggested that in both IL8 and IL18, this association was driven by a more general association of chronically elevated IL levels and NBM atrophy, reflected by preoperative IL concentrations, rather than IL response to surgery, measured as the difference between pre- and postoperative IL concentrations. At follow-up, NBM volume was positively associated with the level of cognitive performance, but NBM atrophy was not significantly related to perioperative cognitive change. Prognostic value of preoperative IL concentrations for NBM atrophy was low. Our results suggest that an association of postoperative interleukin levels with NBM atrophy is driven by preoperatively elevated interleukins due to pre-existing inflammation, rather than perioperative change in interleukin levels in response to surgery and anesthesia. The BioCog study has been registered at clinicaltrials.gov on Oct 15, 2014 (NCT02265263).

Preoperative thalamus volume is not associated with preoperative cognitive impairment (preCI) or postoperative cognitive dysfunction (POCD).

A growing body of literature suggests the important role of the thalamus in cognition and neurodegenerative diseases. This study aims to elucidate whether the preoperative thalamic volume is associated with preoperative cognitive impairment (preCI) and whether it is predictive for postoperative cognitive dysfunction at 3 months (POCD). We enrolled 301 patients aged 65 or older and without signs of dementia who were undergoing elective surgery. Magnetic resonance imaging was conducted prior to surgery. Freesurfer (version 5.3.) was used to automatically segment the thalamus volume. A neuropsychological test battery was administered before surgery and at a 3 month follow-up. It included the computerized tests Paired Associate Learning (PAL), Verbal Recognition Memory (VRM), Spatial Span Length (SSP), Simple Reaction Time (SRT), the pen-and-paper Trail-Making-Test (TMT) and the manual Grooved Pegboard Test (GPT). Using a reliable change index, preCI and POCD were defined as total Z-score > 1.96 (sum score over all tests) and/or Z-scores > 1.96 in ≥ 2 individual cognitive test parameters. For statistical analyses, multivariable logistic regression models were applied. Age, sex and intracranial volume were covariates in the models. Of 301 patients who received a presurgical neuropsychological testing and MRI, 34 (11.3%) had preCI. 89 patients (29.5%) were lost to follow-up. The remaining 212 patients received a follow-up cognitive test after 3 months, of whom 25 (8.3%) presented with POCD. Independently of age, sex and intracranial volume, neither preCI (OR per cm3 increment 0.81 [95% CI 0.60-1.07] p = 0.14) nor POCD (OR 1.02 per cm3 increment [95% CI 0.75-1.40] p = 0.87) were statistically significantly associated with patients' preoperative thalamus volume. In this cohort we could not show an association of presurgical thalamus volume with preCI or POCD.Clinical Trial Number: NCT02265263 ( https://clinicaltrials.gov/ct2/show/results/NCT02265263 ).

Trail making test B in postoperative delirium: a replication study.

Background: The Trail Making Test B (TMT-B) is indicative of cognitive flexibility and several other cognitive domains. Previous studies suggest that it might be associated with the risk of developing postoperative delirium, but evidence is limited and conflicting. We therefore aimed to replicate the association of preoperative TMT-B results with postoperative delirium. Methods: We included older adults (≥65 yr) scheduled for major surgery and without signs of dementia to participate in this binational two-centre longitudinal observational cohort study. Presurgical TMT-B scores were obtained. Delirium was assessed twice daily using validated instruments. Logistic regression was applied and the area under the receiver operating characteristic curve calculated to determine the predictive performance of TMT-B. We subsequently included covariates used in previous studies for consecutive sensitivity analyses. We further analysed the impact of outliers, missing or impaired data. Results: Data from 841 patients were included and of those, 151 (18%) developed postoperative delirium. TMT-B scores were statistically significantly associated with the incidence of postoperative delirium {odds ratio per 10-s increment 1.06 (95% confidence interval [CI] 1.02-1.09), P=0.001}. The area under the receiver operating characteristic curve was 0.60 ([95% CI 0.55-0.64], P<0.001). The association persisted after removing 21 outliers (1.07 [95% CI 1.03-1.07], P<0.001). Impaired or missing TMT-B data (n=88) were also associated with postoperative delirium (odds ratio 2.74 [95% CI 1.71-4.35], P<0.001). Conclusions: The TMT-B was associated with postoperative delirium, but its predictive performance as a stand-alone test was low. The TMT-B alone is not suitable to predict delirium in a clinical setting. Clinical trial registration: NCT02265263. (https://clinicaltrials.gov/ct2/show/results/NCT02265263).

Functional Connectivity of the Supplementary and Presupplementary Motor Areas in Postoperative Transition Between Stages of Frailty.

BACKGROUND: Frailty is a multietiological geriatric syndrome of run-down physical reserves with high vulnerability to stressors. Transitions between physical robustness and frailty often occur in the context of medical interventions. Studies suggest that neurological disorders contribute to faster progression of frailty. In a previous cross-sectional study we found altered functional connectivity of supplementary motor area (SMA) in (pre)frail compared to robust patients. We analyzed functional connectivity of the SMA and presupplementary motor area (pre-SMA) in patients with postoperative transitions between physical robustness and stages of frailty. METHODS: We investigated 120 cognitively healthy patients (49.2% robust, 47.5% prefrail, 3.3% frail, 37.5% female, median age 71 [65-87] years) undergoing elective surgery from the BioCog project, a multicentric prospective cohort study on postoperative delirium and cognitive dysfunction. Assessments took place 14 days before and 3 months after surgery, comprising assessments of a modified frailty phenotype according to Fried and resting-state functional magnetic resonance imaging at 3 T. The associations between functional connectivity of the SMA and pre-SMA networks, preoperative frailty stages, and postoperative transitions were examined using mixed linear effects models. RESULTS: Nineteen patients showed physical improvement after surgery, 24 patients progressed to (pre)frailty and in 77 patients no transition was observed. At follow-up, 57 (47.5%) patients were robust, 52 (43.3%) prefrail, and 11 (9.2%) frail. Lower functional connectivity in the pre-SMA network was associated with more unfavorable postoperative transition types. An exploratory analysis suggested that the association was restricted to patients who were prefrail at baseline. There was no association of transition type with SMA functional connectivity in the primary analysis. In an exploratory analysis, transition from prefrailty to robustness was associated with higher functional connectivity and progression in robust patients was associated with higher SMA network segregation. CONCLUSIONS: Our findings implicate that dysfunctions of cortical networks involved in higher cognitive control of motion are associated with postoperative transitions between frailty stages. The pre-SMA may be a target for neurofeedback or brain stimulation in approaches to prevent frailty. Clinical Trials Registration Number: NCT02265263.

Presurgical diffusion metrics of the thalamus and thalamic nuclei in postoperative delirium: A prospective two-centre cohort study in older patients.

BACKGROUND: The thalamus seems to be important in the development of postoperative delirium (POD) as previously revealed by volumetric and diffusion magnetic resonance imaging. In this observational cohort study, we aimed to further investigate the impact of the microstructural integrity of the thalamus and thalamic nuclei on the incidence of POD by applying diffusion kurtosis imaging (DKI). METHODS: Older patients without dementia (≥65 years) who were scheduled for major elective surgery received preoperative DKI at two study centres. The DKI metrics fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK) and free water (FW) were calculated for the thalamus and - as secondary outcome - for eight predefined thalamic nuclei and regions. Low FA and MK and, conversely, high MD and FW, indicate aspects of microstructural abnormality. To assess patients' POD status, the Nursing Delirium Screening Scale (Nu-DESC), Richmond Agitation Sedation Scale (RASS), Confusion Assessment Method (CAM) and Confusion Assessment Method for the Intensive Care Unit score (CAM-ICU) and chart review were applied twice a day after surgery for the duration of seven days or until discharge. For each metric and each nucleus, logistic regression was performed to assess the risk of POD. RESULTS: This analysis included the diffusion scans of 325 patients, of whom 53 (16.3 %) developed POD. Independently of age, sex and study centre, thalamic MD was statistically significantly associated with POD [OR 1.65 per SD increment (95 %CI 1.17 - 2.34) p = 0.004]. FA (p = 0.84), MK (p = 0.41) and FW (p = 0.06) were not significantly associated with POD in the examined sample. Exploration of thalamic nuclei also indicated that only the MD in certain areas of the thalamus was associated with POD. MD was increased in bilateral hemispheres, pulvinar nuclei, mediodorsal nuclei and the left anterior nucleus. CONCLUSIONS: Microstructural abnormalities of the thalamus and thalamic nuclei, as reflected by increased MD, appear to predispose to POD. These findings affirm the thalamus as a region of interest in POD research.

Neurocognitive disorders in the elderly: altered functional resting-state hyperconnectivities in postoperative delirium patients.

Postoperative delirium (POD) represents a confusional state during days/weeks after surgery and is particularly frequent in elderly patients. Hardly any fMRI studies were conducted to understand the underlying pathophysiology of POD patients. This prospective observational cohort study aims to examine changes of specific resting-state functional connectivity networks across different time points (pre- and 3-5 months postoperatively) in delirious patients compared to no-POD patients. Two-hundred eighty-three elderly surgical patients underwent preoperative resting-state fMRI (46 POD). One-hundred seventy-eight patients completed postoperative scans (19 POD). For functional connectivity analyses, three functional connectivity networks with seeds located in the orbitofrontal cortex (OFC), nucleus accumbens (NAcc), and hippocampus were investigated. The relationship of POD and connectivity changes between both time points (course connectivity) were examined (ANOVA). Preoperatively, delirious patients displayed hyperconnectivities across the examined functional connectivity networks. In POD patients, connectivities within NAcc and OFC networks demonstrated a decrease in course connectivity [max. F = 9.03, p = 0.003; F = 4.47, p = 0.036, resp.]. The preoperative hyperconnectivity in the three networks in the patients at risk for developing POD could possibly indicate existing compensation mechanisms for subtle brain dysfunction. The observed pathophysiology of network function in POD patients at least partially involves dopaminergic pathways.

Resting state brain network functional connectivity is not associated with inflammatory markers and blood cell counts in older adults.

OBJECTIVE: Systemic inflammation and monocyte counts have previously been associated with changes in resting state functional connectivity (rsFC) in cross-sectional neuroimaging studies. We therefore investigated this association in a longitudinal study of older patients. METHODS: We performed a secondary analysis of longitudinal data from older patients who underwent functional magnet resonance imaging (fMRI) scans before and 3 months after elective surgery. Additionally, serum levels of C-reactive protein and Interleukin-6 as markers of inflammation and leukocyte, lymphocyte and monocyte counts were determined. Correlations between these markers and pre- or postoperative rsFC between regions previously associated with inflammatory markers were investigated using general linear regression models. RESULTS: We found no significant correlations between inflammatory markers or blood cell counts and mean connectivity within four resting state networks (RSNs), neither preoperatively nor postoperatively. Significant inter-region rsFC was found within these RSNs between a few regions either pre- or postoperatively, but no inter-region connections were consistently observed in both pre- and postoperative fMRI scans. CONCLUSIONS: Inflammatory markers and monocyte counts were not associated with rsFC in our study, contrasting previous results. SIGNIFICANCE: Multiple measurements in the same individuals, as performed here, provide a way to reduce the high risk of false positive results in fMRI studies. TRIAL REGISTRATION: Clinicaltrials.gov (registration number NCT02265263).

Radiological, Chemical, and Pharmacological Cholinergic System Parameters and Neurocognitive Disorders in Older Presurgical Adults.

BACKGROUND: A pre-existing neurocognitive disorder (NCD) is a relevant factor for the outcome of surgical patients. To improve understanding of these conditions, we investigated the association between parameters of the cholinergic system and NCD. METHOD: This investigation is part of the BioCog project (www.biocog.eu), which is a prospective multicenter observational study including patients aged 65 years and older scheduled for elective surgery. Patients with a Mini-Mental State Examination (MMSE) score ≤23 points were excluded. Neurocognitive disorder was assessed according to the fifth Diagnostic and Statistical Manual of Mental Disorders criteria. The basal forebrain cholinergic system volume (BFCSV) was assessed with magnetic resonance imaging, the peripheral cholinesterase (ChE) activities with point-of-care measurements, and anticholinergic load by analyzing the long-term medication with anticholinergic scales (Anticholinergic Drug Scale [ADS], Anticholinergic Risk Scale [ARS], Anticholinergic Cognitive Burden Scale [ACBS]). The associations of BFCSV, ChE activities, and anticholinergic scales with NCD were studied with logistic regression analysis, adjusting for confounding factors. RESULTS: A total of 797 participants (mean age 72 years, 42% females) were included. One hundred and eleven patients (13.9%) fulfilled criteria for mild NCD and 82 patients (10.3%) for major NCD criteria. We found that AcetylChE activity was associated with major NCD (odds ratio [95% confidence interval]: [U/gHB] 1.061 [1.010, 1.115]), as well as ADS score ([points] 1.353 [1.063, 1.723]) or ARS score, respectively ([points] 1.623 [1.100, 2.397]) with major NCD. However, we found no association between BFCSV or ButyrylChE activity with mild or major NCD. CONCLUSIONS: AcetylChE activity and anticholinergic load were associated with major NCD. Future research should focus on the association of the cholinergic system and the development of postoperative delirium and postoperative NCD.

MEG reveals preference specific increases of sexual-image-evoked responses in paedophilic sexual offenders and healthy controls.

OBJECTIVES: Paedophilic disorder is characterised by sexual attraction towards children. Classification of a counterpart as sexually attractive likely occurs rapidly, and involves both conscious and unconscious attentional and cognitive processes. Magnetoencephalography (MEG) is an imaging method especially well-suited to examine visual and attentional processes triggered by sexual images within the range of milliseconds. METHODS: We investigated brain responses to sexual images depicting adults (frequent) and children (infrequent stimulus) in seventeen paedophilic patients with a history of child sexual offending (P + CSO) and twenty healthy controls (HC) during a passive visual oddball paradigm. Event-related fields (ERF) were measured to extract the magnetic visual mismatch negativity (vMMNm), and how it relates to the processing of different classes of sexual stimuli. RESULTS: P + CSO exhibited significantly longer vMMNm latencies (100-180 ms post-stimulus) than HC. Moreover, P + CSO showed widespread increased amplitudes in response to child images starting from P3a and P3b components and lasting up to 400 ms post-stimulus presentation localised in frontal and temporal brain regions. CONCLUSIONS: This study uncovers the first MEG differences in automatic change detection between P + CSO and HC during the presentation of subliminal sexual images of adults and children, contributing towards a better understanding of the neurobiological processes of P + CSO.

Functional Connectivity of the Supplementary Motor Network Is Associated with Fried's Modified Frailty Score in Older Adults.

Frailty is a geriatric syndrome defined by coexistence of unintentional weight loss, low physical reserve, or activity and is associated with adverse health events. Neuroimaging studies reported structural white matter changes in frail patients. In the current study, we hypothesized that clinical frailty is associated also with functional changes in motion-related cortical areas, that is, (pre-)supplementary motor areas (SMA, pre-SMA). We expected that observed functional changes are related to motor-cognitive test performance. We studied a clinical sample of 143 cognitively healthy patients ≥65 years presenting for elective surgery, enrolled in the BioCog prospective multicentric cohort study on postoperative cognitive disorders. Participants underwent preoperative resting-state functional magnetic resonance imaging, motor-cognitive testing, and assessment of Fried's modified frailty criteria. We analyzed functional connectivity associations with frailty and motor-cognitive test performance. Clinically robust patients (N = 60) showed higher connectivity in the SMA network compared to frail (N = 13) and prefrail (N = 70) patients. No changes were found in the pre-SMA network. SMA connectivity correlated with motor speed (Trail-Making-Test A) and manual dexterity (Grooved Pegboard Test). Our results suggest that diminished functional connectivity of the SMA is an early correlate of functional decline in the older adults . The SMA may serve as a potential treatment target in frailty.

Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network.

Background: Subanesthetic dosages of the NMDAR antagonist, S-Ketamine, can cause changes in behavior in healthy subjects, which are similar to the state acute psychosis and are relevant in translational schizophrenia research. Functional magnetic resonance imaging (fMRI) can be used for non-hypothesis-driven analysis of brain connectivity. The correlation between clinical behavioral scores and neuroimaging can help to characterize ketamine effects on healthy brains in resting state. Method: seventeen healthy, male subjects (mean: 27.42 years, SD: 4.42) were administered an infusion with S-Ketamine (initial bolus 1 mg/kg and continuous infusion of 0.015625 mg/kg/min with dosage reduction -10%/10 min) or saline in a randomized, double-blind, cross-over study. During infusion, resting state connectivity was measured and analyzed with a seed-to-voxel fMRI analysis approach. The seed regions were located in the posterior cingulate cortex, intraparietal sulcus, dorsolateral prefrontal cortex and fronto-insular cortex. Receiver operating characteristics (ROC) were calculated to assess the accuracy of the ketamine-induced functional connectivity changes. Bivariate Pearson correlation was used for correlation testing of functional connectivity changes with changes of clinical scores (PANSS, 5D-ASC). Results: In the executive network (ECN), ketamine significantly increases the functional connectivity with parts of the anterior cingulum and superior frontal gyrus, but no significant correlations with clinical symptoms were found. Decreased connectivity between the salience network (SN) and the calcarine fissure was found, which is significantly correlated with negative symptoms (PANSS) (R2 > 0.4). Conclusion: Decreased ketamine-induced functional connectivity in the salience network may qualify as accurate and highly predictive biomarkers for ketamine induced negative symptoms.

The association between brain volume, cortical brain infarcts, and physical frailty.

Physical frailty is an age-associated syndrome of decreased reserve leading to vulnerability to physiological stressors and associated with negative outcomes. The underlying structural brain abnormalities of physical frailty are unclear. We investigated the association between brain volume, cortical brain infarcts, and physical frailty. In this multicenter study, 214 nondemented participants were classified as frail (n = 32), prefrail (n = 107), or nonfrail (n = 75) based on the Fried frailty phenotype. The associations between frailty and brain volumes and cortical brain infarcts were investigated by linear or logistic regression analyses. Participants in the frail group showed a lower total brain volume (-19.67 mL [95% confidence interval -37.84 to -1.50]) and lower gray matter volume (-12.19 mL [95% confidence interval -23.84 to -0.54]) compared to nonfrail participants. Frailty was associated with cortical brain infarcts [frail 16% [n = 5], prefrail 11% [n = 12], and nonfrail 3% [n = 2]). Reduced total brain volume and gray matter volume and increased cortical brain infarcts seem therefore to be part of the structural substrate of the physical frailty phenotype.

Basal forebrain cholinergic system volume is associated with general cognitive ability in the elderly.

OBJECTIVE: At the present, it is unclear whether association of basal forebrain cholinergic system (BFCS) volume with cognitive performance exists in healthy as well as in cognitively impaired elderly subjects. Whereas one small study reported an association of BFCS volume with general cognitive ability 'g' in healthy ageing, effects on specific cognitive domains have only been found in subjects with cognitive decline. Here we aim to clarify whether an association of BFCS volume and 'g' is present in a larger sample of elderly subjects without obvious symptoms of dementia and whether similar associations can also be observed in specific cognitive domains. METHODS: 282 pre-surgical patients from the BioCog study (aged 72.7 ±â€¯4.9 years with a range of 65-87 years, 110 women) with a median MMSE score of 29 points (range 24-30) were investigated. BFCS and brain volume as well as brain parenchymal fraction were assessed in T1-weighted MR images using SPM12 and a probabilistic map of the BFCS. Neuropsychological assessment comprised the CANTAB cognitive battery and paper-and-pencil based tests. For data analysis, generalised linear models and quantile regression were applied. RESULTS: Significant associations of BFCS volume with 'g' and several cognitive domains were found, with the strongest association found for 'g'. BFCS volume explained less variance in cognitive performance than brain volume. The association was not confounded by brain parenchymal fraction. Furthermore, the association of BFCS volume and 'g' was similar in high- and low-performers. CONCLUSION: Our results extend previous study findings on BFCS volume associations with cognition in elderly subjects. Despite the observed associations of BFCS volume and cognitive performance, this association seems to reflect a more general association of brain volume and cognition. Accordingly, a specific association of BFCS volume and cognition in non-demented elderly subjects is questionable.

Multimodal brain imaging with magnetoencephalography: A method for measuring blood pressure and cardiorespiratory oscillations.

Studies with magnetoencephalography (MEG) are still quite rarely combined simultaneously with methods that can provide a metabolic dimension to MEG investigations. In addition, continuous blood pressure measurements which comply with MEG compatibility requirements are lacking. For instance, by combining methods reflecting neurovascular status one could obtain more information on low frequency fluctuations that have recently gained increasing interest as a mediator of functional connectivity within brain networks. This paper presents a multimodal brain imaging setup, capable to non-invasively and continuously measure cerebral hemodynamic, cardiorespiratory and blood pressure oscillations simultaneously with MEG. In the setup, all methods apart from MEG rely on the use of fibre optics. In particular, we present a method for measuring of blood pressure and cardiorespiratory oscillations continuously with MEG. The potential of this type of multimodal setup for brain research is demonstrated by our preliminary studies on human, showing effects of mild hypercapnia, gathered simultaneously with the presented modalities.