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).

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.

Cerebral microbleeds are not associated with postoperative delirium and postoperative cognitive dysfunction in older individuals.

BACKGROUND: Cerebral microbleeds (CMB) occur in the context of cerebral small vessel disease. Other brain MRI markers of cerebral small vessel disease are associated with the occurrence of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), but for CMB this is unknown. We aimed to study the association between CMB and the occurrence of POD and POCD in older individuals. METHODS: The current study consists of 65 patients (72±5 years) from the BIOCOG study, which is a prospective, observational study of patients who underwent an elective surgery of at least 60 minutes. Patients in the current study received a preoperative cerebral MRI scan including a 3D susceptibility-weighted imaging sequence to detect CMB. The occurrence of POD was screened for twice a day until postoperative day 7 by using the DSM-5, NuDesc, CAM, and CAM-ICU. The occurrence of POCD was determined by the reliable change index model at 7 days after surgery or discharge, respectively, and 3 months after surgery. Statistical analyses consisted of logistic regression adjusted for age and gender. RESULTS: A total of 39 CMB were detected in 17 patients (26%) prior to surgery. POD occurred in 14 out of 65 patients (22%). POCD at 7 days after surgery occurred in 11 out of 54 patients (20%) and in 3 out of 40 patients at the 3 month follow-up (8%). Preoperative CMB were not associated with the occurrence of POD (OR (95%-CI): 0.28 (0.05, 1.57); p = 0.147) or POCD at 7 days after surgery (0.76 (0.16, 3.54); p = 0.727) or at 3 months follow-up (0.61 (0.03, 11.64); p = 0.740). CONCLUSION: We did not find an association between preoperative CMB and the occurrence of POD or POCD. TRIAL REGISTRATION: clinicaltrials.gov (NCT02265263) on 23 September 2014.

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.

Effects of Ncl. Basalis Meynert volume on the Trail-Making-Test are restricted to the left hemisphere.

BACKGROUND: Cortical acetylcholine released from cells in the basal forebrain facilitates cue detection and improves attentional performance. Cholinergic fibres to the cortex originate from the CH4 cell group, sometimes referred to as the Nucleus basalis of Meynert and the Nucleus subputaminalis of Ayala. The aim of this work was to investigate the effects of volumes of cholinergic nuclei on attention and executive function. METHODS: The volumes of CH4 and CH4p subregions were measured in a subgroup of 38 subjects (33.5 ± 11 years, 20 females) from a population-based cohort study of smokers and never-smokers who have undergone additional MR imaging. To define regions of interest, we applied a DARTEL-based procedure implemented in SPM8 and a validated probabilistic map of the basal forebrain. Attention and executive function were measured with Trail-Making Test (TMT A+B) and Stroop-Task. RESULTS: We found a quadratic effect of the left CH4 subregion on performance of the TMT. Extremely small as well as extremely large volumes are associated with poor test performance. CONCLUSIONS: Our results indicate that a small CH4 volume predisposes for a hypocholinergic state, whereas an extremely large volume predisposes for a hypercholinergic state. Both extremes have detrimental effects on attention. Comparable nonlinear effects have already been reported in pharmacological studies on the effects cholinergic agonists on attention.