Theresa Götz

Fetal development of complex autonomic control evaluated from multiscale heart rate patterns

Development of the fetal autonomic nervous systems integrative capacity in relation to gestational age and emerging behavioral pattern is reflected in fetal heart rate patterns. Conventional indices of vagal and sympathetic rhythms cannot sufficiently reflect their complex interrelationship. Universal behavioral indices of developing complex systems may provide additional information regarding the maturating complex autonomic control. We investigated fetal magnetocardiographic recordings undertaken at 10-min intervals in active (n = 248) and quiet (n = 111) states between 22 and 39 wk gestational age. Standard deviation of heartbeat intervals, skewness, contribution of particular rhythms to the total power, and multiscale entropy were analyzed. The multiscale entropy methodology was validated for 10-min data sets. Age dependence was analyzed by linear regression. In the quiet state, contribution of sympathovagal rhythms and their complexity over a range of corresponding short scales increased with rising age, and skewness shifted from negative to positive values. In the active state, age dependencies were weaker. Skewness as the strongest parameter shifted in the same direction. Fluctuation amplitude and the complexity of scales associated with sympathovagal rhythms increased. We conclude that in the quiet state, stable complex organized rhythms develop. In the active state, however, increasing behavioral variability due to multiple internal coordinations, such as movement-related heart rate accelerations, and external influences develop. Hence, the state-selective assessment in association with developmental indices used herein may substantially improve evaluation of maturation age and early detection and interpretation of developmental problems in prenatal diagnosis.

Fetal autonomic brain age scores, segmented heart rate variability analysis, and traditional short term variability

Disturbances of fetal autonomic brain development can be evaluated from fetal heart rate patterns (HRP) reflecting the activity of the autonomic nervous system. Although HRP analysis from cardiotocographic (CTG) recordings is established for fetal surveillance, temporal resolution is low. Fetal magnetocardiography (MCG), however, provides stable continuous recordings at a higher temporal resolution combined with a more precise heart rate variability (HRV) analysis. A direct comparison of CTG and MCG based HRV analysis is pending. The aims of the present study are: (i) to compare the fetal maturation age predicting value of the MCG based fetal Autonomic Brain Age Score (fABAS) approach with that of CTG based Dawes-Redman methodology; and (ii) to elaborate fABAS methodology by segmentation according to fetal behavioral states and HRP. We investigated MCG recordings from 418 normal fetuses, aged between 21 and 40 weeks of gestation. In linear regression models we obtained an age predicting value of CTG compatible short term variability (STV) of R2 = 0.200 (coefficient of determination) in contrast to MCG/fABAS related multivariate models with R2 = 0.648 in 30 min recordings, R2 = 0.610 in active sleep segments of 10 min, and R2 = 0.626 in quiet sleep segments of 10 min. Additionally segmented analysis under particular exclusion of accelerations (AC) and decelerations (DC) in quiet sleep resulted in a novel multivariate model with R2 = 0.706. According to our results, fMCG based fABAS may provide a promising tool for the estimation of fetal autonomic brain age. Beside other traditional and novel HRV indices as possible indicators of developmental disturbances, the establishment of a fABAS score normogram may represent a specific reference. The present results are intended to contribute to further exploration and validation using independent data sets and multicenter research structures.

Task requirements change signal strength of the primary somatosensory M50 : Oddball vs. one-back tasks

Studies on attention to tactile stimuli have produced conflicting results concerning the possibility and/or direction of modulation of early somatosensory-evoked fields (SEFs). To evaluate sources of these conflicting results, the same subjects performed four different tasks in which the stimulation site, type, and intensity were kept constant. Twelve subjects performed an oddball-like tactile task, two different one-back tactile tasks, and a visual task, while two distal phalanges of the index and ring finger were stimulated. Task-dependent SEF modulations were found as early as 50 ms after stimulus onset (M50 component). Target/non-target ratios of M50 revealed enhanced values for the oddball-like tactile task, but decreased values for the tactile one-back task. This indicates that previously obtained conflicting results might be due to different central mechanisms induced by different task requirements.

Prevalence and Characteristics of Chronic Intensive Care-Related Pain: The Role of Severe Sepsis and Septic Shock.

Objective:There is only limited knowledge about chronic pain conditions resulting from critical care. Experimental and clinical data suggest a close relationship between inflammation and pain perception. Since sepsis is the most severe form of systemic inflammation, the primary objective was to evaluate chronic pain states and functional impairment of septic and nonseptic patients 6 months after discharge from ICU. Second, we aimed to obtain the total prevalence and characteristics of chronic ICU-related pain. Design:Case-control study. Setting:Observational study in long-term survivors of mixed surgical and medical ICUs. Patients:Septic and nonseptic survivors of critical care (n = 207) and healthy controls (n = 46). Interventions:None. Measurements and Main Results:We collected comprehensive information on patients’ past and present pain 6 months after ICU discharge by means of the German pain questionnaire. Pain intensity levels and pain interference ratings were compared between septic and nonseptic patients and healthy controls. We found no differences in prevalence, severity, and interference of pain between septic and nonseptic patients. However, both patient groups differed significantly from controls. In secondary analysis, a third of all patients reported chronic clinically relevant pain associated with the ICU stay 6 months after ICU discharge. Half of these patients experienced chronic pain conditions before ICU admission and reported additional sources of pain. Most important, 16% of all patients had no preexisting pain condition and now experience chronic ICU-related pain. The majority of patients with chronic ICU-related pain reported a high degree of disabling pain, limiting daily activities. Conclusions:A high percentage of former ICU patients develop chronic pain conditions associated with critical care. These patients differ significantly from control data in terms of pain intensity and show high levels of interference with pain. The presence of sepsis per se seems to play a marginal role for the development of chronic ICU-related pain.

Long-term sequelae of severe sepsis: cognitive impairment and structural brain alterations – an MRI study (LossCog MRI)

BackgroundThe number of patients with cognitive impairment after sepsis or septic shock is high. However, the underlying neurophysiological basis of sepsis induced cognitive impairment is not fully understood.Methods/DesignThis is a prospective, controlled observational study. We are in the process of recruiting 25 survivors of severe sepsis or septic shock who will be investigated with functional MRI (fMRI), T1-weighted MRI und Diffusion Tensor Imaging (DTI) as well as Magnetoencephalography (MEG). Furthermore, patients will undergo neuropsychological evaluation using the DemTect and the clock drawing tests. In addition, verbal and declarative memory is assessed by the Verbal Learning and Memory Test. The primary aim is to determine the volumetry of the amygdala and the hippocampus. The secondary aim is to analyze the relationship between cognitive tests and MEG, and the (f)MRI results. Moreover, a between-group comparison will be evaluated to an age-matched group of healthy controls.DiscussionIn a previous MEG study, we observed a significant slowing of the prominent background activity in sepsis survivors and hepatic encephalopathy patients in particular shortly after discharge from the ICU. Intriguingly, the rhythmic brain activity after visual flickering stimulation was altered in sepsis survivors in comparison to age-matched healthy volunteers. We propose that this desynchronization is based on affected underlying neuronal responses between various interconnected brain regions. The current project will analyze whether the modifications are related to a damage of the fibers connecting different brain regions or to a disturbance of the functional interaction between different brain regions or even due to an atrophy of certain brain regions.Trial registration“Langzeitfolgen nach schwerer Sepsis: Kognitive Beeinträchtigungen und strukturelle Veränderungen am Gehirn, eine MRT Studie”; German Clinical Trials Register (DRKS00005484).

Parallel processing of somatosensory information: Evidence from dynamic causal modeling of MEG data

The advent of methods to investigate network dynamics has led to discussion of whether somatosensory inputs are processed in serial or in parallel. Both hypotheses are supported by DCM analyses of fMRI studies. In the present study, we revisited this controversy using DCM on magnetoencephalographic (MEG) data during somatosensory stimulation. Bayesian model comparison was used to allow for direct inference on the processing stream. Additionally we varied the duration of the time-window of analyzed data after the somatosensory stimulus. This approach allowed us to explore time dependent changes in the processing stream of somatosensory information and to evaluate the consistency of results. We found that models favoring a parallel processing route best describe neural activities elicited by somatosensory stimuli. This result was consistent for different time-windows. Although it is assumed that the majority of somatosensory information is delivered to the SI, the current results indicate that at least a small part of somatosensory information is delivered in parallel to the SII. These findings emphasize the importance of data analysis with high temporal resolution.

Primary somatosensory contextual modulation is encoded by oscillation frequency change

OBJECTIVE This study characterized thalamo-cortical communication by assessing the effect of context-dependent modulation on the very early somatosensory evoked high-frequency oscillations (HF oscillations). METHODS We applied electrical stimuli to the median nerve together with an auditory oddball paradigm, presenting standard and deviant target tones representing differential cognitive contexts to the constantly repeated electrical stimulation. Median nerve stimulation without auditory stimulation served as unimodal control. RESULTS A model consisting of one subcortical (near thalamus) and two cortical (Brodmann areas 1 and 3b) dipolar sources explained the measured HF oscillations. Both at subcortical and the cortical levels HF oscillations were significantly smaller during bimodal (somatosensory plus auditory) than unimodal (somatosensory only) stimulation. A delay differential equation model was developed to investigate interactions within the 3-node thalamo-cortical network. Importantly, a significant change in the eigenfrequency of Brodmann area 3b was related to the context-dependent modulation, while there was no change in the network coupling. CONCLUSION This model strongly suggests cortico-thalamic feedback from both cortical Brodmann areas 1 and 3b to the thalamus. With the 3-node network model, thalamo-cortical feedback could be described. SIGNIFICANCE Frequency encoding plays an important role in contextual modulation in the somatosensory thalamo-cortical network.

Impaired evoked and resting-state brain oscillations in patients with liver cirrhosis as revealed by magnetoencephalography

A number of studies suggest that the clinical manifestation of neurological deficits in hepatic encephalopathy results from pathologically synchronized neuronal oscillations and altered oscillatory coupling. In the present study spontaneous and evoked oscillatory brain activities were analyzed jointly with established behavioral measures of altered visual oscillatory processing. Critical flicker and fusion frequencies (CFF, FUF) were measured in 25 patients diagnosed with liver cirrhosis and 30 healthy controls. Magnetoencephalography (MEG) data were collected at rest and during a visual task employing repetitive stimulation. Resting MEG and evoked fields were analyzed. CFF and FUF were found to be reduced in patients, providing behavioral evidence for deficits in visual oscillatory processing. These alterations were found to be related to resting brain activity in patients, namely that the lower the dominant MEG frequency at rest, the lower the CFF and FUF. An analysis of evoked fields at sensor level indicated that in comparison to normal controls, patients were not able to dynamically adapt to flickering visual stimulation. Evoked activity was also analyzed based on independent components (ICs) derived by independent component analysis. The similarity between the shape of each IC and an artificial sine function representing the stimulation frequency was tested via magnitude squared coherence. In controls, we observed a small number of components that correlated strongly with the sine function and a high number of ICs that did not correlate with the sine function. Interestingly, patient data were characterized by a high number of moderately correlating components. Taken together, these results indicate a fundamental divergence of the cerebral resonance activity in cirrhotic patients.

Slowed peak resting frequency and MEG overactivation in survivors of severe sepsis and septic shock

OBJECTIVE Survivors of severe sepsis and septic shock suffer from residual severe cognitive impairments, which persist even years after intensive care unit (ICU) discharge. As the awareness of long-term consequences gradually grows, research has focused on cognitive impairments via questionnaires, but only few have focused on structural or electrophysiological features, such as the peak resting frequency, which is commonly seen as a hallmark of brain function. METHODS We aimed to analyze the long-term progression of the peak resting activity in terms of frequency and power in sepsis survivors. Healthy individuals with no history of ICU stay served as controls. Data were collected three times (shortly, 6 and 12 months after ICU discharge) in sepsis survivors and three times in controls. Participants also underwent behavioral neuropsychological assessment. RESULTS Sepsis survivors exhibited significantly higher spectral power of the dominant peak, which was shifted towards lower frequencies. Within one year, resting frequency increased to the level of controls, but power did not decrease. We observed a close correlation between resting frequency and mental status. CONCLUSIONS Results support the assumption of a causal relationship between brain oscillations and behavioral performance. SIGNIFICANCE We suggest that the postseptic frequency shift is due to abnormal thalamocortical dynamics.

Thalamocortical impulse propagation and information transfer in EEG and MEG.

Summary: Measures of functional connectivity and information transfer between the thalamus and the cortex can provide detailed insight into brain function. Employing magnetoencephalography and electrical median nerve stimulation, it has been recently proposed that impulse propagation along the thalamocortical fiber tract can be described by a single moving dipole source. Other studies, however, using electroencephalography observed dipole clustering in the thalamus and the cortex. To assess the source of these conflicting results, we simultaneously recorded somatosensory evoked potentials and fields in 12 healthy volunteers. Using a single dipole model for the time interval of 10 to 30 milliseconds after stimulus onset, we found continuous thalamocortical dipole movement in 10 volunteers and dipole clustering in the precortical near thalamic and cortical regions in 2 volunteers. Thus, independent of the recording method, both clustering and movement can be observed. The degree of temporal overlap between the precortical near thalamic and the cortical activity distinguished the volunteers exhibiting clustering and those exhibiting movement. In a subsequent simulation study, we could show that both dipole clustering and dipole movement can occur, depending on the temporal overlap of the precortical and cortical activities. In conclusion, we propose a two-dipole model to better account for precortical and cortical activity and information transfer.