Uncovering Hemispheric Asymmetry and Directed Oscillatory Brain-Heart Interplay in Anxiety Processing: An fMRI Study.

Brain-heart interactions (BHI) are critical for generating and processing emotions, including anxiety. Understanding specific neural correlates would be instrumental for greater comprehension and potential therapeutic interventions of anxiety disorders. While prior work has implicated the pontine structure as a central processor in cardiac regulation in anxiety, the distributed nature of anxiety processing across the cortex remains elusive. To address this, we performed a whole-brain-heart analysis using the full frequency directed transfer function to study resting-state spectral differences in BHI between high and low anxiety groups undergoing fMRI scans. Our findings revealed a hemispheric asymmetry in low-frequency interplay (0.05 Hz - 0.15 Hz) characterized by ascending BHI to the left insula and descending BHI from the right insula. Furthermore, we provide evidence supporting the "pacemaker hypothesis", highlighting the pons' function in regulating cardiac activity. Higher frequency interplay (0.2 Hz - 0.4Hz) demonstrate a preference for ascending interactions, particularly towards ventral prefrontal cortical activity in high anxiety groups, suggesting the heart's role in triggering a cognitive response to regulate anxiety. These findings highlight the impact of anxiety on BHI, contributing to a better understanding of its effect on the resting-state fMRI signal, with further implications for potential therapeutic interventions in treating anxiety disorders.

Scan-associated anxiety (scanxiety): the enigma of emotional breathing oscillations at 0.32 Hz (19 bpm).

MRI-related anxiety in healthy participants is often characterized by a dominant breathing frequency at around 0.32 Hz (19 breaths per minute, bpm) at the beginning but in a few cases also at the end of scanning. Breathing waves at 19 bpm are also observed in patients with anxiety independently of the scanned body part. In patients with medically intractable epilepsy and intracranial electroencephalography (iEEG), spontaneous breathing through the nose varied between 0.24 and 0.37 Hz (~19 bpm). Remarkable is the similarity of the observed breathing rates at around 0.32 Hz during different types of anxiety states (e.g., epilepsy, cancer, claustrophobia) with the preferred breathing frequency of 0.32 Hz (19 bpm), which is predicted by the binary hierarchy model of Klimesch. This elevated breathing frequency most likely reflects an emotional processing state, in which energy demands are minimized due to a harmonic coupling ratio with other brain-body oscillations.

Respiration-entrained brain oscillations in healthy fMRI participants with high anxiety.

Brain-body interactions can be studied by using directed coupling measurements of fMRI oscillations in the low (0.1-0.2 Hz) and high frequency bands (HF; 0.2-0.4 Hz). Recently, a preponderance of oscillations in the information flow between the brainstem and the prefrontal cortex at around 0.15/0.16 Hz was shown. The goal of this study was to investigate the information flow between BOLD-, respiratory-, and heart beat-to-beat interval (RRI) signals in the HF band in healthy subjects with high anxiety during fMRI examinations. A multivariate autoregressive model was concurrently applied to the BOLD signals from the middle frontal gyrus (MFG), precentral gyrus and the brainstem, as well as to respiratory and RRI signals. Causal coupling between all signals was determined using the Directed Transfer Function (DTF). We found a salience of fast respiratory waves with a period of 3.1 s (corresponding to ~ 0.32 Hz) and a highly significant (p < 0.001) top-down information-flow from BOLD oscillations in the MFG to the brainstem. Additionally, there was a significant (p < 0.01) information flow from RRI to respiratory oscillations. We speculate that brain oscillations around 0.32 Hz, triggered by nasal breathing, are projected downwards to the brainstem. Particularly interesting is the driving force of cardiac to respiratory waves with a ratio of 1:1 or 1:2. These results support the binary hierarchy model with preferred respiratory frequencies at 0.32 Hz and 0.16 Hz.

Computed Tomography Angiography (CTA) in Selected Scenarios with Risk of Possible False-Positive or False-Negative Conclusions in Diagnosing Brain Death.

It is widely accepted that brain death (BD) is a diagnosis based on clinical examination. However, false-positive and false-negative evaluation results may be serious limitations. Ancillary tests are used when there is uncertainty about the reliability of the neurologic examination. Computed tomography angiography (CTA) is an ancillary test that tends to have the lowest false-positive rates. However, there are various influencing factors that can have an unfavorable effect on the validity of the examination method. There are inconsistent protocols regarding the evaluation criteria such as scoring systems. Among the most widely used different scoring systems the 4-point CTA-scoring system has been accepted as the most reliable method. Appropriate timing and/or Doppler pre-testing could reduce the number of possible premature examinations and increase the sensitivity of CTA in diagnosing cerebral circulatory arrest (CCA). In some cases of inconclusive CTA, the whole brain computed tomography perfusion (CTP) could be a crucial adjunct. Due to the increasing significance of CTA/CTP in determining BD, the methodology (including benefits and limitations) should also be conveyed via innovative electronic training tools, such as the BRAINDEXweb teaching tool based on an expert system.

Negative respiratory sinus arrhythmia (nRSA) in the MRI-scanner - a physiologic phenomenon observed during elevated anxiety in healthy persons.

Recently, we reported on a rare manifestation of respiratory sinus arrhythmia (RSA), namely the "switched-off" RSA (Rassler et al., 2018), also called negative RSA (nRSA). It was found in a minority of healthy persons during elevated fMRI-related anxiety characterized by slow spontaneous breathing and synchronous slow beat-to-beat interval (RRI) oscillations. From 23 healthy scanner naïve participants of an fMRI study consisting of 4 resting states, we selected resting states with highest state anxiety (AS) from 10 participants (AS=24.6±2.5) and compared them to those with lowest AS of the same participants (AS=15.1±3.8, p<0.001). During elevated anxiety, the percentage of nRSA (nRSA%) was more than twice of RSA (p=0.045), while RSA prevailed during low anxiety. This indicates that nRSA might be related to elevated anxiety. Interestingly, nRSA was not only associated with slow RRI and breathing oscillations, but also occurred at "normal" breathing rates in the 0.20-0.35 Hz range. We often observed coupled RRI oscillations at 0.1 or 0.15 Hz and respiration at 0.3 Hz (rate ratio 1:3 or 1:2) with respiration-synchronous 0.3 Hz-wavelets in the RRI rhythm (termed "superposition") indicating a reduced dominance of the respiratory rhythm over the RRI rhythm. This novel finding is supported by the work of Perlitz et al., (2004) on a "0.15 Hz rhythm" in brainstem. The concept behind such a 1:n ratio is a pacemaker-like rhythm in the brainstem that "drives" the cardiac RRI signal and secondarily also respiration as reflected in the 1:n rate ratio.

Processing of fMRI-related anxiety and bi-directional information flow between prefrontal cortex and brain stem.

Brain-heart synchronization is fundamental for emotional-well-being and brain-heart desynchronization is characteristic for anxiety disorders including specific phobias. Recording BOLD signals with functional magnetic resonance imaging (fMRI) is an important noninvasive diagnostic tool; however, 1-2% of fMRI examinations have to be aborted due to claustrophobia. In the present study, we investigated the information flow between regions of interest (ROI's) in the cortex and brain stem by using a frequency band close to 0.1 Hz. Causal coupling between signals important in brain-heart interaction (cardiac intervals, respiration, and BOLD signals) was studied by means of Directed Transfer Function based on the Granger causality principle. Compared were initial resting states with elevated anxiety and final resting states with low or no anxiety in a group of fMRI-naïve young subjects. During initial high anxiety the results showed an increased information flow from the middle frontal gyrus (MFG) to the pre-central gyrus (PCG) and to the brainstem. There also was an increased flow from the brainstem to the PCG. While the top-down flow during increased anxiety was predominant, the weaker ascending flow from brainstem structures may characterize a rhythmic pacemaker-like activity that (at least in part) drives respiration. We assume that these changes in information flow reflect successful anxiety processing.

Verification of a Central Pacemaker in Brain Stem by Phase-Coupling Analysis Between HR Interval- and BOLD-Oscillations in the 0.10-0.15 Hz Frequency Band.

The origin of slow intrinsic oscillations in resting states of functional magnetic resonance imaging (fMRI) signals is still a matter of debate. The present study aims to test the hypothesis that slow blood oxygenation level-dependent (BOLD) oscillations with frequency components greater than 0.10 Hz result from a central neural pacemaker located in the brain stem. We predict that a central oscillator modulates cardiac beat-to-beat interval (RRI) fluctuations rapidly, with only a short neural lag around 0.3 s. Spontaneous BOLD fluctuations in the brain stem, however, are considerably delayed due to the hemodynamic response time of about ∼2-3 s. In order to test these predictions, we analyzed the time delay between slow RRI oscillations from thorax and BOLD oscillations in the brain stem by calculating the phase locking value (PLV). Our findings show a significant time delay of 2.2 ± 0.2 s between RRI and BOLD signals in 12 out of 23 (50%) participants in axial slices of the pons/brain stem. Adding the neural lag of 0.3 s to the observed lag of 2.2 s we obtain 2.5 s, which is the time between neural activity increase and BOLD increase, termed neuro-BOLD coupling. Note, this time window for neuro-BOLD coupling in awake humans is surprisingly of similar size as in awake head-fixed adult mice (Mateo et al., 2017).

Heart rate variability (HRV): From brain death to resonance breathing at 6 breaths per minute.

Heart rate variability (HRV) has been associated with various diseases and reflects autonomic cardiac control sensitive to central nervous system function. Examples of the heart-brain interaction are illustrated by extreme clinical conditions such as brain death, orthotopic heart transplantation, weaning from respirator support, and brain maturation in preterm infants. Interactions with the immune system document the importance of HRV for tumor growth and prognosis. Research linking HRV to the regulation of negative emotions including depression and anxiety document the sensitive influence of central commands on cardiac activity. Moreover, 0.1 Hz oscillations in the heart and the brain seem to be coupled, thus indicating central pacemakers on the heart rhythm. Moreover, low frequency oscillations in heart rate seem to be composed of two subcomponents presumably signaling different central-autonomic functions. We conclude by showing that breathing at 6 breaths/minute could induce coherence of the 0.1 Hz oscillations, thus facilitating physical and psychological function. The reviewed findings impressively demonstrate that central nervous system function modifies the rhythm of the heart and vice versa, suggesting that HRV could be a useful indicator of central-autonomic integration and that 0.1 Hz oscillations play a major role in physical and mental health via optimizing energy supply.

"Switch-Off" of Respiratory Sinus Arrhythmia May Be Associated With the Activation of an Oscillatory Source (Pacemaker) in the Brain Stem.

Recently, we reported on the unusual "switch-off" of respiratory sinus arrhythmia (RSA) by analyzing heart rate (HR) beat-to-beat interval (RRI) signals and respiration in five subjects during a potentially anxiety-provoking first-time functional magnetic resonance imaging (fMRI) scanning with slow spontaneous breathing waves (Rassler et al., 2018). This deviation from a fundamental physiological phenomenon is of interest and merits further research. Therefore, in this study, the interplay between blood-oxygen level-dependent (BOLD) activity in the cerebellum/brain stem, RRI, and respiration was probed. Both the cardiovascular and the respiratory centers are located in the medulla oblongata and pons, indicating that dominant slow rhythmic activity is present in the brain stem. The recording of BOLD signals provides a way to investigate associated neural activity fluctuation in the brain stem. We found slow spontaneous breathing waves associated with two types of slow BOLD oscillations with dominant frequencies at 0.10 and 0.15 Hz in the brain stem. Both BOLD oscillations were recorded simultaneously. One is hypothesized as vessel motion-based phenomenon (BOLDv) associated with the start of expiration; the other one as pattern associated with neural activity (BOLDn) acting as a driving force for spontaneous inspiration and RRI increase (unusual cessation of RSA) about 2-3 s after BOLDv. This time delay of 2-3 s corresponds to the neurovascular coupling time.

Monitoring depth of anesthesia utilizing a combination of electroencephalographic and standard measures.

BACKGROUND: For decades, monitoring depth of anesthesia was mainly based on unspecific effects of anesthetics, for example, blood pressure, heart rate, or drug concentrations. Today, electroencephalogram-based monitors promise a more specific assessment of the brain function. To date, most approaches were focused on a "head-to-head" comparison of either electroencephalogram- or standard parameter-based monitoring. In the current study, a multimodal indicator based on a combination of both electro encephalographic and standard anesthesia monitoring parameters is defined for quantification of "anesthesia depth." METHODS: Two hundred sixty-three adult patients from six European centers undergoing surgery with general anesthesia were assigned to 1 of 10 anesthetic combinations according to standards of the enrolling hospital. The anesthesia multimodal index of consciousness was developed using a data-driven approach, which maps standard monitoring and electroencephalographic parameters into an output indicator that separates different levels of anesthesia from awake to electroencephalographic burst suppression. Obtained results were compared with either a combination of standard monitoring parameters or the electroencephalogram-based bispectral index. RESULTS: The anesthesia multimodal index of consciousness showed prediction probability (P(K)) of 0.96 (95% CI, 0.95 to 0.97) to separate different levels of anesthesia (wakefulness to burst suppression), whereas the bispectral index had significantly lower PK of 0.80 (0.76 to 0.81) at corrected threshold P value of less than 0.05. At the transition between consciousness and unconsciousness, anesthesia multimodal index of consciousness yielded a PK of 0.88 (0.85 to 0.91). CONCLUSION: A multimodal integration of both standard monitoring and electroencephalographic parameters may more precisely reflect the level of anesthesia compared with monitoring based on one of these aspects alone.

Airway management and anesthesia in neonates, infants and children during endolaryngotracheal surgery.

BACKGROUND: Endolaryngotracheal surgery in neonates, infants and children poses a big challenge for both anesthesiologist and surgeon. The narrowness of the airways and the great variability of the pathological lesions necessitate close collaboration between the surgical and the anesthesia team to provide optimal operating conditions and ensure adequate ventilation and oxygenation. METHODS: Sixty-two anesthetic records of endolaryngotracheal surgical procedures in neonates, infants and children with ASA physical status 1-3 were analyzed retrospectively. Anesthesia was administered as total intravenous anesthesia; propofol supplemented with remifentanil. Ventilation was performed as supraglottic, superimposed high-frequency jet ventilation via jet laryngoscope with integrated jet nozzles. RESULTS: Age was 58.93 (SD 35.40) months, range 3 weeks to 14 years; body weight 17.83 (SD 8.79) kg, range 2.4-50 kg. The capillary pCO(2) 5 min after the start of the surgical procedure (n = 62) was 40.01 (SD 7.71) mmHg and after 20 min (n = 24) 41.77 (SD 7.12) mmHg. No hypoxemia (oxygen saturation <90%) developed. All patients were hemodynamically stable during jet ventilation. Barotrauma or gas insufflation in the stomach did not occur. No perioperative tracheostomy was necessary. Laryngospasm occurred in one child during emergence from anesthesia. Four infants received postoperative conventional respirator therapy in the ICU overnight. CONCLUSIONS: Supraglottic superimposed high-/low-frequency jet ventilation via jet laryngoscopes with integrated jet nozzles is a minimally invasive ventilation technique for neonates, infants and children in endolaryngotracheal surgery, which allows an unimpaired operating field for the surgeon especially in LASER surgery.

Comparative expression profiling in meristems of inbred-hybrid triplets of maize based on morphological investigations of heterosis for plant height.

Heterosis, the superior performance of hybrids as compared to their parental mean is an agronomically important phenomenon well-described morphologically. However, little is known about its molecular basis. We investigated four genetically unrelated maize (Zea mays L.) inbred lines and their F(1) crosses both at the phenotype and transcriptome level, focusing on plant height (PHT) component traits. Substantial mid-parent heterosis (MPH) was found for all parent-hybrid triplets for PHT in the range of 37.9-56.4% in the field and 11.1-39.5% under controlled greenhouse conditions. Analyses of heterosis for number and length of internodes showed two to three times higher MPH in the field as compared to the greenhouse. All three traits exhibited high heritabilities, highest for PHT 95-98%. Two methods for gene expression quantification were applied. High-density cDNA uni-gene microarrays containing 11,827 ESTs were utilized for the selection of differentially expressed genes related to heterosis for PHT. For the four triplets with eight possible parent-hybrid comparisons we identified 434 consistently differentially expressed genes with a p < or = 0.05. Microarray results were used to verify the dominance/overdominance hypothesis. In our study, more than 50% genes showed overdominance, 26% partial dominance, 12.6% complete dominance and 10.2% additive gene action. Moreover, more consistently differentially expressed genes were detected in related triplets, sharing one parent, than in unrelated triplets. Quantitative RT-PCR was applied in order to validate microarray results. The role of the differentially expressed genes in relation to heterosis for PHT is discussed.

Validation of a real-time PCR for the quantitative estimation of a G143A mutation in the cytochrome bc1 gene of Pyrenophora teres.

A single nucleotide polymorphism (SNP) in the cytochrome b gene confers resistance to strobilurin fungicides for several fungal pathogens. Therefore, on the basis of a change at amino acid position 143 from glycine to alanine, a real-time PCR assay was established for the quantitative detection of the analogous SNP in the cytochrome b sequence of Pyrenophora teres Drechsler, which causes barley net blotch. Allelic discrimination was achieved by using allele specific primers with artificially mismatched nucleic acid bases and minor groove binding probes. Validation parameters for the lower limits of the working range, namely limits of detection (LOD) and limits of quantification (LOQ), were statistically determined by the variance of calibration data, as well as by the variance of the 100% non-strobilurin-resistant allele DNA sample (blank values). It was found that the detection was limited by the variance of blank values (five in 801 458 copies; 0.0006%), whereas the quantification was limited by the variance of calibration data (37 in 801 458 copies; 0.0046%). The real-time PCR assay was finally used to monitor strobilurin-resistant cytochrome b alleles in barley net blotch field samples, which were already classified in in vivo biotests to be fully sensitive to strobilurins. All signals for strobilurin-resistant cytochrome b alleles were below the LOD, and therefore the results are in total agreement with the phenotypes revealed by biotests.

[Increases of intracranial pressure and changes of blood flow velocity due to acupressure, needle and laser needle acupuncture?]. / Intrakranieller Druckanstieg nach zerebralen Blutflussgeschwindigkeitsänderungen durch Akupressur, Nadelakupunktur und Lasernadelakupunktur?

BACKGROUND: Pressure on the acupoints St.7 and SJ.22 can lead to significant, reversible increases in intracranial pressure (ICP) in patients with elevated ICP. OBJECTIVE: In this study, we investigated whether changes in cerebral parameters in healthy volunteers can also be registered, when the mentioned acupoints associated with ICP, are stimulated. SUBJECTS AND METHODS: We investigated a total of 34 volunteers (24 females, 10 males) and a 15-year-old intensive care patient after severe head injury. The mean age of volunteers was 25.2 +/- 3.4 years (range 20-35). Stimulation was performed using acupressure techniques, manual needle and laser needle methods. We evaluated the main parameter of mean blood flow velocity in the middle cerebral artery (left and right) as well as the pulsatility index. In addition, near infrared spectroscopy and blood pressure parameters were registered. RESULTS: Acupressure, manual needle acupuncture and laser needle acupuncture partially led to significant changes in the main goal values. CONCLUSION: Acupressure as well as acupuncture (needle and laser needle) can evoke reproducible functional changes in the brain. These accompanying effects are not to be ignored, in particular in patients with increased ICP.

An NIRS matrix for detecting and correcting cerebral oxygen desaturation events during surgery and neuroendovascular procedures.

BACKGROUND: Transcranial cerebral oximetry was developed for early detection of cerebral hypoxia and to avoid cerebral dysfunctions. However, near infrared spectroscopy (NIRS) data obtained during surgery are subject to intrinsic and extrinsic influences that have to be accounted for when interpreting the recordings. METHODS: We developed an NIRS matrix to provide brief information for specific intervention to correct changes of cerebral oxygen saturation (COS). Selected vital data and the descriptors of cerebrovascular and neurofunctional status were linked to logistic chains. RESULTS: The matrix is horizontally and vertically grouped and contains five descriptors: 1. change of COS; 2. key variable (parameter related to the change of COS); 3. associated parameters (vital data that do not cause COS alterations); 4. interpretation of values or preconditions most probably due to COS changes; and 5. the intervention most likely to normalize the COS or return it to baseline. The descriptors are grouped horizontally to a logistics chain. CONCLUSION: The modular expandable NIRS matrix we describe has promise for clinical use in surgical, neurointerventional, and anaesthesiological contexts.

Pseudoparadoxical dissociation of cerebral oxygen saturation and cerebral blood flow velocity after acupuncture in a woman with cerebrovascular dementia: a case report.

Acupuncture can increase both cerebral oxygen saturation and cerebral blood flow velocity. We describe a 77-year-old woman with cerebrovascular dementia in whom acupuncture reproducibly induced an increase of blood flow velocity but a decrease of regional oxygen saturation. At four of 11 acupuncture sessions, blood flow velocity was measured in the middle cerebral artery with transcranial Doppler sonography and cerebral regional oxygen saturation (rSO(2)) with transcranial near infrared spectroscopy. Cerebral blood flow velocity increased by an average of 20% (range: 7-27%) at all four study points whereas rSO(2) consistently decreased by an average of 7% (range: 4-13%). Clinical status and cognitive function improved. These findings in a patient with vascular dementia may suggest increased oxygen extraction by activated neuronal structures.

Determination of detection and quantification limits for SNP allele frequency estimation in DNA pools using real time PCR.

The quantification of single nucleotide polymorphism (SNP) allele frequencies in pooled DNA samples using real time PCR is a promising approach for large-scale diagnostics and genotyping. The limits of detection (LOD) and limits of quantification (LOQ) for mutant SNP alleles are of particular importance for determination of the working range, which, in the case of allele-specific real time PCR, can be limited by the variance of calibration data from serially diluted mutant allele samples as well as by the variance of the 100% wild-type allele samples (blank values). In this study, 3sigma and 10sigma criteria were applied for the calculation of LOD and LOQ values. Alternatively, LOQ was derived from a 20% threshold for the relative standard deviation (%RSD) of measurements by fitting a curve for the relationship between %RSD and copy numbers of the mutant alleles. We found that detection and quantification of mutant alleles were exclusively limited by the variance of calibration data since the estimated LOD(calibration) (696 in 30 000 000 copies, 0.0023%), LOQ(20%RSD) (1470, 0.0049%) and LOQ(calibration) (2319, 0.0077) values were significantly higher than the LOD(blank) (130, 0.0004%) and LOQ(blank) (265, 0.0009%) values derived from measurements of wild-type allele samples. No significant matrix effects of the genomic background DNA on the estimation of LOD and LOQ were found. Furthermore, the impact of large genome sizes and the general application of the procedure for the estimation of LOD and LOQ in quantitative real time PCR diagnostics are discussed.