Complexity analysis of heartbeat-related signals in brain MRI time series as a potential biomarker for ageing and cognitive performance.

Getting older affects both the structure of the brain and some cognitive capabilities. Until now, magnetic resonance imaging (MRI) approaches have been unable to give a coherent reflection of the cognitive declines. It shows the limitation of the contrast mechanisms used in most MRI investigations, which are indirect measures of brain activities depending on multiple physiological and cognitive variables. However, MRI signals may contain information of brain activity beyond these commonly used signals caused by the neurovascular response. Here, we apply a zero-spin echo (ZSE) weighted MRI sequence, which can detect heartbeat-evoked signals (HES). Remarkably, these MRI signals have properties only known from electrophysiology. We investigated the complexity of the HES arising from this sequence in two age groups; young (18-29 years) and old (over 65 years). While comparing young and old participants, we show that the complexity of the HES decreases with age, where the stability and chaoticity of these HES are particularly sensitive to age. However, we also found individual differences which were independent of age. Complexity measures were related to scores from different cognitive batteries and showed that higher complexity may be related to better cognitive performance. These findings underpin the affinity of the HES to electrophysiological signals. The profound sensitivity of these changes in complexity shows the potential of HES for understanding brain dynamics that need to be tested in more extensive and diverse populations with clinical relevance for all neurovascular diseases. Supplementary Information: The online version contains supplementary material available at 10.1140/epjs/s11734-022-00696-2.

Elucidating the complex organization of neural micro-domains in the locust Schistocerca gregaria using dMRI.

To understand brain function it is necessary to characterize both the underlying structural connectivity between neurons and the physiological integrity of these connections. Previous research exploring insect brain connectivity has typically used electron microscopy techniques, but this methodology cannot be applied to living animals and so cannot be used to understand dynamic physiological processes. The relatively large brain of the desert locust, Schistercera gregaria (Forksȧl) is ideal for exploring a novel methodology; micro diffusion magnetic resonance imaging (micro-dMRI) for the characterization of neuronal connectivity in an insect brain. The diffusion-weighted imaging (DWI) data were acquired on a preclinical system using a customised multi-shell diffusion MRI scheme optimized to image the locust brain. Endogenous imaging contrasts from the averaged DWIs and Diffusion Kurtosis Imaging (DKI) scheme were applied to classify various anatomical features and diffusion patterns in neuropils, respectively. The application of micro-dMRI modelling to the locust brain provides a novel means of identifying anatomical regions and inferring connectivity of large tracts in an insect brain. Furthermore, quantitative imaging indices derived from the kurtosis model that include fractional anisotropy (FA), mean diffusivity (MD) and kurtosis anisotropy (KA) can be extracted. These metrics could, in future, be used to quantify longitudinal structural changes in the nervous system of the locust brain that occur due to environmental stressors or ageing.

Early hippocampal volume loss as a marker of eventual memory deficits caused by repeated stress.

Exposure to severe and prolonged stress has detrimental effects on the hippocampus. However, relatively little is known about the gradual changes in hippocampal structure, and its behavioral consequences, over the course of repeated stress. Behavioral analyses during 10 days of chronic stress pointed to a delayed decline in spatial memory, the full impact of which is evident only after the end of stress. In contrast, concurrent volumetric measurements in the same animals revealed significant reduction in hippocampal volumes in stressed animals relative to their unstressed counterparts, as early as the third day of stress. Notably, animals that were behaviorally the worst affected at the end of chronic stress suffered the most pronounced early loss in hippocampal volume. Together, these findings support the view that not only is smaller hippocampal volume linked to stress-induced memory deficits, but it may also act as an early risk factor for the eventual development of cognitive impairments seen in stress-related psychiatric disorders.

Imaging and finite element analysis: a methodology for non-invasive characterization of aortic tissue.

Characterization of the mechanical properties of arterial tissues usually involves an invasive procedure requiring tissue removal. In this work we propose a non-invasive method to perform a biomechanical analysis of cardiovascular aortic tissue. This method is based on combining medical imaging and finite element analysis (FEA). Magnetic resonance imaging (MRI) was chosen since it presents relatively low risks for human health. A finite element model was created from the MRI images and loaded with systolic physiological pressures. By means of an optimization routine, the structural material properties were changed until average strains matched those measured by MRI. The method outlined in this work produced an estimate of the in situ properties of cardiovascular tissue based on non-invasive image datasets and finite element analysis.

Chronic immobilization stress occludes in vivo cortical activation in an animal model of panic induced by carbon dioxide inhalation.

Breathing high concentrations of carbon dioxide (CO2) can trigger panic and anxiety in humans. CO2 inhalation has been hypothesized to activate neural systems similar to those underlying fear learning, especially those involving the amygdala. Amygdala activity is also upregulated by stress. Recently, however, a separate pathway has been proposed for interoceptive panic and anxiety signals, as patients exhibited CO2-inhalation induced panic responses despite bilateral lesions of the amygdala. This paradoxical observation has raised the possibility that cortical circuits may underlie these responses. We sought to examine these divergent models by comparing in vivo brain activation in unstressed and chronically-stressed rats breathing CO2. Regional cerebral blood flow measurements using functional Magnetic Resonance Imaging (fMRI) in lightly-anaesthetized rats showed especially strong activation of the somatosensory cortex by CO2 inhalation in the unstressed group. Strikingly, prior exposure to chronic stress occluded this effect on cortical activity. This lends support to recent clinical observations and highlights the importance of looking beyond the traditional focus on limbic structures, such as the hippocampus and amygdala, to investigate a role for cortical areas in panic and anxiety in humans.

Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury.

Traumatic brain injury is the leading cause of death in children and young adults globally. Malignant cerebral oedema has a major role in the pathophysiology that evolves after severe traumatic brain injury. Added to this is the significant morbidity and mortality from cerebral oedema associated with acute stroke, hypoxic ischemic coma, neurological cancers and brain infection. Therapeutic strategies to prevent cerebral oedema are limited and, if brain swelling persists, the risks of permanent brain damage or mortality are greatly exacerbated. Here we show that a temporary and size-selective modulation of the blood-brain barrier allows enhanced movement of water from the brain to the blood and significantly impacts on brain swelling. We also show cognitive improvement in mice with focal cerebral oedema following administration in these animals of short interfering RNA directed against claudin-5. These observations may have profound consequences for early intervention in cases of traumatic brain injury, or indeed any neurological condition where cerebral oedema is the hallmark pathology.

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability.

In view of the increase in the aging population and the unavoidable parallel increase in the incidence of age-related neurodegenerative diseases, a key challenge in neuroscience is the identification of clinical signatures which change with age and impact on neuronal and cognitive function. Early diagnosis offers the possibility of early therapeutic intervention, thus magnetic resonance imaging (MRI) is potentially a powerful diagnostic tool. We evaluated age-related changes in relaxometry, blood flow, and blood-brain barrier (BBB) permeability in the rat by magnetic resonance imaging and assessed these changes in the context of the age-related decrease in synaptic plasticity. We report that T2 relaxation time was decreased with age; this was coupled with a decrease in gray matter perfusion, suggesting that the observed microglial activation, as identified by increased expression of CD11b, MHCII, and CD68 by immunohistochemistry, flow cytometry, or polymerase chain reaction (PCR), might be a downstream consequence of these changes. Increased permeability of the blood-brain barrier was observed in the perivascular area and the hippocampus of aged, compared with young, rats. Similarly there was an age-related increase in CD45-positive cells by flow cytometry, which are most likely infiltrating macrophages, with a parallel increase in the messenger mRNA expression of chemokines IP-10 and MCP-1. These combined changes may contribute to the deficit in long-term potentiation (LTP) in perforant path-granule cell synapses of aged animals.

Propofol allows precise quantitative arterial spin labelling functional magnetic resonance imaging in the rat.

Functional magnetic resonance imaging (fMRI) techniques highlight cerebral vascular responses which are coupled to changes in neural activation. However, two major difficulties arise when employing these techniques in animal studies. First is the disturbance of cerebral blood flow due to anaesthesia and second is the difficulty of precise reproducible quantitative measurements. These difficulties were surmounted in the current study by using propofol and quantitative arterial spin labelling (QASL) to measure relative cerebral blood volume of labelled water (rCBV(lw),) mean transit time (MTT) and capillary transit time (CTT). The ASL method was applied to measure the haemodynamic response in the primary somatosensory cortex following forepaw stimulation in the rat. Following stimulation an increase in signal intensity and rCBV(lw) was recorded, this was accompanied by a significant decrease in MTT (1.97+/-0.06s to 1.44+/-0.04s) and CTT (1.76+/-0.06s to 1.39+/-0.07s). Two animals were scanned repeatedly on two different experimental days. Stimulation in the first animal was applied to the same forepaw during the initial and repeat scan. In the second animal stimulation was applied to different forepaws on the first and second days. The control and activated ASL signal intensities, rCBVlw on both days were almost identical in both animals. The basal MTT and CTT during the second scan were also very similar to the values obtained during the first scan. The MTT recorded from the animal that underwent stimulation to the same paw during both scanning sessions was very similar on the first and second days. In conclusion, propofol induces little physiological disturbance and holds potential for longitudinal QASL fMRI studies.

Quantitative functional magnetic resonance imaging of brain activity using bolus-tracking arterial spin labeling.

Blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) is the most widely used method for mapping neural activity in the brain. The interpretation of altered BOLD signals is problematic when cerebral blood flow (CBF) or cerebral blood volume change because of aging and/or neurodegenerative diseases. In this study, a recently developed quantitative arterial spin labeling (ASL) approach, bolus-tracking ASL (btASL), was applied to an fMRI experiment in the rat brain. The mean transit time (MTT), capillary transit time (CTT), relative cerebral blood volume of labeled water (rCBV(lw)), relative cerebral blood flow (rCBF), and perfusion coefficient in the forelimb region of the somatosensory cortex were quantified during neuronal activation and in the resting state. The average MTT and CTT were 1.939+/-0.175 and 1.606+/-0.106 secs, respectively, in the resting state. Both times decreased significantly to 1.616+/-0.207 and 1.305+/-0.201 secs, respectively, during activation. The rCBV(lw), rCBF, and perfusion coefficient increased on average by a factor of 1.123+/-0.006, 1.353+/-0.078, and 1.479+/-0.148, respectively, during activation. In contrast to BOLD techniques, btASL yields physiologically relevant indices of the functional hyperemia that accompanies neuronal activation.

Experimental neonatal status epilepticus and the development of temporal lobe epilepsy with unilateral hippocampal sclerosis.

Hippocampal sclerosis is a common pathological finding in patients with temporal lobe epilepsy, including children, but a causal relationship to early-life seizures remains in question. Neonatal status epilepticus in animals can result in neuronal death within the hippocampus, although macroscopic features of hippocampal shrinkage are not evident at adulthood. Here, we examined electrophysiological and pathological consequences of focally evoked status epilepticus triggered by intra-amygdala microinjection of kainic acid in postnatal day 10 rat pups. Neonatal status epilepticus resulted in extensive neuronal death in the ipsilateral hippocampal CA1 and CA3 subfields and hilus, as assessed by DNA fragmentation and Fluoro-Jade B staining 72 hours later. The contralateral hippocampus was not significantly damaged. Histopathology at P55/P65 revealed unilateral hippocampal sclerosis (grade IV, modified Wyler/Watson scale) comprising >50% CA1 and CA3 neuron loss and astrogliosis. Additional features included hydrocephalus ex vacuo, modest dentate granule cell layer widening, and altered neuropeptide Y immunoreactivity indicative of synaptic rearrangement. Hippocampal atrophy was also evident on magnetic resonance imaging. Depth electrode recordings at adulthood detected spontaneous seizures that involved the ipsilateral hippocampus and amygdala. A significant positive correlation was found between hippocampal pathology grade and both frequency and duration of epileptic seizures at adulthood. The current study demonstrates that experimental neonatal status epilepticus can result in classical unilateral hippocampal sclerosis and temporal lobe epilepsy.

Langevin equation approach to diffusion magnetic resonance imaging.

The normal phase diffusion problem in magnetic resonance imaging (MRI) is treated by means of the Langevin equation for the phase variable using only the properties of the characteristic function of Gaussian random variables. The calculation may be simply extended to anomalous diffusion using a fractional generalization of the Langevin equation proposed by Lutz [E. Lutz, Phys. Rev. E 64, 051106 (2001)] pertaining to the fractional Brownian motion of a free particle coupled to a fractal heat bath. The results compare favorably with diffusion-weighted experiments acquired in human neuronal tissue using a 3 T MRI scanner.

Evaluation of an AIF correction algorithm for dynamic susceptibility contrast-enhanced perfusion MRI.

For longitudinal studies in patients suffering from cerebrovascular diseases the poor reproducibility of perfusion measurements via dynamic susceptibility-weighted contrast-enhanced MRI (DSC-MRI) is a relevant concern. We evaluate a novel algorithm capable of overcoming limitations in DSC-MRI caused by partial volume and saturation issues in the arterial input function (AIF) by a blood flow stimulation-study. In 21 subjects, perfusion parameters before and after administration of blood flow stimulating L-arginine were calculated utilizing a block-circulant singular value decomposition (cSVD). A total of two different raters and three different rater conditions were employed to select AIFs: Besides 1) an AIF selection by an experienced rater, a beginner rater applied a steady state-oriented strategy, returning; 2) raw; and 3) corrected AIFs. Highly significant changes in regional cerebral blood flow (rCBF) by 9.0% (P < 0.01) could only be found when the AIF correction was performed. To further test for improved reproducibility, in a subgroup of seven subjects the baseline measurement was repeated 6 weeks after the first examination. In this group as well, using the correction algorithm decreased the SD of the difference between the two baseline measurements by 42%.

Quantifying the spatial resolution of the gradient echo and spin echo BOLD response at 3 Tesla.

The blood oxygen level dependent (BOLD) response, as measured with fMRI, offers good spatial resolution compared to other non-invasive neuroimaging methods. The use of a spin echo technique rather than the conventional gradient echo technique may further improve the resolution by refocusing static dephasing effects around the larger vessels, so sensitizing the signal to the microvasculature. In this work the width of the point spread function (PSF) of the BOLD response at a field strength of 3 Tesla is compared for these two approaches. A double echo EPI pulse sequence with simultaneous collection of gradient echo and spin echo signal allows a direct comparison of the techniques. Rotating multiple-wedge stimuli of different spatial frequencies are used to estimate the width of the BOLD response. Waves of activation are created on the surface of the visual cortex, which begin to overlap as the wedge separation decreases. The modulation of the BOLD response decreases with increasing spatial frequency in a manner dependent on its width. The spin echo response shows a 13% reduction in the width of the PSF, but at a cost of at least 3-fold reduction in contrast to noise ratio.

Progressive change in primary progressive multiple sclerosis normal-appearing white matter: a serial diffusion magnetic resonance imaging study.

In spite of marked disability, patients with primary progressive multiple sclerosis (PPMS) display smaller lesion volumes on conventional magnetic resonance imaging (MRI) compared with other forms of multiple sclerosis (MS). Hence, damage to the normal-appearing brain tissue (NABT) may play an important role in explaining the pathogenesis of disability in PPMS. Diffusion-weighted MRI (DW-MRI) probes water diffusion in vivo that can be altered by pathologic changes. Using DW-MRI we investigated diffusion in the NABT of 15 patients with PPMS over one year. The average apparent diffusion coefficient (ADCav) was measured in 10 regions of interest located in the normal-appearing thalamus and the normal-appearing white matter (NAWM). Six healthy subjects served as a reference. In contrast to healthy subjects, patients with PPMS showed an increment within 12 months of the ADCav in NAWM which was associated with an increase of the T2- and T1-lesion volumes. The ADCav in frontal NAWM was associated with disability as measured by the MS Functional Composite Measure. Serial DW-MRI depicts progressive changes in the NAWM of patients with PPMS. Our preliminary findings suggest that the processes causing structural damage in NAWM and lesions in patients with PPMS are partially linked and that changes of water diffusion in NAWM depicted by DW-MRI are clinically relevant.

Reduced BOLD response to periodic visual stimulation.

The blood oxygenation level-dependent (BOLD) response to entrained neuronal firing in the human visual cortex and lateral geniculate nuclei was investigated. Periodic checkerboard flashes at a range of frequencies (4-20 Hz) were used to drive the visual cortex neurons into entrained oscillatory firing. This is compared to a checkerboard flashing aperiodically, with the same average number of flashes per unit time. A magnetoencephalography (MEG) measurement was made to confirm that the periodic paradigm elicited entrainment. We found that for frequencies of 10 and 15 Hz, the periodic stimulus gave a smaller BOLD response than for the aperiodic stimulus. Detailed investigation at 15 Hz showed that the aperiodic stimulus gave a similar BOLD increase regardless of the magnitude of jitter (+/-17 ms compared to +/-33 ms), indicating that flashes need to be precise to at least 17 ms to maintain entrainment. This is also evidence that for aperiodic stimuli, the amplitude of the BOLD response ordinarily reflects the total number of flashes per unit time, irrespective of the precise spacing between them, suggesting that entrainment is the main cause of the BOLD reduction in the periodic condition. The results indicate that, during entrainment, there is a reduction in the neuronal metabolic demand. We suggest that because of the selective frequency band of this effect, it could be connected to synchronised reverberations around an internal feedback loop.

Time course of circulatory and metabolic recovery of cat brain after cardiac arrest assessed by perfusion- and diffusion-weighted imaging and MR-spectroscopy.

Brain recovery after cardiac arrest (CA) was assessed in cats using arterial spin tagging perfusion-weighted imaging (PWI), diffusion-weighted imaging (DWI), and 1H-spectroscopy (1H-MRS). Cerebral reperfusion and metabolic recovery was monitored in the cortex and in basal ganglia for 6 h after cardiopulmonary resuscitation (CPR). Furthermore, the effects of an hypertonic/hyperoncotic solution (7.5% NaCl/6% hydroxyl ethyl starch, HES) and a tissue-type plasminogen activator (TPA), applied during CPR, were assessed on brain recovery. CA and CPR were carried out in the MR scanner by remote control. CA for 15-20 min was induced by electrical fibrillation of the heart, followed by CPR using a pneumatic vest. PWI after successful CPR revealed initial cerebral hyperperfusion followed by delayed hypoperfusion. Initial cerebral recirculation was improved after osmotic treatment. Osmotic and thrombolytic therapy were ineffective in ameliorating delayed hypoperfusion. Calculation of the apparent diffusion coefficient (ADC) from DWI demonstrated complete recovery of ion and water homeostasis in all animals. 1H-MRS measurements of lactate suggested an extended preservation of post-ischaemic anaerobic metabolism after TPA treatment. The combination of noninvasive MR techniques is a powerful tool for the evaluation of therapeutical strategies on circulatory and metabolic cerebral recovery after experimental cerebral ischaemia.

Assessment of diffusion and perfusion deficits in patients with small subcortical ischemia.

BACKGROUND AND PURPOSE: Using perfusion- and diffusion-weighted MR imaging in acute ischemic stroke of the middle cerebral artery (MCA), previous studies have shown a typical pathophysiologic pattern that is characterized by a perfusion deficit larger than the diffusion lesion (mismatch), with the final lesion usually comprising the initial diffusion lesion (core) plus parts of the initial mismatch area. Little is known about underlying pathophysiology in small ischemic stroke. In this study, we used perfusion- and diffusion-weighted MR imaging to investigate the underlying pathophysiology of small subcortical ischemia. METHODS: Six consecutive patients (age range, 42-76 years) with small subcortical ischemia were examined by using a 1.5-T MR system 2-5, 22-55, and 144-392 hours after the onset of symptoms. T2-weighted, diffusion-weighted imaging at b=0 s/mm2 and b=1000 s/mm2, and bolus-track perfusion-weighted imaging were performed. Lesion sizes were determined on the basis of T2-weighted findings as well as those of apparent diffusion coefficient (ADC) maps and CBF. RESULTS: In every patient, the initial CBF lesion was smaller than the initial ADC lesion. Both the CBF lesion and the ADC lesion increased in size from first to second examination. In all instances, however, the CBF lesion remained smaller than the ADC lesion. The CBF lesion observed during the acute phase and the one seen on the following days were both smaller than the final T2 lesion. CONCLUSION: Our data suggest that in contrast to previous findings in MCA ischemia in small subcortical infarcts tissue damage may spread beyond the area of the initial perfusion disturbance. In light of the small number of patients, further studies will have to address the relevance of this observation.