Developmental Switch in Neurovascular Coupling in the Immature Rodent Barrel Cortex

Neurovascular coupling (NVC) in the adult central nervous system (CNS) is a mechanism that provides regions of the brain with more oxygen and glucose upon increased levels of neural activation. Hemodynamic changes that go along with neural activation evoke a blood oxygen level-dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) that can be used to study brain activity non-invasively. A correct correlation of the BOLD signal to neural activity is pivotal to understand this signal in neuronal development, health and disease. However, the function of NVC during development is largely unknown. The rodent whisker-to-barrel cortex is an experimentally well established model to study neurovascular interdependences. Using extracellular multi-electrode recordings and laser-Doppler-flowmetry (LDF) we show in the murine barrel cortex of postnatal day 7 (P7) and P30 mice in vivo that NVC undergoes a physiological shift during the first month of life. In the mature CNS it is well accepted that cortical sensory processing results in a rise in regional cerebral blood flow (rCBF). We show in P7 animals that rCBF decreases during prolonged multi-whisker stimulation and goes along with multi unit activity (MUA) fatigue. In contrast at P30, MUA remains stable during repetitive stimulation and is associated with an increase in rCBF. Further we characterize in both age groups the responses in NVC to single sensory stimuli. We suggest that the observed shift in NVC is an important process in cortical development that may be of high relevance for the correct interpretation of brain activity e.g. in fMRI studies of the immature central nervous system (CNS).     

Changes in Cerebral Blood Flow during Olfactory Stimulation in Patients with Multiple Chemical Sensitivity: A Multi-Channel Near-Infrared Spectroscopic Study

Multiple chemical sensitivity (MCS) is characterized by somatic distress upon exposure to odors. Patients with MCS process odors differently from controls. This odor-processing may be associated with activation in the prefrontal area connecting to the anterior cingulate cortex, which has been suggested as an area of odorant-related activation in MCS patients. In this study, activation was defined as a significant increase in regional cerebral blood flow (rCBF) because of odorant stimulation. Using the well-designed card-type olfactory test kit, changes in rCBF in the prefrontal cortex (PFC) were investigated after olfactory stimulation with several different odorants. Near-infrared spectroscopic (NIRS) imaging was performed in 12 MCS patients and 11 controls. The olfactory stimulation test was continuously repeated 10 times. The study also included subjective assessment of physical and psychological status and the perception of irritating and hedonic odors. Significant changes in rCBF were observed in the PFC of MCS patients on both the right and left sides, as distinct from the center of the PFC, compared with controls. MCS patients adequately distinguished the non-odorant in 10 odor repetitions during the early stage of the olfactory stimulation test, but not in the late stage. In comparison to controls, autonomic perception and negative affectivity were poorer in MCS patients. These results suggest that prefrontal information processing associated with odor-processing neuronal circuits and memory and cognition processes from past experience of chemical exposure play significant roles in the pathology of this disorder.     

Influence of isoflurane concentration and hypoxia on functional magnetic resonance imaging for the detection of bicuculline-induced neuronal activation

Our present study shows that transient changes in relative cerebral blood volume (rCBV) induced by stimulation with bicuculline under six different conditions of anesthesia can be detected with high spatial resolution functional magnetic resonance imaging (fMRI). Bicuculline was administered at a low dose to induce neural activation, and no seizure activity was noted. Of the six conditions, the maximal reaction to bicuculline was observed under 1.5% isoflurane in 60% nitrogen and 40% oxygen. Our results imply that the rCBV changes under this level of isoflurane anesthesia with body temperature maintained at 37.5 degrees C are probably suitable for further fMRI studies.     

Sustained negative BOLD,blood flow and oxygen consumption response and its coupling to the positive response in the human brain

Most fMRI studies are based on the detection of a positive BOLD response (PBR). Here, we demonstrate and characterize a robust sustained negative BOLD response (NBR) in the human occipital cortex, triggered by stimulating part of the visual field. The NBR was spatially adjacent to but segregated from the PBR. It depended on the stimulus and thus on the pattern of neuronal activity. The time courses of the NBR and PBR were similar, and their amplitudes covaried both with increasing stimulus duration and increasing stimulus contrast. The NBR was associated with reductions in blood flow and with decreases in oxygen consumption. Our findings support the contribution to the NBR of (1) a significant component of reduction in neuronal activity and (2) possibly a component of hemodynamic changes independent of the local changes in neuronal activity.     

Functional Imaging of Auditory Cortex in Adult Cats using High-field fMRI

Current knowledge of sensory processing in the mammalian auditory system is mainly derived from electrophysiological studies in a variety of animal models, including monkeys, ferrets, bats, rodents, and cats. In order to draw suitable parallels between human and animal models of auditory function, it is important to establish a bridge between human functional imaging studies and animal electrophysiological studies. Functional magnetic resonance imaging (fMRI) is an established, minimally invasive method of measuring broad patterns of hemodynamic activity across different regions of the cerebral cortex. This technique is widely used to probe sensory function in the human brain, is a useful tool in linking studies of auditory processing in both humans and animals and has been successfully used to investigate auditory function in monkeys and rodents. The following protocol describes an experimental procedure for investigating auditory function in anesthetized adult cats by measuring stimulus-evoked hemodynamic changes in auditory cortex using fMRI. This method facilitates comparison of the hemodynamic responses across different models of auditory function thus leading to a better understanding of species-independent features of the mammalian auditory cortex.     

Linear and nonlinear relationships between neuronal activity, oxygen metabolism, and hemodynamic responses

We investigated the relationship between neuronal activity, oxygen metabolism, and hemodynamic responses in rat somatosensory cortex with simultaneous optical intrinsic signal imaging and spectroscopy, laser Doppler flowmetry, and local field potential recordings. Changes in cerebral oxygen consumption increased linearly with synaptic activity but with a threshold effect consistent with the existence of a tissue oxygen buffer. Modeling analysis demonstrated that the coupling between neuronal activity and hemodynamic response magnitude may appear linear over a narrow range but incorporates nonlinear effects that are better described by a threshold or power law relationship. These results indicate that caution is required in the interpretation of perfusion-based indicators of brain activity, such as functional magnetic resonance imaging (fMRI), and may help to refine quantitative models of neurovascular coupling.     

High-resolution functional magnetic resonance imaging of the animal brain

To fully understand brain function, one must look beyond the level of a single neuron. By elucidating the spatial properties of the columnar and laminar functional architectures, information regarding the neural processing in the brain can be gained. To map these fine functional structures noninvasively and repeatedly, functional magnetic resonance imaging (fMRI) can be employed. In this article the basic principles of fMRI are introduced, including specific hardware requirements and the equipment necessary for animal magnetic resonance research. Since fMRI measures a change in secondary hemodynamic responses induced by neural activity, it is critical to understand the principles and potential pitfalls of fMRI techniques. Thus, the underlying physics of conventional blood oxygenation, cerebral blood flow, and cerebral blood volume-based fMRI techniques are extensively discussed. Tissue-specific signal change is close to the site of neural activity, while signals from large vessels can be distant from the actual active site. Thus, methods to minimize large vessel contributions and to maximize tissue signals are described. The fundamental limitation of fMRI spatial resolution is the intrinsic hemodynamic response. Based on our high-resolution fMRI studies, the hemodynamic response is regulated at submillimeter functional domains and thus spatial resolution can be achieved to an order of 100 microm. Since hemodynamic responses are sluggish, it is difficult to obtain very high temporal resolution. By using an approach with multiple experiments with different stimulus conditions, temporal resolution can be improved on the order of 100 ms. With current fMRI technologies, submillimeter columnar- and laminar-specific specific functional images can be obtained from animal brains.     

CT灌注成像技术用于重型颅脑损伤患者脑室型颅内压探头植入的临床价值评估

目的:探讨CT灌注成像技术用于重型颅脑损伤患者脑室型颅内压(Intracranial Pressure, ICP)探头植入的临床价值。方法:选取60例重型颅脑损伤患者,均行患侧开颅去骨瓣减压和颅内压监测探头置入术。其中,行普通型颅内压监测探头置入术28例,脑室型颅内压监测探头置入术32例。比较两组术后甘露醇应用剂量和应用时间,术后局部脑血流参数区域脑血流量(regional Cerebral Blood Flow, r CBF)、相对脑血容量(relative Cerebral Blood Volume, r CBV)、平均通过时间(Mean Transit Time, MTT)、对比剂达峰时间(time to peak, TTP)恢复情况。结果:脑室型颅内压监测组患者术后应用甘露醇的剂量和天数较普通颅内压监测组明显缩短(P0.05),术后3个月随访提示脑室型ICP监测组预后良好比例较普通型ICP组显著增加(P0.05)。并且螺旋CT灌注成像结果提示脑室型颅内压监测组患者术后局部脑血流参数r CBF、r CBV、MTT、TTP恢复情况明显优于普通型颅内压监测组(P0.05)。结论:重型颅脑损伤患者应用脑室型颅内监测探头改变了脱水剂在临床应用中的治疗模式,通过螺旋CT灌注成像检测患者损伤部位的r CBF、r CBV、MTT和TTP可评估脑损伤的程度以及预后,对重型颅脑损伤的临床治疗和改善患者预后具有重要意义。     

Modulation of the neuronal activity and evoked potentials of the cerebral cortex by stimulation of the dorsal hippocampus]

In experiments on alert rabbits high frequency stimulation of the CA1 field of the dorsal hippocampus reduced the peak latency of the main negative component of the evoked potential (EP) to a light flash in the sensorimotor and occipital tests areas of the cerebral cortex. A single stimulation of the same part of the hippocampus resulted in a gradually developing facilitation of secondary negativity of the EP 5th component, predominantly in the sensorimotor cortex. Investigation of neuronal responses in the same cortical areas to a stimulation of the CA1 field with different parameters has shown that the effects of EP modulation are due to dynamic reorganizations of cortical neuronal activity.     

Assessment of single-vessel cerebral blood velocity by phase contrast fMRI

Current approaches to high-field functional MRI (fMRI) provide 2 means to map hemodynamics at the level of single vessels in the brain. One is through changes in deoxyhemoglobin in venules, i.e., blood oxygenation level–dependent (BOLD) fMRI, while the second is through changes in arteriole diameter, i.e., cerebral blood volume (CBV) fMRI. Here, we introduce cerebral blood flow–related velocity-based fMRI, denoted CBFv-fMRI, which uses high-resolution phase contrast (PC) MRI to form velocity measurements of flow. We use CBFv-fMRI in measure changes in blood velocity in single penetrating microvessels across rat parietal cortex. In contrast to the venule-dominated BOLD and arteriole-dominated CBV fMRI signals, CBFv-fMRI is comparable from both arterioles and venules. A single fMRI platform is used to map changes in blood pO₂ (BOLD), volume (CBV), and velocity (CBFv). This combined high-resolution single-vessel fMRI mapping scheme enables vessel-specific hemodynamic mapping in animal models of normal and diseased states and further has translational potential to map vascular dementia in diseased or injured human brains with ultra–high-field fMRI.

This study presents a phase contrast-based, high field MRI-based approach for the functional mapping of cerebral blood velocity in individual cortical arterioles and venules in the rat cortex; this approach can be combined with previously established approaches to map BOLD, CBV, and blood velocity from penetrating microvessels.     

Localizing Movement-Related Primary Sensorimotor Cortices with Multi-Band EEG Frequency Changes and Functional MRI

Electroencephalographic (EEG) oscillations in multiple frequency bands can be observed during functional activity of the cerebral cortex. An important question is whether activity of focal areas of cortex, such as during finger movements, is tracked by focal oscillatory EEG changes. Although a number of studies have compared EEG changes to functional MRI hemodynamic responses, we can find no previous research that relates the fMRI hemodynamic activity to localization of the multiple EEG frequency changes observed in motor tasks. In the present study, five participants performed similar thumb and finger movement tasks in parallel EEG and functional MRI studies. We examined changes in five frequency bands (from 5–120 Hz) and localized them using 256 dense-array EEG (dEEG) recordings and high-resolution individual head models. These localizations were compared with fMRI localizations in the same participants. Results showed that beta-band (14–30 Hz) desynchronizations (power decreases) were the most robust effects, appearing in all individuals, consistently localized to the hand region of the primary motor cortex, and consistently aligned with fMRI localizations.     

Alterations of Regional Cerebral Blood Flow in Tinnitus Patients as Assessed Using Single-Photon Emission Computed Tomography

Tinnitus is the perception of phantom sound without an external auditory stimulus. Using neuroimaging techniques, such as positron emission tomography, electroencephalography, magnetoencephalography, and functional magnetic resonance imaging (fMRI), many studies have demonstrated that abnormal functions of the central nervous system are closely associated with tinnitus. In our previous research, we reported using resting-state fMRI that several brain regions, including the rectus gyrus, cingulate gyrus, thalamus, hippocampus, caudate, inferior temporal gyrus, cerebellar hemisphere, and medial superior frontal gyrus, were associated with tinnitus distress and loudness. To reconfirm these results and probe target regions for repetitive transcranial magnetic stimulation (rTMS), we investigated the regional cerebral blood flow (rCBF) between younger tinnitus patients (<60 years old) and the age-matched controls using single-photon emission computed tomography and easy Z-score imaging system. Compared with that of controls, the rCBF of tinnitus patients was significantly lower in the bilateral medial superior frontal gyri, left middle occipital gyrus and significantly higher in the bilateral cerebellar hemispheres and vermis, bilateral middle temporal gyri, right fusiform gyrus. No clear differences were observed between tinnitus patients with normal and impaired hearing. Regardless of the assessment modality, similar brain regions were identified as characteristic in tinnitus patients. These regions are potentially involved in the pathophysiology of chronic subjective tinnitus.     

Deep Brain Stimulation with Simultaneous fMRI in Rodents

In order to visualize the global and downstream neuronal responses to deep brain stimulation (DBS) at various targets, we have developed a protocol for using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to image rodents with simultaneous DBS. DBS fMRI presents a number of technical challenges, including accuracy of electrode implantation, MR artifacts created by the electrode, choice of anesthesia and paralytic to minimize any neuronal effects while simultaneously eliminating animal motion, and maintenance of physiological parameters, deviation from which can confound the BOLD signal. Our laboratory has developed a set of procedures that are capable of overcoming most of these possible issues. For electrical stimulation, a homemade tungsten bipolar microelectrode is used, inserted stereotactically at the stimulation site in the anesthetized subject. In preparation for imaging, rodents are fixed on a plastic headpiece and transferred to the magnet bore. For sedation and paralysis during scanning, a cocktail of dexmedetomidine and pancuronium is continuously infused, along with a minimal dose of isoflurane; this preparation minimizes the BOLD ceiling effect of volatile anesthetics. In this example experiment, stimulation of the subthalamic nucleus (STN) produces BOLD responses which are observed primarily in ipsilateral cortical regions, centered in motor cortex. Simultaneous DBS and fMRI allows the unambiguous modulation of neural circuits dependent on stimulation location and stimulation parameters, and permits observation of neuronal modulations free of regional bias. This technique may be used to explore the downstream effects of modulating neural circuitry at nearly any brain region, with implications for both experimental and clinical DBS.     

The regional cerebral blood flow pattern of the normal human brain and its factor structure

The regional cerebral blood flow (rCBF) pattern of the normal human brain was drawn, and its structure was studied. Relative rCBF estimates for 66 regions of interest (cerebral anatomical-functional areas) were obtained using positron emission tomography in 158 healthy subjects aged 18–49 years. The rCBF rate variation range was 89–121% of the rCBF rate averaged over all regions of interest, taken as 100%. The rCBF rates were the highest (>115%) in the paracentral lobule, precuneus, insular cortex, primary visual cortex, and Broca’s area and the lowest (<95%) in the mediobasal regions of the temporal gyri and caudate nuclei. Analysis of the factor structure of the resultant pattern made it possible to classify cerebral anatomical-functional areas according to a predominant effect of one of the following factors on the interdependence between rCBF rates: (1) cytoarchitectonic characteristics; (2) the functional state of the cortex during quiet wakefulness; or (3) the brain vascular region to which the area belongs. The obtained pattern should be taken into account in both mapping of the functions of a normal brain and clinical diagnosis.     

Cortical control of tongue protrusion and lateral movements in the cat

Based on area P lesion experiments, we hypothesized that tongue protrusion adapted for licking might be regulated by the lateral wall of the presylvian sulcus (bilateral areas P) of the cerebral cortex (Hiraba H, Sato T, Nakakawa K, Ueda K. . Cortical control of appropriate tongue protrusion during licking in cats—Increase in regional cerebral blood flow (rCBF) of the contralateral area P and in tongue protrusion after the unilateral area P lesion. Somatosens Mot Res 26:82–89). We propose that the right and left lingual muscles are dominated by the right and left hypoglossal nucleus, respectively, and that right and left pyramidal cells projecting to the right and left hypoglossal nucleus, respectively, exist in unilateral area P. These cells project via an inhibitory interneuron relay to the lateral branches toward the left or right pyramidal cells in contralateral area P. In this study, we aimed to demonstrate the existence of inhibitory interneurons using injections of a gamma-aminobutyric acid (GABA) agonist (muscimol), a GABA antagonist (bicuculline), and kainic acid into unilateral area P, followed by examination of tongue protrusion and lateral movements during trained licking and changes in regional cerebral blood flow (rCBF) values in the contralateral area P. We found disordered protrusion toward both sides and a marked decrease in rCBF values in the contralateral area P after bicuculline injection. We also found abnormal tongue protrusion toward the front and a marked increase in rCBF values after muscimol and kainic acid injections. These results suggest that cortical networks between the bilateral areas P are relayed by inhibitory interneurons.     

The Effect of Morphine on Regional Cerebral Blood Flow Measured by 99mTc-ECD SPECT in Dogs

To gain insights into the working mechanism of morphine, regional cerebral blood flow (rCBF) patterns after morphine administration were assessed in dogs. In a randomized cross-over experimental study, rCBF was estimated with ^99mTc-Ethylcysteinate Dimer single photon emission computed tomography in 8 dogs at baseline, at 30 minutes and at 120 minutes after a single bolus of morphine. Perfusion indices (PI) in the frontal, parietal, temporal and occipital cortex and in the subcortical and cerebellar region were calculated. PI was significantly decreased 30 min after morphine compared to baseline in the right frontal cortex. The left parietal cortex and subcortical region showed a significantly increased PI 30 min after morphine compared to baseline. No significant differences were noted for the other regions or at other time points. In conclusion, a single bolus of morphine generated a changing rCBF pattern at different time points.     

Functional neuroanatomy of the hypnotic state

The neural mechanisms underlying hypnosis and especially the modulation of pain perception by hypnosis remain obscure. Using PET we first described the distribution of regional cerebral blood flow during the hypnotic state. Hypnosis relied on revivification of pleasant autobiographical memories and was compared to imaging autobiographical material in "normal alertness". The hypnotic state was related to the activation of a widespread set of cortical areas involving occipital, parietal, precentral, premotor, and ventrolateral prefrontal and anterior cingulate cortices. This pattern of activation shares some similarities with mental imagery, from which it mainly differs by the relative deactivation of precuneus. Second, we looked at the anti-nociceptive effects of hypnosis. Compared to the resting state, hypnosis reduced pain perception by approximately 50%. The hypnosis-induced reduction of affective and sensory responses to noxious thermal stimulation were modulated by the activity in the midcingulate cortex (area 24a'). Finally, we assessed changes in cerebral functional connectivity related to hypnosis. Compared to normal alertness (i.e., rest and mental imagery), the hypnotic state, significantly enhanced the functional modulation between midcingulate cortex and a large neural network involved in sensory, affective, cognitive and behavioral aspects of nociception. These findings show that not only pharmacological but also psychological strategies for pain control can modulate the cerebral network involved in noxious perception.     

The role of perfusion computed tomography in the prediction of cerebral hyperperfusion syndrome

Background

Hyperperfusion syndrome (HPS) following carotid angioplasty with stenting (CAS) is associated with significant morbidity and mortality. At present, there are no reliable parameters to predict HPS. The aim of this study was to clarify whether perfusion computed tomography (CT) is a feasible and reliable tool in predicting HPS after CAS.

Methodology/Principal Findings

We performed a retrospective case-control study of 54 patients (11 HPS patients and 43 non-HPS) with unilateral severe stenosis of the carotid artery who underwent CAS. We compared the prevalence of vascular risk factors and perfusion CT parameters including regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), and time to peak (TTP) within seven days prior to CAS. Demographic information, risk factors for atherosclerosis, and perfusion CT parameters were evaluated by multivariable logistic regression analysis. The rCBV index was calculated as [(ipsilateral rCBV - contralateral rCBV)/contralateral rCBV], and indices of rCBF and TTP were similarly calculated. We found that eleven patients had HPS, including five with intracranial hemorrhages (ICHs) of whom three died. After a comparison with non-HPS control subjects, independent predictors of HPS included the severity of ipsilateral carotid artery stenosis, 3-hour mean systolic blood pressure (3 h SBP) after CAS, pre-stenting rCBV index >0.15 and TTP index >0.22.

Conclusions/Significance

The combination of severe ipsilateral carotid stenosis, 3 h SBP after CAS, rCBV index and TTP index provides a potential screening tool for predicting HPS in patients with unilateral carotid stenosis receiving CAS. In addition, adequate management of post-stenting blood pressure is the most important treatable factor in preventing HPS in these high risk patients.     

Effect of Satiation on Brain Activity in Obese and Lean Women

Objective: To investigate the response of the brains of women to the ingestion of a meal. Research Methods and Procedures: We used measures of regional cerebral blood flow (rCBF), a marker of neuronal activity, by positron emission tomography to describe the functional anatomy of satiation, i.e., the response to a liquid meal in the context of extreme hunger (36‐hour fast) in 10 lean (BMI ≤ 25 kg/m²; 32 ± 10 years old, 61 ± 7 kg; mean ± SD) and 12 obese (BMI ≥ 35 kg/m²; 30 ± 7 years old, 110 ± 14 kg) women. Results: In lean and obese women, satiation produced significant increases in rCBF in the vicinity of the prefrontal cortex (p < 0.005). Satiation also produced significant decreases in rCBF in several regions including the thalamus, insular cortex, parahippocampal gyrus, temporal cortex, and cerebellum (in lean and obese women), and hypothalamus, cingulate, nucleus accumbens, and amygdala (in obese women only; all p < 0.005). Compared with lean women, obese women had significantly greater increases in rCBF in the ventral prefrontal cortex and had significantly greater decreases in the paralimbic areas and in areas of the frontal and temporal cortex. Discussion: This study indicates that satiation elicits differential brain responses in obese and lean women. It also lends additional support to the hypothesis that the paralimbic areas participate in a central orexigenic network modulated by the prefrontal cortex through feedback loops.     

Comparison of Regional Cerebral Blood Flow Responses to Hypoglycemia Using Pulsed Arterial Spin Labeling and Positron Emission Tomography

Different brain regions sense and modulate the counterregulatory responses that can occur in response to declining plasma glucose levels. The aim of this study was to determine if changes in regional cerebral blood flow (rCBF) during hypoglycemia relative to euglycemia are similar for two imaging modalities–pulsed arterial spin labeling magnetic resonance imaging (PASL-MRI) and positron emission tomography (PET). Nine healthy non-diabetic participants underwent a hyperinsulinemic euglycemic (92±3 mg/dL) – hypoglycemic (53±1 mg/dL) clamp. Counterregulatory hormone levels were collected at each of these glycemic levels and rCBF measurements within the previously described network of hypoglycemia-responsive regions (thalamus, medial prefrontal cortex and globus pallidum) were obtained using PASL-MRI and [¹⁵O] water PET. In response to hypoglycemia, rCBF was significantly increased in the thalamus, medial prefrontal cortex, and globus pallidum compared to euglycemia for both PASL-MRI and PET methodologies. Both imaging techniques found similar increases in rCBF in the thalamus, medial prefrontal cortex, and globus pallidum in response to hypoglycemia. These brain regions may be involved in the physiologic and symptom responses to hypoglycemia. Compared to PET, PASL-MRI may provide a less invasive, less expensive method for assessing changes in rCBF during hypoglycemia without radiation exposure.