Axon fiber orientation as the source of T1 relaxation anisotropy in white matter: A study on corpus callosum in vivo and ex vivo.

PURPOSE: Recent studies indicate that T1 in white matter (WM) is influenced by fiber orientation in B0 . The purpose of the study was to investigate the interrelationships between axon fiber orientation in corpus callosum (CC) and T1 relaxation time in humans in vivo as well as in rat brain ex vivo. METHODS: Volunteers were scanned for relaxometric and diffusion MRI at 3 T and 7 T. Angular T1 plots from WM were computed using fractional anisotropy and fiber-to-field-angle maps. T1 and fiber-to-field angle were measured in five sections of CC to estimate the effects of inherently varying fiber orientations on T1 within the same tracts in vivo. Ex vivo rat-brain preparation encompassing posterior CC was rotated in B0 and T1 , and diffusion MRI images acquired at 9.4 T. T1 angular plots were determined at several rotation angles in B0 . RESULTS: Angular T1 plots from global WM provided reference for estimated fiber orientation-linked T1 changes within CC. In anterior midbody of CC in vivo, where small axons are dominantly present, a shift in axon orientation is accompanied by a change in T1 , matching that estimated from WM T1 data. In CC, where large and giant axons are numerous, the measured T1 change is about 2-fold greater than the estimated one. Ex vivo rotation of the same midsagittal CC region of interest produced angular T1 plots at 9.4 T, matching those observed at 7 T in vivo. CONCLUSION: These data causally link axon fiber orientation in B0 to the T1 relaxation anisotropy in WM.

Detection of lentiviral suicide gene therapy in C6 rat glioma using hyperpolarised [1-13 C]pyruvate.

Hyperpolarised [1-13 C]pyruvate MRI has shown promise in monitoring therapeutic efficacy in a number of cancers including glioma. In this study, we assessed the pyruvate response to the lentiviral suicide gene therapy of herpes simplex virus-1 thymidine kinase with the prodrug ganciclovir (HSV-TK/GCV) in C6 rat glioma and compared it with traditional MR therapy markers. Female Wistar rats were inoculated with 106 C6 glioma cells. Treated animals received intratumoural lentiviral HSV-TK gene transfers on days 7 and 8 followed by 2-week GCV therapy starting on day 10. Animals were repeatedly imaged during therapy using volumetric MRI, diffusion and relaxation mapping, as well as metabolic [1-13 C]pyruvate MRS imaging. Survival (measured as time before animals reached a humane endpoint and were euthanised) was assessed up to day 30 posttherapy. HSV-TK/GCV gene therapy lengthened the median survival time from 12 to 25 days. This was accompanied by an apparent tumour growth arrest, but no changes in diffusion or relaxation parameters in treated animals. The metabolic response was more evident in the case-by-case analysis than in the group-level analysis. Treated animals also showed a 37 ± 15% decrease (P < 0.05, n = 5) in lactate-to-pyruvate ratio between therapy weeks, whereas a 44 ± 18% increase (P < 0.05, n = 6) was observed in control animals. Hyperpolarised [1-13 C]pyruvate MRI can offer complementary metabolic information to traditional MR methods to give a more comprehensive picture of the slowly developing gene therapy response. This may benefit the detection of the successful therapy response in patients.

Determining T2 relaxation time and stroke onset relationship in ischaemic stroke within apparent diffusion coefficient-defined lesions. A user-independent method for quantifying the impact of stroke in the human brain.

BACKGROUND AND OBJECTIVE: In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions. METHODS: Six rats were subjected to permanent middle cerebral occlusion to induce focal ischaemia, and a consecutive cohort of acute stroke patients (n = 38) were recruited within 9 hours from symptom onset. T1-weighted structural, T2 relaxometry, and diffusion MRI for apparent diffusion coefficient (ADC) were acquired. Ischaemic lesions were defined as regions of lowered ADC. The median T2 difference (ΔT2) between lesion and contralateral non-ischaemic control region was determined by the newly-developed spherical reference method, and data compared to that obtained by the mirror reference method. Linear regressions and receiver operating characteristics (ROC) were compared between the two methods. RESULTS: ΔT2 increases linearly in rat brain ischaemia by 1.9 ± 0.8 ms/h during the first 6 hours, as determined by the spherical reference method. In patients, ΔT2 linearly increases by 1.6 ± 1.4 and 1.9 ± 0.9 ms/h in the lesion, as determined by the mirror reference and spherical reference method, respectively. ROC analyses produced areas under the curve of 0.83 and 0.71 for the spherical and mirror reference methods, respectively. CONCLUSIONS: Data from the spherical reference method showed that the median T2 increase in the ischaemic lesion is correlated with stroke onset time in a rat as well as in a human patient cohort, opening the possibility of using the approach as a timing tool in clinics.

Spontaneous BOLD waves - A novel hemodynamic activity in Sprague-Dawley rat brain detected by functional magnetic resonance imaging.

We report spontaneous hemodynamic activity termed "Spontaneous BOLD Waves" (SBWs) detected by BOLD fMRI in Sprague-Dawley rats under medetomidine anesthesia. These SBWs, which lasted several minutes, were observed in cortex, thalamus and hippocampus. The SBWs' correlates were undetectable in electrophysiological recordings, suggesting an exclusive gliovascular phenomenon dissociated from neuronal activity. SBWs were insensitive to the NMDA receptors antagonist MK-801 but were inhibited by the α1-adrenoceptor blocker prazosin. Since medetomidine is a potent agonist of α2 adrenoceptors, we suggested that imbalance in α1/α2 receptor-mediated signalling pathways alter the vascular reactivity leading to SBWs. The frequency of SBWs increased with intensity of mechanical lung ventilation despite the stable pH levels. In summary, we present a novel type of propagating vascular brain activity without easily detectable underlying neuronal activity, which can be utilized to study the mechanisms of vascular reactivity in functional and pharmacological MRI and has practical implications for designing fMRI experiments in anesthetized animals.

Detection of Hyperexcitability by Functional Magnetic Resonance Imaging after Experimental Traumatic Brain Injury.

Diagnosis of ongoing epileptogenesis and associated hyperexcitability after brain injury is a major challenge. Given that increased neuronal activity in the brain triggers a blood oxygenation level-dependent (BOLD) response in functional magnetic resonance imaging (fMRI), we hypothesized that fMRI could be used to identify the brain area(s) with hyperexcitability during post-injury epileptogenesis. We applied fMRI to detect onset and spread of BOLD activation after pentylenetetrazol (PTZ)-induced seizures (PTZ, 30 mg/kg, intraperitoneally) in 16 adult male rats at 2 months after lateral fluid percussion (FPI)-induced traumatic brain injury (TBI). In sham-operated controls, onset of the PTZ-induced BOLD response was bilateral and first appeared in the cortex. After TBI, 5 of 9 (56%) rats exhibited ipsilateral perilesional cortical BOLD activation, followed by activation of the contralateral cortex. In 4 of 9 (44%) rats, onset of BOLD response was bilateral. Interestingly, latency from the PTZ injection to onset of the BOLD response increased in the following order: sham-operated controls (ipsilateral 132 ± 57 sec, contralateral 132 ± 57 sec; p > 0.05) < TBI with bilateral BOLD onset (ipsilateral 176 ± 54 sec, contralateral 178 ± 52 sec; p > 0.05) < TBI with ipsilateral BOLD onset (ipsilateral 406 ± 178 sec, contralateral 509 ± 140 sec; p < 0.05). Cortical lesion area did not differ between rats with ipsilateral versus bilateral BOLD onset (p > 0.05). In the group of rats with ipsilateral onset of PTZ-induced BOLD activation, none of the rats showed a robust bilateral thalamic BOLD response, only 1 of 5 rats had robust ipsilateral thalamic calcifications, and 4 of 5 rats had perilesional astrocytosis. These findings suggest the evolution of the epileptogenic zone in the perilesional cortex after TBI, which is sensitive to PTZ-induced hyperexcitability. Further studies are warranted to explore the evolution of thalamo-cortical pathology as a driver of epileptogenesis after lateral FPI.

Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia.

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1 and T2 MRI relaxation times (qT1 and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT1 and qT2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT1 and qT2 relaxation times and the location and volume of abnormal qT1 and qT2 voxels within the lesion. Uncertainties associated with onset time estimates of qT1 and qT2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT1 and qT2 lesion volumes, termed 'Voverlap' (± 25 min) or by quantifying hemispheric differences in qT2 relaxation times only (± 28 min). Overall, qT2 derived parameters outperform those from qT1. The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

A Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia.

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1 and T2 MRI relaxation times (qT1 and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT1 and qT2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT1 and qT2 relaxation times and the location and volume of abnormal qT1 and qT2 voxels within the lesion. Uncertainties associated with onset time estimates of qT1 and qT2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT1 and qT2 lesion volumes, termed 'Voverlap' (± 25 min) or by quantifying hemispheric differences in qT2 relaxation times only (± 28 min). Overall, qT2 derived parameters outperform those from qT1. The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

Stroke Onset Time Determination Using MRI Relaxation Times without Non-Ischaemic Reference in A Rat Stroke Model.

BACKGROUND: Objective timing of stroke in emergency departments is expected to improve patient stratification. Magnetic resonance imaging (MRI) relaxations times, T2 and T1ρ , in abnormal diffusion delineated ischaemic tissue were used as proxies of stroke time in a rat model. METHODS: Both 'non-ischaemic reference'-dependent and -independent estimators were generated. Apparent diffusion coefficient (ADC), T2 and T1ρ , were sequentially quantified for up to 6 hours of stroke in rats (n = 8) at 4.7T. The ischaemic lesion was identified as a contiguous collection of voxels with low ADC. T2 and T1ρ in the ischaemic lesion and in the contralateral non-ischaemic brain tissue were determined. Differences in mean MRI relaxation times between ischaemic and non-ischaemic volumes were used to create reference-dependent estimator. For the reference-independent procedure, only the parameters associated with log-logistic fits to the T2 and T1ρ distributions within the ADC-delineated lesions were used for the onset time estimation. RESULT: The reference-independent estimators from T2 and T1ρ data provided stroke onset time with precisions of ±32 and ±27 minutes, respectively. The reference-dependent estimators yielded respective precisions of ±47 and ±54 minutes. CONCLUSIONS: A 'non-ischaemic anatomical reference'-independent estimator for stroke onset time from relaxometric MRI data is shown to yield greater timing precision than previously obtained through reference-dependent procedures.

Protective Effects and Magnetic Resonance Imaging Temperature Mapping of Systemic and Focal Hypothermia in Cerebral Ischemia.

BACKGROUND AND PURPOSE: Hypothermia is potentially the most effective protective therapy for brain ischemia; however, its use is limited because of serious side effects. Although focal hypothermia (FH) has a significantly lower stress profile than systemic hypothermia (SH), its efficacy in ischemia has been poorly studied. We aimed to compare the therapeutic effects of each treatment on various short- and long-term clinically relevant end points. METHODS: Sprague-Dawley rats were subjected to transient (45 minutes) occlusion of the middle cerebral artery. One hour after arterial reperfusion, animals were randomly assigned to groups for treatment with SH or FH (target temperature: 32°C) for 4 or 24 hours. Lesion volume, edema, functional recovery, and histological markers of cellular injury were evaluated for 1 month after ischemic injury. Effects of SH and FH on cerebral temperature were also analyzed for the first time by magnetic resonance thermometry, an approach that combines spectroscopy with gradient-echo-based phase mapping. RESULTS: Both therapeutic approaches reduced ischemic lesion volume (P<0.001), although a longer FH treatment (24 hours) was required to achieve similar protective effects to those induced by 4 hours of SH. In addition, magnetic resonance thermometry demonstrated that systemic hypothermia reduced whole-brain temperature, whereas FH primarily reduced the temperature of the ischemic region. CONCLUSIONS: Focal brain hypothermia requires longer cooling periods to achieve the same protective efficacy as SH. However, FH mainly affects the ischemic region, and therefore represents a promising and nonstressful alternative to SH.

A spatiotemporal theory for MRI T2 relaxation time and apparent diffusion coefficient in the brain during acute ischaemia: Application and validation in a rat acute stroke model.

The objective of this study is to present a mathematical model which can describe the spatiotemporal progression of cerebral ischaemia and predict magnetic resonance observables including the apparent diffusion coefficient (ADC) of water and transverse relaxation time T2 This is motivated by the sensitivity of the ADC to the location of cerebral ischaemia and T2 to its time-course, and that it has thus far proven challenging to relate observations of changes in these MR parameters to stroke timing, which is of considerable importance in making treatment choices in clinics. Our mathematical model, called the cytotoxic oedema/dissociation (CED) model, is based on the transit of water from the extra- to the intra-cellular environment (cytotoxic oedema) and concomitant degradation of supramacromolecular and macromolecular structures (such as microtubules and the cytoskeleton). It explains experimental observations of ADC and T2, as well as identifying the rate of spread of effects of ischaemia through a tissue as a dominant system parameter. The model brings the direct extraction of the timing of ischaemic stroke from quantitative MRI closer to reality, as well as providing insight on ischaemia pathology by imaging in general. We anticipate that this may improve patient access to thrombolytic treatment as a future application.

Involvement of NMDA receptor subtypes in cortical spreading depression in rats assessed by fMRI.

Cortical spreading depression (CSD) is a phenomenon implicated in migraine with aura and associated with other neurological disorders (e.g. stroke, brain trauma). Current evidence points to the essential role of NMDA receptors in CSD mechanisms. However, the roles of multiple subunits of NMDA receptors expressed in neurons, glia and blood vessels in vivo, are little explored. Using BOLD fMRI of urethane anesthetized rats as an integrative CSD readout, we tested the involvement of different NMDA receptor subtypes in CSD induction and propagation. Rats were treated with a non-selective NMDA blocker (MK-801), NR2B antagonist (ifenprodil) or a NR2A selective antagonist (TCN-201). CSD was induced during fMRI scanning by application of KCl onto the cerebral cortex and fMRI data were collected by 9.4 T MRI. The non-specific NMDA antagonist MK-801 completely blocked CSD, which was not observed in the NR2A group where TCN-201 did not alter the CSD features. Unexpectedly, the NR2B specific antagonist ifenprodil largely promoted the initial negative phase of the BOLD CSD response, likely due to altered neurovascular coupling. Our data suggest key roles and differential involvement of NMDA receptor subtypes in CSD generation and propagation, highlighting an important role for the NR2B subtype.

Measurement of T1 relaxation time of osteochondral specimens using VFA-SWIFT.

PURPOSE: To evaluate the feasibility of SWIFT with variable flip angle (VFA) for measurement of T1 relaxation time in Gd-agarose-phantoms and osteochondral specimens, including regions of very short T2 *, and compare with T1 measured using standard methods METHODS: T1 s of agarose phantoms with variable concentration of Gd-DTPA2- and nine pairs of native and trypsin-treated bovine cartilage-bone specimens were measured. For specimens, VFA-SWIFT, inversion recovery (IR) fast spin echo (FSE) and saturation recovery FSE were used. For phantoms, additionally spectroscopic IR was used. Differences and agreement between the methods were assessed using nonparametric Wilcoxon and Kruskal-Wallis tests and intraclass correlation. RESULTS: The different T1 mapping methods agreed well in the phantoms. VFA-SWIFT allowed reliable measurement of T1 in the osteochondral specimens, including regions where FSE-based methods failed. The T1 s measured by VFA-SWIFT were shifted toward shorter values in specimens. However, the measurements correlated significantly (highest correlation VFA-SWIFT versus FSE was r = 0.966). SNR efficiency was generally highest for SWIFT, especially in the subchondral bone. CONCLUSION: Feasibility of measuring T1 relaxation time using VFA-SWIFT in osteochondral specimens and phantoms was demonstrated. A shift toward shorter T1 s was observed for VFA-SWIFT in specimens, reflecting the higher sensitivity of SWIFT to short T2 * spins. Magn Reson Med 74:175-184, 2015. © 2014 Wiley Periodicals, Inc.

Ultrasound imaging with bolus delivered contrast agent for the detection of angiogenesis and blood flow irregularities.

Highly increased blood flow and vascularity after angiogenic gene therapy have raised concerns of shunting and hemangioma-like blood pool formation that might decrease effective perfusion and ruin the beneficial effects of the therapy. Contrast enhanced ultrasound is a promising noninvasive tool for studying skeletal muscle perfusion. The objectives of the present study were to test bolus and infusion administrations of ultrasound microbubble contrast media in imaging vascular growth in skeletal muscle and assess the functionality of vessels grown with angiogenic gene therapy. Contrast enhanced ultrasound was used to study changes in skeletal muscle perfusion in normal and gene-transduced rabbit hindlimbs 6 days after gene transfer. Adenoviral gene transfer of VEGF (10e(9)-10e(11) viral particles) or ß-galactosidase control gene (10e(11) viral particles) was done under anesthesia and induced up to 16-fold increases in relative tissue perfusion. Contrast intensity versus time curves were plotted and analyzed for contrast kinetics. Bolus administration of the contrast media was highly feasible in analyzing skeletal muscle blood flow and its kinetics. Maximal signal intensity of the bolus signal reflected relative changes in both blood flow and volume equally to the infusion method. Flow irregularities were detected after angiogenic gene therapy. In conclusion, bolus delivery of ultrasound contrast agent is highly feasible for the relative analysis of both quantity and quality of blood flow after angiogenic gene therapy. The kinetics of blood flow can and should be studied more extensively in both preclinical and clinical trials of angiogenic gene therapy since there is increasing evidence of flow irregularities in angiogenic vessels.

Timing the ischaemic stroke by 1H-MRI: improved accuracy using absolute relaxation times over signal intensities.

One in four ischaemic stroke patients are ineligible for thrombolytic treatment due to unknown onset time. Quantification of absolute MR relaxation times and signal intensities are potential methods for estimating stroke duration. We compared the accuracy of these approaches and determined whether changes in relaxation times and signal intensities identify the same ischaemic tissue as diffusion MRI. Seven Wistar rats underwent permanent middle cerebral artery occlusion to induce focal ischaemia and were scanned at six time points. The trace of the diffusion tensor (DAV), T1ρ and T2 were acquired at 4.7 T. Results show relaxation times, and signal intensities of the MR relaxation parameters increase linearly with ischaemia duration (P<0.001). Using T1ρ and T2 relaxation times, an estimate of 4.5 h after occlusion has an uncertainty of ± 12 and ± 35 min, respectively, compared with over 50 min for signal intensities. In addition, we present a pixel-by-pixel method that simultaneously estimates stroke onset time and identifies potentially irreversible ischaemic tissue using absolute relaxation times. This method demonstrates signal intensity changes during ischaemia display an ambiguous pattern and highlights the possibility that diffusion MRI overestimates the true extent of irreversible ischaemia. In conclusion, quantification of absolute relaxation times at a single time point enables a more accurate estimation of stroke duration than signal intensities and provides more information about tissue status in ischaemia.

Parenchymal spin-lock fMRI signals associated with cortical spreading depression.

We found novel types of parenchymal functional magnetic resonance imaging (fMRI) signals in the rat brain during large increases in metabolism. Cortical spreading depression (CSD), a self-propagating wave of cellular activation, is associated with several pathologic conditions such as migraine and stroke. It was used as a paradigm to evoke transient neuronal depolarization leading to enhanced energy consumption. Activation of CSD was investigated using spin-lock (SL), diffusion, blood oxygenation level-dependent and cerebral blood volume fMRI techniques. Our results show that the SL-fMRI signal is generated by endogenous parenchymal mechanisms during CSD propagation, and these mechanisms are not associated with hemodynamic changes or cellular swelling. Protein phantoms suggest that pH change alone does not explain the observed SL-fMRI signal changes. However, increased amounts of inorganic phosphates released from high-energy phosphates combined with pH changes may produce SL- power-dependent longitudinal relaxation in the rotating frame (R1ρ) changes in protein phantoms that are similar to those observed during CSD, as seen before in acute ischemia under our experimental conditions. This links SL-fMRI changes intimately to energy metabolism and supports the use of the SL technique as a new, promising functional approach for noninvasive imaging of metabolic transitions in the active or pathologic brain.

Relaxation along a fictitious field (RAFF) and Z-spectroscopy using alternating-phase irradiation (ZAPI) in permanent focal cerebral ischemia in rat.

Cerebral ischemia alters the molecular dynamics and content of water in brain tissue, which is reflected in NMR relaxation, diffusion and magnetization transfer (MT) parameters. In this study, the behavior of two new MRI contrasts, Relaxation Along a Fictitious Field (RAFF) and Z-spectroscopy using Alternating-Phase Irradiation (ZAPI), were quantified together with conventional relaxation parameters (T1, T2 and T1ρ) and MT ratios in acute cerebral ischemia in rat. The right middle cerebral artery was permanently occluded and quantitative MRI data was acquired sequentially for the above parameters for up to 6 hours. The following conclusions were drawn: 1) Time-dependent changes in RAFF and T1ρ relaxation are not coupled to those in MT. 2) RAFF relaxation evolves more like transverse, rather than longitudinal relaxation. 3) MT measured with ZAPI is less sensitive to ischemia than conventional MT. 4) ZAPI data suggest alterations in the T2 distribution of macromolecules in acute cerebral ischemia. It was shown that both RAFF and ZAPI provide complementary MRI information from acute ischemic brain tissue. The presented multiparametric MRI data may aid in the assessment of brain tissue status early in ischemic stroke.

Monitoring functional impairment and recovery after traumatic brain injury in rats by FMRI.

The present study was designed to test a hypothesis that functional magnetic resonance imaging (fMRI) can be used to monitor functional impairment and recovery after moderate experimental traumatic brain injury (TBI). Moderate TBI was induced by lateral fluid percussion injury in adult rats. The severity of brain damage and functional recovery in the primary somatosensory cortex (S1) was monitored for up to 56 days using fMRI, cerebral blood flow (CBF) by arterial spin labeling, local field potential measurements (LFP), behavioral assessment, and histology. All the rats had reduced blood-oxygen-level-dependent (BOLD) responses during the 1st week after trauma in the ipsilateral S1. Forty percent of these animals showed recovery of the BOLD response during the 56 day follow-up. Unexpectedly, no association was found between the recovery in BOLD response and the volume of the cortical lesion or thalamic neurodegeneration. Instead, the functional recovery occurred in rats with preserved myelinated fibers in layer VI of S1. This is, to our knowledge, the first study demonstrating that fMRI can be used to monitor post-TBI functional impairment and consequent spontaneous recovery. Moreover, the BOLD response was associated with the density of myelinated fibers in the S1, rather than with neurodegeneration. The present findings encourage exploration of the usefulness of fMRI as a noninvasive prognostic biomarker for human post-TBI outcomes and therapy responses.

Simultaneous BOLD fMRI and local field potential measurements during kainic acid-induced seizures.

PURPOSE: To investigate how kainic acid-induced epileptiform activity is related to hemodynamic changes probed by blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI). METHODS: Epileptiform activity was induced with kainic acid (KA) (10 mg/kg, i.p.), and simultaneous fMRI at 7 Tesla, and deep electrode local field potential (LFP) recordings were performed from the right hippocampus in awake and medetomidine-sedated adult Wistar rats. KEY FINDINGS: Recurrent seizure activity induced by KA was detected in LFP both in medetomidine-sedated and awake rats, even though medetomidine sedation reduced the mean duration of individual seizures as compared to awake rats (33 ± 24 and 46 ± 34 s, respectively, mean ± SD p < 0.01). KA administration also triggered robust positive BOLD responses bilaterally in the hippocampus both in awake and medetomidine-sedated rats; however, in both animal groups some of the seizures detected in LFP recording did not cause detectable BOLD signal change. SIGNIFICANCE: Our data suggest that medetomidine sedation can be used for simultaneous fMRI and electrophysiologic studies of normal and epileptic brain function, even though seizure duration after medetomidine administration was shorter than that in awake animals. The results also indicate that neuronal activity and BOLD response can become decoupled during recurrent kainic acid-induced seizures, which may have implications to interpretation of fMRI data obtained during prolonged epileptiform activity.

NMR relaxation times of trabecular bone-reproducibility, relationships to tissue structure and effects of sample freezing.

Nuclear magnetic resonance (NMR) spectroscopy provides a potential tool for non-invasive evaluation of the trabecular bone structure. The objective of this study was to determine the reproducibility of the NMR relaxation parameters (T(2), Carr-Purcel-T(2), T(1ρ)) for fat and water and relate those to the structural parameters obtained by micro-computed tomography (µCT). Especially, we aimed to evaluate the effect of freezing on the relaxation parameters. For storing bone samples, freezing is the standard procedure during which the biochemical and cellular organization of the bone marrow may be affected. Bovine trabecular bone samples were stored at -20 °C for 7 days and measured by NMR spectroscopy before and after freezing. The reproducibility of NMR relaxation parameters, as expressed by the coefficient of variation, ranged from 3.1% to 27.9%. In fresh samples, some correlations between NMR and structural parameters (Tb.N, Tb.Sp) were significant (e.g. the relaxation rate for T(2) of fat versus Tb.Sp: r = -0.716, p < 0.01). Freezing did not significantly change the NMR relaxation times but the correlations between relaxation parameters and the µCT structural parameters were not statistically significant after freezing, suggesting some nonsystematic alterations of the marrow structure. Therefore, the use of frozen bone samples for NMR relaxation studies may provide inferior information about the trabecular bone structure.

Estimation of the onset time of cerebral ischemia using T1rho and T2 MRI in rats.

BACKGROUND AND PURPOSE: Time of ischemia onset is the most critical factor for patient selection for available drug treatment strategies. The purpose of this study was to evaluate the abilities of the absolute longitudinal rotating frame (T(1ρ)) and transverse (T(2)) MR relaxation times to estimate the onset time of ischemia in rats. METHODS: Permanent middle cerebral artery occlusion in rats was used to induce focal cerebral ischemia and animals were imaged with multiparametric MRI at several time points up to 7 hours postischemia. Ischemic parenchyma was defined as tissue with apparent diffusion coefficient of water <70% from that in the contralateral nonischemic brain. RESULTS: The difference in the absolute T(1ρ) and T(2) between ischemic and contralateral nonischemic striatum increased linearly within the first 6 hours of middle cerebral artery occlusion. The slopes for T(1ρ) and T(2) fits for both tissue types were similar; however, the time offsets were significantly longer for both MR parameters in the cortex than in the striatum. CONCLUSIONS: T(1ρ) and T(2) MRI provide estimates for the onset time of cerebral ischemia requiring regional calibration curves from ischemic brain. Assuming that patients with suspected ischemic stroke are scanned by MRI within this timeframe, these MRI techniques may constitute unbiased tools for stroke onset time evaluation potentially aiding the decision-making for drug treatment strategies.