Comparison of fast Fourier transform infrared spectroscopy biotyping with whole genome sequencing-based genotyping in common nosocomial pathogens.

Early detection of bacterial transmission and outbreaks in hospitals is important because nosocomial infections can result in health complications and longer hospitalization. Current practice to detect outbreaks uses genotyping methods amplified fragment length polymorphism (AFLP) and whole genome sequencing (WGS), which are not suitable methods for real-time transmission screening of both susceptible and resistant bacteria. The aim was to assess the typing technique Fourier transform infrared (FTIR) spectroscopy as real-time screening method to discriminate large amounts of susceptible and resistant bacteria at strain level when there is no evident outbreak in comparison with the WGS reference. Isolates of past hospital outbreak strains of Acinetobacter baumannii/calcoaceticus complex (n = 25), Escherichia coli (n = 31), Enterococcus faecium (n = 22), Staphylococcus aureus (n = 37) and Pseudomonas aeruginosa (n = 30) were used for validation of FTIR. Subsequently, Enterococcus faecalis (n = 106) and Enterococcus faecium (n = 104) isolates from weekly routine screening samples when no potential outbreak was present were analysed. FTIR showed reproducibility and congruence of cluster composition with WGS for A. baumannii/calcoaceticus complex and E. faecium outbreak isolates. The FTIR results of E. faecalis and E. faecium isolates from routine samples showed reproducibility, but the congruence of cluster composition with WGS was low. For A. baumannii/calcoaceticus complex and E. faecium outbreak isolates, FTIR appears to be a discriminatory typing tool. However, our study shows the discriminatory power is too low to screen real-time for transmission of E. faecium and E. faecalis at patient wards based on isolates acquired in routine surveillance cultures when there is no clear suspicion of an ongoing outbreak.

Idiopathic acute myocarditis during treatment for controlled human malaria infection: a case report.

A 23-year-old healthy male volunteer took part in a clinical trial in which the volunteer took chloroquine chemoprophylaxis and received three intradermal doses at four-week intervals of aseptic, purified Plasmodium falciparum sporozoites to induce protective immunity against malaria. Fifty-nine days after the last administration of sporozoites and 32 days after the last dose of chloroquine the volunteer underwent controlled human malaria infection (CHMI) by the bites of five P. falciparum-infected mosquitoes. Eleven days post-CHMI a thick blood smear was positive (6 P. falciparum/µL blood) and treatment was initiated with atovaquone/proguanil (Malarone®). On the second day of treatment, day 12 post-CHMI, troponin T, a marker for cardiac tissue damage, began to rise above normal, and reached a maximum of 1,115 ng/L (upper range of normal = 14 ng/L) on day 16 post-CHMI. The volunteer had one ~20 minute episode of retrosternal chest pain and heavy feeling in his left arm on day 14 post-CHMI. ECG at the time revealed minor repolarization disturbances, and cardiac MRI demonstrated focal areas of subepicardial and midwall delayed enhancement of the left ventricle with some oedema and hypokinesia. A diagnosis of myocarditis was made. Troponin T levels were normal within 16 days and the volunteer recovered without clinical sequelae. Follow-up cardiac MRI at almost five months showed normal function of both ventricles and disappearance of oedema. Delayed enhancement of subepicardial and midwall regions decreased, but was still present. With the exception of a throat swab that was positive for rhinovirus on day 14 post-CHMI, no other tests for potential aetiologies of the myocarditis were positive. A number of possible aetiological factors may explain or have contributed to this case of myocarditis including, i) P. falciparum infection, ii) rhinovirus infection, iii) unidentified pathogens, iv) hyper-immunization (the volunteer received six travel vaccines between the last immunization and the CHMI), v) atovaquone/proguanil treatment, or vi) a combination of these factors. Definitive aetiology and pathophysiological mechanism for the myocarditis have not been established.

Extent of bilateral neuronal network reorganization and functional recovery in relation to stroke severity.

Remodeling of neuronal structures and networks is believed to significantly contribute to (partial) restoration of functions after stroke. However, it has been unclear to what extent the brain reorganizes and how this correlates with functional recovery in relation to stroke severity. We applied serial resting-state functional MRI and diffusion tensor imaging together with behavioral testing to relate longitudinal modifications in functional and structural connectivity of the sensorimotor neuronal network to changes in sensorimotor function after unilateral stroke in rats. We found that gradual improvement of functions is associated with wide-ranging changes in functional and structural connectivity within bilateral neuronal networks, particularly after large stroke. Both after medium and large stroke, brain reorganization eventually leads to (partial) normalization of neuronal signal synchronization within the affected sensorimotor cortical network (intraregional signal coherence), as well as between the affected and unaffected sensorimotor cortices (interhemispheric functional connectivity). Furthermore, the bilateral network configuration shifts from subacutely increased "small-worldness," possibly reflective of initial excessive neuronal clustering and wiring, toward a baseline small-world topology, optimal for global information transfer and local processing, at chronic stages. Cortical network remodeling was accompanied by recovery of initially disrupted structural integrity in corticospinal tract regions, which correlated positively with retrieval of sensorimotor functions. Our study demonstrates that the degree of functional recovery after stroke is associated with the extent of preservation or restoration of ipsilesional corticospinal tracts in combination with reinstatement of interhemispheric neuronal signal synchronization and normalization of small-world cortical network organization.

No difference in bacterial contamination of hip capsule sutures and control sutures in hip arthroplasty surgery.

BACKGROUND: Perioperative preventive measures are important to further reduce the rate of periprosthetic joint infections (PJI) in patients undergoing total hip arthroplasty (THA). During THA surgery, joint capsule sutures are commonly placed to optimize exposure and reinsertion of the capsule. Bacterial contamination of these sutures during the procedure poses a potential risk for postoperative infection. In this exploratory study, we assessed the contamination rate of capsule sutures compared to the contamination of the remains of exchanged control sutures at the time of closure. METHODS: In 100 consecutive patients undergoing primary THA capsule sutures were exchanged by sterile sutures at the time of capsule closure. Both the original sutures and the remainder of the newly placed (control) sutures were retrieved, collected and cultured for ten days. Types of bacterial growth and contamination rates of both sutures were assessed. RESULTS: Sutures from 98 patients were successfully collected and analyzed. Bacterial growth was observed in 7/98 (7.1%) of the capsule sutures versus 6/98 (6.1%) of the control sutures, with a difference of 1% [CI -6-8]. There was no clear pattern in differences in subtypes of bacteria between groups. CONCLUSIONS: This study showed that around 7% of capsule sutures used in primary THA were contaminated with bacteria and as such exchange by new sutures at the time of capsule closure could be an appealing PJI preventive measure. However, since similar contamination rates were encountered with mainly non-virulent bacteria for both suture groups, the PJI preventive effect of this measure appears to be minimal.

Impact of hemodynamic effects on diffusion-weighted fMRI signals.

In some recent studies, diffusion weighted functional MRI has been proposed to provide contrast immune to vascular changes. Increases in relative signal change during neuronal activation observed under increasing diffusion weighting support the possible diffusion based origin of this contrast. A recent diffusion tensor imaging (DTI) study has also reported the use of Fractional Anisotropy (FA) to track activation in white matter. In this study we aimed to establish if relatively high diffusion weighting (b=1200 and 1800 s/mm(2)) eliminates the strong vascular influences brought about by 100% O(2) and carbogen (95%O(2)+5% CO(2)) induced vascular challenges in gray matter (GM) and white matter (WM) of rat brain. We also aimed to characterize the influences of these vascular changes on FA, both in GM and in WM. Our study endorses previous reports that even relatively heavily diffusion weighted data can be significantly influenced by hemodynamic changes. However, this was not only observed in GM, but also in WM. Moreover, our study demonstrates that the estimator used to calculate the relative changes should be carefully chosen in order to avoid biases at low signal-to-noise ratios (SNRs) which accompany increasing diffusion weighting. With the use of robust estimators, we found no increases in relative change with increasing b-value during both vascular challenges. Our data also demonstrate that FA can be significantly influenced by hemodynamics, both in GM and in WM. The observed influence of diffusion weighting direction on relative signal change in GM was shown to be associated with structural differences among various regions. If diffusion based functional contrasts immune to hemodynamics do exist, our results highlight the difficulty in discerning those diffusion changes from accompanying vascular changes.

The concordance between preoperative synovial fluid culture and intraoperative tissue cultures in periprosthetic joint infection: a systematic review.

Background: this systematic review aims to evaluate the concordance between preoperative synovial fluid culture and intraoperative tissue cultures in patients with periprosthetic joint infection (PJI) undergoing total hip (THA) or knee arthroplasty (TKA) revision surgery. Methods: this review was conducted in accordance with the preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies (PRISMA-DTA) statement. Cochrane, Embase, PubMed, and Web of Science databases were searched to identify studies involving patients who had THA or TKA revision surgery for PJI and for whom preoperative synovial fluid culture and intraoperative tissue cultures were performed. Studies were only included if the diagnosis of PJI was based on the EBJIS (the European Bone and Joint Infection Society) or MSIS (Musculoskeletal Infection Society) criteria. Risk of bias was assessed using an amended version of Joanna Briggs Institute's (JBI) critical appraisal checklist for case series. Results: seven studies were included in this review comprising 1677 patients. All studies had a retrospective study design and five studies explored patients undergoing revision surgery of THA or TKA. Concordance rates varied between 52 % and 79 %, but different authors defined and calculated concordance differently. Six studies were judged as having an unclear to high risk of bias and one study as having a low risk of bias. Conclusions: the included studies showed a wide range of concordance rates between preoperative synovial fluid culture and intraoperative tissue cultures and the majority of studies had a high risk of bias. Higher-quality studies are warranted to obtain a more accurate estimate of this concordance rate. We recommend continuing the use of a system such as the EBJIS definition or MSIS criteria when diagnosing PJI.

Capnocytophaga canimorsus Mycotic Aortic Aneurysm After a Dog Bite.

Introduction: Mycotic aortic aneurysm is defined as dilatation of the aortic wall due to infection caused by a variety of microorganisms and is associated with high mortality rates. This case report describes a patient with a rapid growing mycotic infrarenal aneurysm caused by Capnocytophaga canimorsus following a dog bite. Report: A 61 year old male professional dog handler presented with a history of progressive abdominal pain and constitutional symptoms. He had been bitten by a Pit Bull Terrier dog that was attacking a young girl three weeks prior to the onset of complaints. Investigations revealed a mycotic infrarenal aortic aneurysm that grew 0.5 cm in only three days. Open surgical repair consisting of an infrarenal aorto-aortic bypass with a 21 mm × 15 cm bovine bioprosthesis was performed successfully. All cultures and biopsies were negative and the subsequent 16S-23S rRNA intergenic spacer region based polymerase chain reaction (IS-pro) technique revealed C. canimorsus, a Gram negative bacterial pathogen that lives as a commensal in the gingival flora of dogs and cats that can cause a variety of severe infections, as the causative agent. Identification made it possible to treat the patient with eight weeks of intravenous followed by four weeks of oral antibiotics. At the last follow up over a year after surgery, the patient was symptom free, without infection and on ultrasound examination there were no signs of complications or aneurysm formation. Discussion: This case highlights C. canimorsus as a rare cause of a rapid growing mycotic aortic aneurysm following a dog bite. 16S-23S rRNA profiling (IS-pro) led to the identification of the bacterial pathogen. The use of biological grafts should be considered in the management of mycotic aortic aneurysms.

Recovery of sensorimotor function after experimental stroke correlates with restoration of resting-state interhemispheric functional connectivity.

Despite the success of functional imaging to map changes in brain activation patterns after stroke, spatiotemporal dynamics of cerebral reorganization in correlation with behavioral recovery remain incompletely characterized. Here, we applied resting-state functional magnetic resonance imaging (rs-fMRI) together with behavioral testing to longitudinally assess functional connectivity within neuronal networks, in relation to changes in associated function after unilateral stroke in rats. Our specific goals were (1) to identify temporal alterations in functional connectivity within the bilateral cortical sensorimotor system and (2) to elucidate the relationship between those alterations and changes in sensorimotor function. Our study revealed considerable loss of functional connectivity between ipsilesional and contralesional primary sensorimotor cortex regions, alongside significant sensorimotor function deficits in the first days after stroke. The interhemispheric functional connectivity restored in the following weeks, but remained significantly reduced up to 10 weeks after stroke in animals with lesions that comprised subcortical and cortical tissue, whereas transcallosal neuroanatomical connections were preserved. Intrahemispheric functional connectivity between primary somatosensory and motor cortex areas was preserved in the lesion border zone and moderately enhanced contralesionally. The temporal pattern of changes in functional connectivity between bilateral primary motor and somatosensory cortices correlated significantly with the evolution of sensorimotor function scores. Our study (1) demonstrates that poststroke loss and recovery of sensorimotor function is associated with acute deterioration and subsequent retrieval of interhemispheric functional connectivity within the sensorimotor system and (2) underscores the potential of rs-fMRI to assess spatiotemporal characteristics of functional brain reorganization that may underlie behavioral recovery after brain injury.

Temporal scaling properties and spatial synchronization of spontaneous blood oxygenation level-dependent (BOLD) signal fluctuations in rat sensorimotor network at different levels of isoflurane anesthesia.

Spontaneous fluctuations in the blood oxygenation level-dependent (BOLD) MRI signal during the resting state are increasingly being studied in healthy and diseased brain in humans and animal models. Yet, the relationship between functional brain status and the characteristics of spontaneous BOLD fluctuations remains poorly understood. In order to obtain more insights into this relationship and, in particular, the effects of anesthesia thereupon, we investigated the spatial and temporal correlations of spontaneous BOLD fluctuations in somatosensory and motor regions of rat brain at different inhalation levels of the frequently applied anesthetic isoflurane. We found that the temporal scaling, characterized by the Hurst exponent (H), showed persistent behavior (H > 0.5) at 0.5-1.0% isoflurane. Furthermore, low-pass-filtered spontaneous BOLD oscillations were correlated significantly in bilateral somatosensory and bilateral motor cortices, reflective of interhemispheric functional connectivity. Under 2.9% isoflurane anesthesia, the temporal scaling characteristics approached those of Gaussian white noise (H = 0.5), the relative amplitude of BOLD low-frequency fluctuations declined, and cross-correlations of these oscillations between functionally connected regions decreased significantly. Loss of interhemispheric functional connectivity at 2.9% isoflurane anesthesia was stronger between bilateral motor regions than between bilateral somatosensory regions, which points to distinct effects of anesthesia on differentially organized neuronal networks. Although we cannot completely rule out a possible contribution from hemodynamic signals with a non-neuronal origin, our results emphasize that spatiotemporal characteristics of spontaneous BOLD fluctuations are related to the brain's specific functional status and network organization, and demonstrate that these are largely preserved under light to mild anesthesia with isoflurane.

Mortality related to Verona Integron-encoded Metallo-ß-lactamase-positive Pseudomonas aeruginosa: assessment by a novel clinical tool.

Background: Verona Integron-encoded Metallo-ß-lactamase-positive Pseudomonas aeruginosa (VIM-PA) can cause nosocomial infections and may be responsible for increased mortality. Multidrug resistance in VIM-PA complicates treatment. We aimed to assess the contribution of VIM-PA to mortality in patients in a large tertiary care hospital in the Netherlands. Methods: A focus group of five members created a scheme to define related mortality based on clinical and diagnostic findings. Contribution to mortality was categorized as "definitely", "probably", "possibly", or "not" related to infection with VIM-PA, or as "unknown". Patients were included when infected with or carrier of VIM-PA between January 2008 and January 2016. Patient-related data and specific data on VIM-PA cultures were retrieved from the electronic laboratory information system. For patients who died in our hospital, medical records were independently reviewed and thereafter discussed by three physicians. Results: A total of 198 patients with any positive culture with VIM-PA were identified, of whom 95 (48.0%) died. Sixty-seven patients died in our hospital and could be included in the analysis. The death of 15 patients (22.4%) was judged by all reviewers to be definitely related to infection with VIM-PA. In 17 additional patients (25.4%), death was probably or possibly related to an infection with VIM-PA. The level of agreement was 65.7% after the first evaluation, and 98.5% after one session of discussion. Conclusion: Using our assessment tool, infections with VIM-PA were shown to have an important influence on mortality in our complex and severely ill patients. The tool may be used for other (resistant) bacteria as well but this needs further exploration.

Functional MRI of delayed chronic lithium treatment in rat focal cerebral ischemia.

BACKGROUND AND PURPOSE: The use of lithium as a neuroprotective agent has been demonstrated using various models in which improvements in infarct size, DNA damage, and neurological function were reported. We further investigated neurohemodynamic aspects of the treatment-associated recovery by assessing the therapeutic efficacy of delayed chronic lithium treatment using functional MRI. METHODS: Ipsilesional functional MRI activations in the somatosensory cortex, acquired 2 weeks after the 90-minute transient middle cerebral artery occlusion, were compared between lithium- and saline-treated rats. Specifically, MRI signal changes based on blood oxygenation level dependence and functional cerebral blood volume responses were examined using electrical stimulation of forelimbs. Additional immunohistochemical assays were performed. RESULTS: The ratio of ipsilesional to contralesional blood oxygenation level dependence response magnitudes significantly improved with lithium treatments. In contrast, the increase of the functional cerebral blood volume response magnitude ratio was not statistically significant. Nonetheless, the lithium treatment induced significant enhancements of total functional MRI activation (defined as a product of activation volume and response magnitude) for both blood oxygenation level dependence and functional cerebral blood volume methods. Increased cerebral blood volume in periinfarct tissues suggests a possible stroke-induced vascular transformation in both saline- and lithium-treated rats; however, other MRI-derived vascular parameters (vascular size index and microvascular volume) and immunohistochemical staining (CD31, glia fibrillary-associated protein, and matrix metalloproteinase-9) may imply that the neoformation of vasculature was differently affected by the lithium treatment. CONCLUSIONS: The delayed chronic lithium treatment enhanced the blood oxygenation level dependence functional MRI response magnitude in the absence of neurological improvement and influenced vascular formation in poststroke animal models.

[Infections during glucocorticoid use]. / Infecties bij gebruik van glucocorticoïden.

Glucocorticoid treatment increases the risk of opportunistic infection. Infections that can arise during glucocorticoid use, and for which preventative measures can be taken, include reactivation of latent tuberculosis and hepatitis B, pneumococcal and Pneumocystis jiroveci pneumonia, influenza, herpes zoster and Strongyloides stercoralis hyperinfection syndrome. The risk of such infections depends upon the duration of glucocorticoid use and dosage, as well as comorbidity and comedication. It is important to enquire about vaccinations, travel, exposure and previous infections when taking a case history. Possible infectious complications should be considered in patients who are receiving high-dose glucocorticoids treatment amounting to more than 420 mg PED per 4 weeks. Preventative measures are not usually required in patients who receive a short high-dosed treatment (30 mg PED in 7 days) or prednisolone at a dosage of < 15 mg/day.

fMRI of delayed albumin treatment during stroke recovery in rats: implication for fast neuronal habituation in recovering brains.

Accumulating experimental and clinical data suggest that albumin may be neuroprotective for stroke. Here, we use functional magnetic resonance imaging (fMRI) to evaluate the therapeutic efficacy of albumin and its effects on the recovery of stimuli-induced cerebral hemodynamics. For this purpose, fMRI activity in the ipsilesional somatosensory (SS) cortex was assessed using a well established rat model of transient 90 min focal ischemia and electrical forelimb stimulation. Rats were treated with either saline or albumin via intracerebroventricular injections at 12 h post-stroke onset. Despite this delayed treatment time, when compared to the saline-treated rats (n=7), there were significant enhancements of the fMRI activation in the albumin-treated rats (n=6) for both blood oxygenation level dependence (BOLD) and functional cerebral blood volume (fCBV) responses. Interestingly, the temporal characteristics of the ipsilesional SS BOLD responses in the albumin-treated rats appeared considerably altered compared to those of contralesional responses while such temporal alterations were not pronounced for the fCBV responses. These characteristic fMRI temporal profiles of the albumin-treated brains may be due to altered neuronal responses rather than altered integrity of neurovascular coupling, which implies an unusually fast habituation of neuronal responses in the lesional SS cortex. The correlation between various MRI-derived structural parameters and the fMRI response magnitude was also characteristic for albumin and control groups. Taken together, these data suggest that restoration of fMRI response magnitudes, temporal profiles, and correlations with structure may reveal the extent and specific traits of albumin treatment associated stroke recovery.

A quantitative method for microstructural analysis of myelinated axons in the injured rodent brain.

MRI studies (e.g. using diffusion tensor imaging) revealed that injury to white matter tracts, as observed in for instance perinatal white matter injury and multiple sclerosis, leads to compromised microstructure of myelinated axonal tracts. Alterations in white matter microstructure are also present in a wide range of neurological disorders including autism-spectrum disorders, schizophrenia and ADHD. Whereas currently myelin quantity measures are often used in translational animal models of white matter disease, it can be an important valuable addition to study the microstructural organization of myelination patterns in greater detail. Here, we describe methods to extensively study the microstructure of cortical myelination by immunostaining for myelin. To validate these methods, we carefully analyzed the organization of myelinated axons running from the external capsule towards the outer layers of the cortex in three rodent models of neonatal brain injury and in an adult stroke model, that have all been associated with myelination impairments. This unique, relatively easy and sensitive methodology can be applied to study subtle differences in myelination patterns in animal models in which aberrations in myelination integrity are suspected. Importantly, the described methods can be applied to determine efficacy of novel experimental treatments on microstructural organization of cortical myelination.

Re-evaluation of routine dengue virus serology in travelers in the era of Zika virus emergence.

BACKGROUND: Diagnostic requests for both Zika virus (ZIKV) and dengue virus (DENV) infections in returning travelers have significantly increased during the recent ZIKV outbreak in the Americás. These flaviviruses have overlapping clinical syndromes and geographical distribution, but diagnostic differentiation is important because of different clinical consequences. As flaviviruses are known to have a short viremic period, diagnostics often rely on serological methods, which are challenging due to extensive cross-reactive antibodies. OBJECTIVE: To re-evaluate the performance of DENV serological assays in laboratory confirmed ZIKV-infected travelers. STUDY DESIGN: The extent of cross-reactivity of the DENV NS1 antigen, IgM and IgG ELISA was analyzed in 152 clinical blood samples collected from 69 qRT-PCR and 24 virus neutralization titer (VNT) confirmed ZIKV-infected travelers. RESULTS: The majority of travelers in the presented cohort returned to the Netherlands from Suriname and presented with symptoms of fever and rash. Twenty-three percent of the female travelers were pregnant. None of the 39 ZIKV RNA positive blood samples were cross-reactive in the DENV NS1 antigen ELISA. The rates of cross-reactivity of the DENV IgM and IgG ELISÁs were 31% and 54%, respectively, after excluding travelers with (potential) previous DENV exposure. CONCLUSIONS: Although the DENV NS1 antigen assay was highly specific in this cohort of laboratory confirmed ZIKV-infected travelers, we demonstrate high percentages of cross-reactivity of DENV IgM and IgG ELISÁs of which diagnostic laboratories should be aware. In addition, the high rate of DENV IgG background of >25% complicates a proper serological diagnosis in this group.

Safety, Immunogenicity, and Protective Efficacy of Intradermal Immunization with Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites in Volunteers Under Chloroquine Prophylaxis: A Randomized Controlled Trial.

Immunization of volunteers under chloroquine prophylaxis by bites of Plasmodium falciparum sporozoite (PfSPZ)-infected mosquitoes induces > 90% protection against controlled human malaria infection (CHMI). We studied intradermal immunization with cryopreserved, infectious PfSPZ in volunteers taking chloroquine (PfSPZ chemoprophylaxis vaccine [CVac]). Vaccine groups 1 and 3 received 3× monthly immunizations with 7.5 × 10(4) PfSPZ. Control groups 2 and 4 received normal saline. Groups 1 and 2 underwent CHMI (#1) by mosquito bite 60 days after the third immunization. Groups 3 and 4 were boosted 168 days after the third immunization and underwent CHMI (#2) 137 days later. Vaccinees (11/20, 55%) and controls (6/10, 60%) had the same percentage of mild to moderate solicited adverse events. After CHMI #1, 8/10 vaccinees (group 1) and 5/5 controls (group 2) became parasitemic by microscopy; the two negatives were positive by quantitative real-time polymerase chain reaction (qPCR). After CHMI #2, all vaccinees in group 3 and controls in group 4 were parasitemic by qPCR. Vaccinees showed weak antibody and no detectable cellular immune responses. Intradermal immunization with up to 3 × 10(5) PfSPZ-CVac was safe, but induced only minimal immune responses and no sterile protection against Pf CHMI.

Measurements of BOLD/CBV ratio show altered fMRI hemodynamics during stroke recovery in rats.

Brain responses to external stimuli after permanent and transient ischemic insults have been documented using cerebral blood volume weighted (CBVw) functional magnetic resonance imaging (fMRI) in correlation with tissue damage and neurological recovery. Here, we extend our previous studies of stroke recovery in rat models of focal cerebral ischemia by comparing blood oxygen level-dependent (BOLD) and cerebral blood volume (CBV) changes. Responses to forepaw stimulation were measured in normal rats (n=5) and stroke rats subjected to 2 h of middle cerebral artery occlusion (n=6). Functional magnetic resonance imaging was performed 2 weeks after stroke to evaluate the recovery process. After stroke, animals showed variable degrees of fMRI activation in ipsilesional cortex, the extent of which did not correlate with structural damages as measured using apparent diffusion coefficient, fractional anisotropy, blood volume, and vessel size index. While the contralesional cortex showed good overlap between BOLD and CBV-activated regions, the ipsilesional cortex showed low covariance between significantly activated voxels by BOLD and CBVw techniques. In particular, the relative activation during contralateral stimuli in the ipsilesional somatosensory cortex was significantly higher for CBVw responses than BOLD, which might be due to stroke-related alterations in fMRI hemodynamic coupling. Aberrant subcortical activations were also observed. When unaffected forelimbs were stimulated, strong bilateral responses were observed. However, little thalamic responses accompanied stimulation of affected forelimbs despite significant activation in the ipsilesional somatosensory cortex. These results suggest that stroke affects not only local hemodynamics and coupling but also other factors including neural connectivity.

Altered contralateral sensorimotor system organization after experimental hemispherectomy: a structural and functional connectivity study.

Hemispherectomy is often followed by remarkable recovery of cognitive and motor functions. This reflects plastic capacities of the remaining hemisphere, involving large-scale structural and functional adaptations. Better understanding of these adaptations may (1) provide new insights in the neuronal configuration and rewiring that underlies sensorimotor outcome restoration, and (2) guide development of rehabilitation strategies to enhance recovery after hemispheric lesioning. We assessed brain structure and function in a hemispherectomy model. With MRI we mapped changes in white matter structural integrity and gray matter functional connectivity in eight hemispherectomized rats, compared with 12 controls. Behavioral testing involved sensorimotor performance scoring. Diffusion tensor imaging and resting-state functional magnetic resonance imaging were acquired 7 and 49 days post surgery. Hemispherectomy caused significant sensorimotor deficits that largely recovered within 2 weeks. During the recovery period, fractional anisotropy was maintained and white matter volume and axial diffusivity increased in the contralateral cerebral peduncle, suggestive of preserved or improved white matter integrity despite overall reduced white matter volume. This was accompanied by functional adaptations in the contralateral sensorimotor network. The observed white matter modifications and reorganization of functional network regions may provide handles for rehabilitation strategies improving functional recovery following large lesions.

Experimental focal neocortical epilepsy is associated with reduced white matter volume growth: results from multiparametric MRI analysis.

Focal epilepsy has recently been associated with remote white matter damage, including reduced white matter volume. Longitudinal assessment of these white matter changes, in relation to functional mechanisms and consequences, may be ideally done by in vivo neuroimaging in well-controlled experimental animal models. We assessed whether advanced machine learning algorithm models could accurately detect volumetric changes in white matter from multiparametric MR images, longitudinally collected in a neocortical focal epilepsy rat model. We measured classification accuracy in two supervised segmentation models: i.e. the generalized linear model and the nonlinear random forest model-by comparing computed white matter probabilities with actual neuroanatomically identified white matter. We found excellent overall discriminatory power for both models. However, the random forest model demonstrated a superior goodness-of-fit calibration plot that was close to the ideal calibration line. Based on this model, we measured that total white matter volume increased in young adult control and epileptic rats over a period of 10 weeks, but the average white matter volume was significantly lower in the focal epilepsy group. Changes in gray matter volume were not significantly different between control and epileptic rats. Our results (1) indicate that recurrent spontaneous seizures have an adverse effect on global white matter growth and (2) show that individual whole brain white matter volume can be accurately determined using a combination of multiparametric MRI and supervised segmentation models, offering a powerful tool to assess white matter volume changes in preclinical studies of neurological disease.