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Background: Huntington's disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease‐modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery. Methods: We characterised the progression of altered dynamics of whole‐brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting‐state fMRI and identified quasi‐periodic patterns (QPPs) of brain activity constituting the most prominent resting‐state networks. Results: The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. To better understand the potential underlying cause of the observed changes in these brain states, we further assessed how mutant huntingtin (mHTT) protein deposition affects astrocytes and pericytes – one of the most important effectors of neurovascular coupling, along phenotypic progression. Increased cell‐type dependent mHTT deposition was observed at the age of onset of motor anomalies, in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans. Conclusion: Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model and open new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research. Highlights: Hyperactivity in the LCN‐linked regions within short QPPs observed before motor impairment onset.DMLN QPP presents a progressive decrease in DMLN activity and occurrence along HD‐like phenotype development.Breakdown of the LCN DMLN state flux at motor onset leads to a subsequent absence of the LCN DMLN QPP at an advanced HD‐like stage. [ABSTRACT FROM AUTHOR]

Seasonality in songbirds includes not only reproduction but also seasonal changes in singing behavior and its neural substrate, the song control system (SCS). Prior research mainly focused on the role of sex steroids on this seasonal SCS neuroplasticity in males. In this review, we summarize the advances made in the field of seasonal neuroplasticity by applying in vivo magnetic resonance imaging (MRI) in male and female starlings, analyzing the entire brain, monitoring birds longitudinally and determining the neuronal correlates of seasonal variations in plasma hormone levels and song behavior. The first MRI studies in songbirds used manganese enhanced MRI to visualize the SCS in a living bird and validated previously described brain volume changes related to different seasons and testosterone. MRI studies with testosterone implantation established how the consequential boost in singing was correlated to structural changes in the SCS, indicating activity‐induced neuroplasticity as song proficiency increased. Next, diffusion tensor MRI explored seasonal neuroplasticity in the entire brain, focusing on networks beyond the SCS, revealing that other sensory systems and even the cerebellum, which is important for the integration of sensory perception and song behavior, experience neuroplasticity starting in the photosensitive period. Functional MRI showed that olfactory, and auditory processing was modulated by the seasons. The convergence of seasonal variations in so many sensory and sensorimotor systems resembles multisensory neuroplasticity during the critical period early in life. This sheds new light on seasonal songbirds as a model for unlocking the brain by recreating seasonally the permissive circumstances for heightened neuroplasticity. RESEARCH HIGHLIGHTS: Longitudinal MRI studies unraveled photoperiod, singing‐activity induced and hormonally modulated neuroplasticity in a seasonal songbird (European starling).This neuroplasticity extended beyond the song control system including multiple sensory systems and the cerebellum. [ABSTRACT FROM AUTHOR]

Introduction In Alzheimer's disease (AD), pathologic amyloid-beta (Aβ) is synaptotoxic and impairs neuronal function at the microscale, influencing brain networks at the macroscale before Aβ deposition. The latter can be detected noninvasively, in vivo , using resting-state functional MRI (rsfMRI), a technique used to assess brain functional connectivity (FC). Methods RsfMRI was performed longitudinally in TG2576 and PDAPP mice, starting before Aβ deposition to determine the earliest FC changes. Additionally, the role of pathologic Aβ on early FC alterations was investigated by treating TG2576 mice with the 3D6 anti-Aβ-antibody. Results Both transgenic models showed hypersynchronized FC before Aβ deposition and hyposynchronized FC at later stages. Early anti-Aβ treatment in TG2576 mice prevented hypersynchronous FC and the associated synaptic impairments and excitatory/inhibitory disbalances. Discussion Hypersynchrony of FC may be used as a new noninvasive read out of early AD and can be recovered by anti-Aβ treatment, encouraging preventive treatment strategies in familial AD. [ABSTRACT FROM AUTHOR]

ABSTRACT Functional hemispheric asymmetry is a common feature of vertebrate brain organization, yet little is known about how hemispheric dominance is implemented at the neural level. One notable example of hemispheric dominance in birds is the leading role of the left hippocampal formation in controlling navigational processes that support homing in pigeons. Relying on resting state fMRI analyses (where Functional connectivity (FC) can be determined by placing a reference 'seed' for connectivity in one hemisphere), we show that following seeding in either an anterior or posterior region of the hippocampal formation of homing pigeons and starlings, the emergent FC maps are consistently larger following seeding of the left hippocampus. Left seedings are also more likely to result in FC maps that extend to the contralateral hippocampus and outside the boundaries of the hippocampus. The data support the hypothesis that broader FC is one neural-organizational property that confers, with respect to navigation, functional dominance to the left hippocampus of birds. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (1H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3CL1/CX3CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX3CR1+/− C57BL/6 mice and wild type CX3CR1+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3CR1−/− C57BL/6 mice. Second, we show that 1H-MRS metabolite spectra are different when comparing cuprizone-treated CX3CR1−/− mice showing mild demyelination with cuprizone-treated CX3CR1+/+ mice showing severe demyelination and demyelination-associated inflammation. Following cuprizone treatment, CX3CR1+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX3CR1−/− mice only showed a decrease in tCho and tNAA concentrations. Therefore, 1H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: The abrupt loss of ovarian hormones before menopause, induced by oophorectomy, has been associated with accelerated aging, multimorbidity, and Alzheimer's disease (AD). We investigated the impact of prolonged loss of ovarian hormones on AD progression in a transgenic mouse model of amyloid pathology using in vivo diffusion tensor MRI, resting‐state functional MRI (rsfMRI) and spectroscopy (MRS). Method: Female 3.5‐month‐old TG2576 (TG) (N=27) and wild‐type (WT) (N=27) mice were ovariectomized (TGOVX) or sham‐operated (TGSHAM). When they became 18‐month‐old, 1‐H MRS (ROIs: hypothalamus, hippocampus, and cerebral cortex), DTI and rsfMRI was performed. ROI based analysis was performed on rsfMRI and DTI (Fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity, and radial diffusivity). The brain samples were then evaluated by histology and ELISA to assess Aβ load and activated glial cells. The loss of ovarian hormones via OVX was validated with elevated plasma luteinizing hormone level: OVX>SHAM (p<0.05). Two‐way ANOVA and post‐hoc (Student's‐t) tests were used for statistical analysis. P values were adjusted for multiple comparisons (FDR‐p). Result: The multimodel imaging data showed that there was a significant increase in taurine and total creatine (markers for inflammation and energy metabolism) in the hypothalamus, decrease in FA and AxD (markers for white matter integrity) in the white matter regions, and decrease in the functional connectivity between the prefrontal cortex and the hippocampus and dorsal and ventral hippocampus regions (a neural marker of network activity and integrity) (FDR‐p <0.05 (Figure 1)) in TGOVX mice compared to TGSHAM mice (post‐hoc t‐test). rsFMRI showed a significant increase in rsfMRI connectivity in WTOVX mice compared to WTSHAM mice. Complementary histological (and ELISA) analysis revealed no differences in Aβ load (plaque and soluble) and activated glial cells between the TG groups. Conclusion: The MRI results suggest that inflammatory response was elevated, energy metabolism was disrupted and white matter and network integrity decreased after prolonged ovarian hormone loss. These MRI results support other data from human and animal studies suggesting that abrupt hormonal changes associated with premenopausal removal of ovaries may increase the risk factors of AD, and accelerate the disease progression by causing abnormalities in brain structure, function and metabolism. [ABSTRACT FROM AUTHOR]

Endogenous neural stem cells (eNSCs) reside in defined regions of the adult brain and have the potential to generate new brain cells, including neurons. Stimulation of adult neurogenesis presents an enormous potential for regenerative therapies in the central nervous system. However, the methods used to monitor the proliferation, migration, differentiation, and functional integration of eNSCs and their progeny are often invasive and limited in studying dynamic processes. To overcome this limitation, novel techniques and contrast mechanisms for in vivo imaging of neurogenesis have recently been developed and successfully applied. In vivo labeling of endogenous neuronal progenitor cells in situ with contrast agents or tracers enables longitudinal visualization of their proliferation and/or migration. Labeling of these cells with magnetic nanoparticles has proven to be very useful for tracking neuroblast migration with MRI. Alternatively, genetic labeling using reporter gene technology has been demonstrated for optical and MR imaging, leading to the development of powerful tools for in vivo optical imaging of neurogenesis. More recently, the iron storage protein ferritin has been used as an endogenously produced MRI contrast agent to monitor neuroblast migration. The use of specific promoters for neuronal progenitor cell imaging increases the specificity for visualizing neurogenesis. Further improvements of detection sensitivity and neurogenesis-specific contrast are nevertheless required for each of these imaging techniques to further improve the already high utility of this toolbox for preclinical neurogenesis research. WIREs Nanomed Nanobiotechnol 2012, 4:663-679. doi: 10.1002/wnan.1192 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: All authors declare to have no conflicts of interest. [ABSTRACT FROM AUTHOR]

Currently, much attention is given to the development of cellular therapies for treatment of central nervous system (CNS) injuries. Diverse cell implantation strategies, either to directly replace damaged neural tissue or to create a neuroregenerative environment, are proposed to restore impaired brain function. However, because of the complexity of the CNS, it is now becoming clear that the contribution of cell implantation into the brain will mainly act in a supportive manner. In addition, given the time dependence of neural development during embryonic and post-natal life, cellular implants, either self or non-self, will most likely have to interact for a sustained period of time with both healthy and injured neural tissue. The latter also implies potential recognition of cellular implants by the innate immune system of the brain. In this review, we will emphasize on preclinical observations in rodents, regarding the recognition and immunogenicity of autologous, allogeneic and xenogeneic cellular implants in the CNS of immune-competent hosts. Taken together, we here suggest that a profound study of the interaction between cellular grafts and the brain's innate immune system will be inevitable before clinical cell transplantation in the CNS can be performed successfully. [ABSTRACT FROM AUTHOR]

With diffusion tensor imaging, the diffusion of water molecules through brain structures is quantified by parameters, which are estimated assuming monoexponential diffusion-weighted signal attenuation. The estimated diffusion parameters, however, depend on the diffusion weighting strength, the b-value, which hampers the interpretation and comparison of various diffusion tensor imaging studies. In this study, a likelihood ratio test is used to show that the diffusion kurtosis imaging model provides a more accurate parameterization of both the Gaussian and non-Gaussian diffusion component compared with diffusion tensor imaging. As a result, the diffusion kurtosis imaging model provides a b-value-independent estimation of the widely used diffusion tensor parameters as demonstrated with diffusion-weighted rat data, which was acquired with eight different b-values, uniformly distributed in a range of [0,2800 sec/mm2]. In addition, the diffusion parameter values are significantly increased in comparison to the values estimated with the diffusion tensor imaging model in all major rat brain structures. As incorrectly assuming additive Gaussian noise on the diffusion-weighted data will result in an overestimated degree of non-Gaussian diffusion and a b-value-dependent underestimation of diffusivity measures, a Rician noise model was used in this study. Magn Reson Med, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The advent of high-field MRI systems has allowed the implementation of blood oxygen level-dependent functional MRI (BOLD fMRI) on small animals. An increased magnetic field improves the signal-to-noise ratio and thus allows an improvement in the spatial resolution. However, it also increases susceptibility artefacts in the commonly acquired gradient-echo images. This problem is particularly prominent in songbird MRI because of the presence of numerous air cavities in the skull of birds. These T2*-related image artefacts can be circumvented using spin-echo BOLD fMRI. In this article, we describe the implementation of spin-echo BOLD fMRI in zebra finches, a small songbird of 15-25 g, extensively studied in the behavioural neurosciences of birdsong. Because the main topics in this research domain are song perception and song learning, the protocol implemented used auditory stimuli. Despite the auditory nature of the stimuli and the weak contrast-to-noise ratio of spin-echo BOLD fMRI compared with gradient-echo BOLD fMRI, we succeeded in detecting statistically significant differences in BOLD responses triggered by different stimuli. This study shows that spin-echo BOLD fMRI is a viable approach for the investigation of auditory processing in the whole brain of small songbirds. It can also be applied to study auditory processing in other small animals, as well as other sensory modalities. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The song control system of songbirds displays a remarkable seasonal neuroplasticity in species in which song output also changes seasonally. Thus far, this song control system has been extensively analyzed by histological and electrophysiological methods. However, these approaches do not provide a global view of the brain and/or do not allow repeated measurements, which are necessary to establish causal correlations between alterations in neural substrate and behavior. Research has primarily been focused on the song nuclei themselves, largely neglecting their interconnections and other brain regions involved in seasonally changing behavior. In this review, we introduce and explore the song control system of songbirds as a natural model for brain plasticity. At the same time, we point out the added value of the songbird brain model for in vivo diffusion tensor techniques and its derivatives. A compilation of the diffusion tensor imaging (DTI) data obtained thus far in this system demonstrates the usefulness of this in vivo method for studying brain plasticity. In particular, it is shown to be a perfect tool for long-term studies of morphological and cellular changes of specific brain circuits in different endocrine/photoperiod conditions. The method has been successfully applied to obtain quantitative measurements of seasonal changes of fiber tracts and nuclei from the song control system. In addition, outside the song control system, changes have been discerned in the optic chiasm and in an interhemispheric connection. DTI allows the detection of seasonal changes in a region analogous to the mammalian secondary auditory cortex and in regions of the 'social behavior network', an interconnected group of structures that controls multiple social behaviors, including aggression and courtship. DTI allows the demonstration, for the first time, that the songbird brain in its entirety exhibits an extreme seasonal plasticity which is not merely limited to the song control system as was generally believed. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterised by degeneration of the nigrostrial connection causing dramatic changes in the dopaminergic pathway underlying clinical pathology. Till now, no MRI tools were available to follow up any specific PD-related neurodegeneration. However, recently, diffusion tensor imaging (DTI) has received considerable attention as a new and potential in vivo diagnostic tool for various neurodegenerative diseases. To assess this in PD, we performed DTI in the acute 6-hydroxydopamine (6-OHDA) rat model of PD to evaluate diffusion properties in the degenerating nigrostriatal pathway and its connecting structures. Injection of a neurotoxin in the striatum causes retrograde neurodegeneration of the nigrostriatal tract, and selective degeneration of nigral neurons. The advantage of this model is that the lesion size is well controllable by the injected dose of the toxin. The degree of functional impairment was evaluated in vivo using the amphetamine rotation test and µPET imaging of the dopamine transporter (DAT). Despite a nearly complete lesion of the nigrostriatal tract, DTI changes were limited to the ipsilateral substantia nigra (SN). In this study we demonstrate, using voxel-based statistics (VBS), an increase in fractional anisotropy (FA), whereas all eigenvalues were significantly decreased. VBS enabled us to visualise neurodegeneration of a cluster of neurons but failed to detect degeneration of more diffuse microstructures such as the nigrostriatal fibres or the dopaminergic endings in the striatum. VBS without a priori information proved to be better than manual segmentation of brain structures as it does not suffer from volume averaging and is not susceptible to erroneous segmentations of brain regions that show very little contrast on MRI images such as SN. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The song control system (SCS) of songbirds displays a remarkable plasticity in species where song output changes seasonally. The mechanisms underlying this plasticity are barely understood and research has primarily been focused on the song nuclei themselves, largely neglecting their interconnections and connections with other brain regions. We investigated seasonal changes in the entire brain, including the song nuclei and their connections, of nine male starlings ( Sturnus vulgaris). At two times of the year, during the breeding (April) and nonbreeding (July) seasons, we measured in the same subjects cellular attributes of brain regions using in vivo high-resolution diffusion tensor imaging (DTI) at 7 T. An increased fractional anisotropy in the HVC–RA pathway that correlates with an increase in axonal density (and myelination) was found during the breeding season, confirming multiple previous histological reports. Other parts of the SCS, namely the occipitomesencephalic axonal pathway, which contains fiber tracts important for song production, showed increased fractional anisotropy due to myelination during the breeding season and the connection between HVC and Area X showed an increase in axonal connectivity. Beyond the SCS we discerned fractional anisotropy changes that correlate with myelination changes in the optic chiasm and axonal organization changes in an interhemispheric connection, the posterior commissure. These results demonstrate an unexpectedly broad plasticity in the connectivity of the avian brain that might be involved in preparing subjects for the competitive and demanding behavioral tasks that are associated with successful reproduction. [ABSTRACT FROM AUTHOR]

Song perception in songbirds, just as music and speech perception in humans, requires processing the spectral and temporal structure found in the succession of song-syllables. Using functional magnetic resonance imaging and synthetic songs that preserved exclusively either the temporal or the spectral structure of natural song, we investigated how vocalizations are processed in the avian forebrain. We found bilateral and equal activation of the primary auditory region, field L. The more ventral regions of field L showed depressed responses to the synthetic songs that lacked spectral structure. These ventral regions included subarea L3, medial-ventral subarea L and potentially the secondary auditory region caudal medial nidopallium. In addition, field L as a whole showed unexpected increased responses to the temporally filtered songs and this increase was the largest in the dorsal regions. These dorsal regions included L1 and the dorsal subareas L and L2b. Therefore, the ventral region of field L appears to be more sensitive to the preservation of both spectral and temporal information in the context of song processing. We did not find any differences in responses to playback of the bird's own song vs other familiar conspecific songs. We also investigated the effect of three commonly used anaesthetics on the blood oxygen level-dependent response: medetomidine, urethane and isoflurane. The extent of the area activated and the stimulus selectivity depended on the type of anaesthetic. We discuss these results in the context of what is known about the locus of action of the anaesthetics, and reports of neural activity measured in electrophysiological experiments. [ABSTRACT FROM AUTHOR]

This review aims to make the reader aware of the potential of functional MRI (fMRI) in brain activation studies in small animal models. As small animals generally require anaesthesia for immobilization during MRI protocols, this is believed to be a serious limitation to the type of question that can be addressed with fMRI. We intend to introduce a fresh view with an in-depth overview of the surprising number of fMRI applications in a wide range of important research domains in neuroscience. These include the pathophysiology of brain functioning, the basic science of activity, and functional connectivity of different sensory circuits, including sensory brain mapping, the challenges when studying the hypothalamus as the major control centre in the central nervous system, and the limbic system as neural substrate for emotions and reward. Finally the contribution of small animal fMRI research to cognitive neuroscience is outlined. This review avoids focusing exclusively on traditional small laboratory animals such as rodents, but rather aims to broaden the scope by introducing alternative lissencephalic animal models such as songbirds and fish, as these are not yet well recognized as neuroimaging study subjects. These models are well established in many other neuroscience disciplines, and this review will show that their investigation with in vivo imaging tools will open new doors to cognitive neuroscience and the study of the autonomous nervous system in experimental animals. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Songbirds share with humans the capacity to produce learned vocalizations (song). Recently, two major regions within the songbird's neural substrate for song learning and production; nucleus robustus arcopallii (RA) and area X (X) are visualized in vivo using Manganese Enhanced MRI (MEMRI). The aim of this study is to extend this to all main interconnected forebrain Song Control Nuclei. The ipsilateral feedback circuits allow Mn2+ to reach all main Song Control Nuclei after stereotaxic injection of very small doses of MnCl2 (10 nl of 10 mM) into HVC of one and MAN (nucleus magnocellularis nidopallii anterioris) of the other hemisphere. Application of a high resolution (80 µ) Spin Echo Inversion Recovery sequence instead of conventional T1-weighted Spin Echo images improves the image contrast dramatically such that some Song Control Nuclei, ventricles, several laminae, fibre tracts and other specific brain regions can be discerned. The combination of this contrast-rich IR-SE sequence with the transsynaptic transport property of Manganese (Inversion Recovery based MEMRI (IR-MEMRI)) enables the visualization of all main interconnected components of the Song Control System in telencephalon and thalamus. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose To implement and optimize cerebral blood volume (CBV)-weighted functional magnetic resonance imaging (fMRI) in the rat cerebral and cerebellar cortex during electrical paw stimulation. Materials and Methods fMRI of the cerebral and cerebellar cortex was performed during electrical paw stimulation on a 7-T MRI system (MRRS, Guilford, UK) comparing the blood oxygenation level-dependent (BOLD) and CBV-weighted contrast with different ultrasmall particles of iron oxide (USPIO) contrast doses (NC100150, 30 mg Fe/mL; Amersham Health, Oslo, Norway) and different TE. Results Doses of 15 and 20 mg/kg USPIO at TE = T [ABSTRACT FROM AUTHOR]

The song control system of song birds is an excellent model for studying brain plasticity and has thus far been extensively analyzed by histological and electrophysiological methods. However, these approaches do not provide a global view of the brain and/or do not allow repeated measures, which are necessary to establish correlations between alterations in neural substrate and behavior. Application of in vivo manganese-enhanced MRI enabled us for the first time to visualize the song control system repeatedly in the same bird, making it possible to quantify dynamically the volume changes in this circuit as a function of seasonal and hormonal influences. In this review, we introduce and explore the song control system of song birds as a natural model for brain plasticity to validate a new cutting edge technique, which we called 'repeated dynamic manganese enhanced MRI' or D-MEMRI. This technique is based on the use of implanted permanent cannulae-for accurate repeated manganese injections in a defined target area-and the subsequent MRI acquisition of the dynamics of the accumulation of manganese in projection brain targets. A compilation of the D-MEMRI data obtained thus far in this system demonstrates the usefulness of this new method for studying brain plasticity. In particular it is shown to be a perfect tool for long-term studies of morphological and functional responses of specific brain circuits to changes in endocrine conditions. The method was also successfully applied to obtain quantitative measures of changes in activity as a function of auditory stimuli in different neuronal populations of a same nucleus that project to different targets. D-MEMRI, combined with other MRI techniques, clearly harbors potential for unraveling seasonal, hormonal, pharmacological or even genetically driven changes in a neuronal circuit, by simultaneously measuring changes in morphology, activity and connectivity. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]