A radiofrequency coil for infants and toddlers.

Infants and toddlers are a challenging population upon which to perform magnetic resonance imaging (MRI) of the brain, both in research and clinical settings. Because of the large range in head size during the early years of development, paediatric neuro-MRI requires a radiofrequency (RF) coil, or set of coils, that is tailored to head size to provide the highest image quality. Mitigating techniques must also be employed to reduce and correct for subject motion. This manuscript describes an RF coil with a tailored mechanical-electrical design that can adapt to the head size of 3-month-old infants to 3-year-old toddlers. The RF coil was designed with tight-fitting coil elements to improve the signal-to-noise ratio (SNR) in comparison with commercially available adult head coils, while simultaneously aiding in immobilization. The coil was designed without visual obstruction to facilitate an unimpeded view of the child's face and the potential application of camera or motion-tracking systems. Despite the lack of elements over the face, the paediatric coil produced higher SNR over most of the brain compared with adult coils, including more than twofold in the periphery. Acceleration rates of fourfold in each Cartesian direction could be achieved. High SNR allowed for short acquisition times through accelerated imaging protocols and reduced the probability of motion during a scan. Modification of the acquisition protocol, with immobilization of the head through the adjustable coil geometry, and subsequently being combined with a motion-tracking system, provides a compelling platform for scanning paediatric populations without sedation and with improved image quality.

Divergence of rodent and primate medial frontal cortex functional connectivity.

With the medial frontal cortex (MFC) centrally implicated in several major neuropsychiatric disorders, it is critical to understand the extent to which MFC organization is comparable between humans and animals commonly used in preclinical research (namely rodents and nonhuman primates). Although the cytoarchitectonic structure of the rodent MFC has mostly been conserved in humans, it is a long-standing question whether the structural analogies translate to functional analogies. Here, we probed this question using ultra high field fMRI data to compare rat, marmoset, and human MFC functional connectivity. First, we applied hierarchical clustering to intrinsically define the functional boundaries of the MFC in all three species, independent of cytoarchitectonic definitions. Then, we mapped the functional connectivity "fingerprints" of these regions with a number of different brain areas. Because rats do not share cytoarchitectonically defined regions of the lateral frontal cortex (LFC) with primates, the fingerprinting method also afforded the unique ability to compare the rat MFC and marmoset LFC, which have often been suggested to be functional analogs. The results demonstrated remarkably similar intrinsic functional organization of the MFC across the species, but clear differences between rodent and primate MFC whole-brain connectivity. Rat MFC patterns of connectivity showed greatest similarity with premotor regions in the marmoset, rather than dorsolateral prefrontal regions, which are often suggested to be functionally comparable. These results corroborate the viability of the marmoset as a preclinical model of human MFC dysfunction, and suggest divergence of functional connectivity between rats and primates in both the MFC and LFC.

An open access resource for functional brain connectivity from fully awake marmosets.

The common marmoset (Callithrix jacchus) is quickly gaining traction as a premier neuroscientific model. However, considerable progress is still needed in understanding the functional and structural organization of the marmoset brain to rival that documented in longstanding preclinical model species, like mice, rats, and Old World primates. To accelerate such progress, we present the Marmoset Functional Brain Connectivity Resource (marmosetbrainconnectome.org), currently consisting of over 70 h of resting-state fMRI (RS-fMRI) data acquired at 500 µm isotropic resolution from 31 fully awake marmosets in a common stereotactic space. Three-dimensional functional connectivity (FC) maps for every cortical and subcortical gray matter voxel are stored online. Users can instantaneously view, manipulate, and download any whole-brain functional connectivity (FC) topology (at the subject- or group-level) along with the raw datasets and preprocessing code. Importantly, researchers can use this resource to test hypotheses about FC directly - with no additional analyses required - yielding whole-brain correlations for any gray matter voxel on demand. We demonstrate the resource's utility for presurgical planning and comparison with tracer-based neuronal connectivity as proof of concept. Complementing existing structural connectivity resources for the marmoset brain, the Marmoset Functional Brain Connectivity Resource affords users the distinct advantage of exploring the connectivity of any voxel in the marmoset brain, not limited to injection sites nor constrained by regional atlases. With the entire raw database (RS-fMRI and structural images) and preprocessing code openly available for download and use, we expect this resource to be broadly valuable to test novel hypotheses about the functional organization of the marmoset brain.

Integration of an RF coil and commercial field camera for ultrahigh-field MRI.

PURPOSE: To develop an RF coil with an integrated commercial field camera for ultrahigh field (7T) neuroimaging. The RF coil would operate within a head-only gradient coil and be subject to the corresponding design constraints. The RF coil can thereafter be used for subject-specific correction of k-space trajectories-notably in gradient-sensitive sequences such as single-shot spiral imaging. METHODS: The transmit and receive performance was evaluated before and after the integration of field probes, whereas field probes were evaluated when in an optimal configuration external to the coil and after their integration. Diffusion-weighted EPI and single-shot spiral acquisitions were employed to evaluate the efficacy of correcting higher order field perturbations and the consequent effect on image quality. RESULTS: Field probes had a negligible effect on RF-coil performance, including the transmit efficiency, transmit uniformity, and mean SNR over the brain. Modest reductions in field-probe signal lifetimes were observed, caused primarily by nonidealities in the gradient and shim fields of the head-only gradient coil at the probe positions. The field-monitoring system could correct up to second-order field perturbations in single-shot spiral imaging. CONCLUSION: The integrated RF coil and field camera was capable of concurrent-field monitoring within a 7T head-only scanner and facilitated the subsequent correction of k-space trajectories during spiral imaging.

Cortico-Subcortical Functional Connectivity Profiles of Resting-State Networks in Marmosets and Humans.

Understanding the similarity of cortico-subcortical networks topologies between humans and nonhuman primate species is critical to study the origin of network alternations underlying human neurologic and neuropsychiatric diseases. The New World common marmoset (Callithrix jacchus) has become popular as a nonhuman primate model for human brain function. Most marmoset connectomic research, however, has exclusively focused on cortical areas, with connectivity to subcortical networks less extensively explored. Here, we aimed to first isolate patterns of subcortical connectivity with cortical resting-state networks in awake marmosets using resting-state fMRI, then to compare these networks with those in humans using connectivity fingerprinting. In this study, we used 5 marmosets (4 males, 1 female). While we could match several marmoset and human resting-state networks based on their functional fingerprints, we also found a few striking differences, for example, strong functional connectivity of the default mode network with the superior colliculus in marmosets that was much weaker in humans. Together, these findings demonstrate that many of the core cortico-subcortical networks in humans are also present in marmosets, but that small, potentially functionally relevant differences exist.SIGNIFICANCE STATEMENT The common marmoset is becoming increasingly popular as an additional preclinical nonhuman primate model for human brain function. Here we compared the functional organization of cortico-subcortical networks in marmosets and humans using ultra-high field fMRI. We isolated the patterns of subcortical connectivity with cortical resting-state networks (RSNs) in awake marmosets using resting-state fMRI and then compared these networks with those in humans using connectivity fingerprinting. While we could match several marmoset and human RSNs based on their functional fingerprints, we also found several striking differences. Together, these findings demonstrate that many of the core cortico-subcortical RSNs in humans are also present in marmosets, but that small, potentially functionally relevant differences exist.

Effects of phase regression on high-resolution functional MRI of the primary visual cortex.

High-resolution functional MRI studies have become a powerful tool to non-invasively probe the sub-millimeter functional organization of the human cortex. Advances in MR hardware, imaging techniques and sophisticated post-processing methods have allowed high resolution fMRI to be used in both the clinical and academic neurosciences. However, consensus within the community regarding the use of gradient echo (GE) or spin echo (SE) based acquisition remains largely divided. On one hand, GE provides a high temporal signal-to-noise ratio (tSNR) technique sensitive to both the macro- and micro-vascular signal while SE based methods are more specific to microvasculature but suffer from lower tSNR and specific absorption rate limitations, especially at high field and with short repetition times. Fortunately, the phase of the GE-EPI signal is sensitive to vessel size and this provides a potential avenue to reduce the macrovascular weighting of the signal (phase regression, Menon 2002). In order to determine the efficacy of this technique at high-resolution, phase regression was applied to GE-EPI timeseries and compared to SE-EPI to determine if GE-EPI's specificity to the microvascular compartment improved. To do this, functional data was collected from seven subjects on a neuro-optimized 7 T system at 800 µm isotropic resolution with both GE-EPI and SE-EPI while observing an 8 Hz contrast reversing checkerboard. Phase data from the GE-EPI was used to create a microvasculature-weighted time series (GE-EPI-PR). Anatomical imaging (MP2RAGE) was also collected to allow for surface segmentation so that the functional results could be projected onto a surface. A multi-echo gradient echo sequence was collected and used to identify venous vasculature. The GE-EPI-PR surface activation maps showed a high qualitative similarity with SE-EPI and also produced laminar activity profiles similar to SE-EPI. When the GE-EPI and GE-EPI-PR distributions were compared to SE-EPI it was shown that GE-EPI-PR had similar distribution characteristics to SE-EPI (p < 0.05) across the top 60% of cortex. Furthermore, it was shown that GE-EPI-PR has a higher contrast-to-noise ratio (0.5 ± 0.2, mean ± std. dev. across layers) than SE-EPI (0.27 ± 0.07) demonstrating the technique has higher sensitivity than SE-EPI. Taken together this evidence suggests phase regression is a useful method in low SNR studies such as high-resolution fMRI.

Radiofrequency coil for routine ultra-high-field imaging with an unobstructed visual field.

Many neuroscience applications have adopted functional MRI as a tool to investigate the healthy and diseased brain during the completion of a task. While ultra-high-field MRI has allowed for improved contrast and signal-to-noise ratios during functional MRI studies, it remains a challenge to create local radiofrequency coils that can accommodate an unobstructed visual field and be suitable for routine use, while at the same time not compromise performance. Performance (both during transmission and reception) can be improved by using close-fitting coils; however, maintaining sensitivity over the whole brain often requires the introduction of coil elements proximal to the eyes, thereby partially occluding the subject's visual field. This study presents a 7 T head coil, with eight transmit dipoles and 32 receive loops, that is designed to remove visual obstructions from the subject's line of sight, allowing for an unencumbered view of visual stimuli, the reduction of anxiety induced from small enclosures, and the potential for eye-tracking measurements. The coil provides a practical solution for routine imaging, including a split design (anterior and posterior halves) that facilitates subject positioning, including those with impaired mobility, and the placement of devices required for patient comfort and motion reduction. The transmit and receive coils displayed no degradation of performance due to adaptions to the design topology (both mechanical and electrical) required to create an unobstructed visual field. All computer-aided design files, electromagnetic simulation models, transmit field maps and local specific absorption rate matrices are provided to promote reproduction.

Frontal-striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS.

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high-frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR)-increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal-striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling of resting state fMRI in a sample of 19 first episode psychosis subjects. We found that the total score of positive symptoms of schizophrenia is strongly associated with the frontostriatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as decreased bidirectional excitatory influence between the LDLPFC and the LSTR is related to the severity of positive symptoms, especially delusions. We interpret that an increase in striatal dopaminergic tone that underlies positive symptoms is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal 'brake'. Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low-frequency (1 Hz) rTMS of the prefrontal area.

Altered Resting-State Functional Connectivity Between Awake and Isoflurane Anesthetized Marmosets.

The common marmoset (Callithrix jacchus) is a New World primate that is becoming increasingly popular as a preclinical model. To assess functional connectivity (FC) across the marmoset brain, resting-state functional MRI (RS-fMRI) is often performed under isoflurane anesthesia to avoid the effects of motion, physiological stress, and training requirements. In marmosets, however, it remains unclear how isoflurane anesthesia affects patterns of FC. Here, we investigated the effects of isoflurane on FC when delivered with either medical air or 100% pure oxygen, two canonical methods of inhalant isoflurane anesthesia delivery. The results demonstrated that when delivered with either medical air or 100% oxygen, isoflurane globally decreased FC across resting-state networks that were identified in awake marmosets. Generally, although isoflurane globally decreased FC in resting-state networks, the spatial structure of the networks was preserved. Outside of the context of RS networks, we indexed pair-wise functional connectivity between regions across the brain and found that isoflurane substantially altered interhemispheric and thalamic FC. Taken together, these findings indicate that RS-fMRI under isoflurane anesthesia is useful to evaluate the global structure of functional networks, but may obfuscate important nodes of some network components when compared to data acquired in fully awake marmosets.

Intrinsic Functional Boundaries of Lateral Frontal Cortex in the Common Marmoset Monkey.

The common marmoset (Callithrix jacchus) is a small New World primate species that has been recently targeted as a potentially powerful preclinical model of human prefrontal cortex dysfunction. Although the structural boundaries of frontal cortex were described in marmosets at the start of the 20th century (Brodmann, 1909) and refined more recently (Paxinos et al., 2012), the broad functional boundaries of marmoset frontal cortex have yet to be established. In this study, we sought to functionally derive boundaries of the marmoset lateral frontal cortex (LFC) using ultra-high field (9.4 T) resting-state functional magnetic resonance imaging (RS-fMRI). We collected RS-fMRI data in seven (four females, three males) lightly anesthetized marmosets and used a data-driven hierarchical clustering approach to derive subdivisions of the LFC based on intrinsic functional connectivity. We then conducted seed-based analyses to assess the functional connectivity between these clusters and the rest of the brain. The results demonstrated seven distinct functional clusters within the LFC. The functional connectivity patterns of these clusters with the rest of the brain were also found to be distinct and organized along a rostrocaudal gradient, consonant with those found in humans and macaques. Overall, these results support the view that marmosets are a promising preclinical modeling species for studying LFC dysfunction related to neuropsychiatric or neurodegenerative human brain diseases.SIGNIFICANCE STATEMENT The common marmoset is a New World primate that has garnered recent attention as a powerful complement to canonical Old World primate (e.g., macaques) and rodent models (e.g., rats, mice) for preclinical modeling of the human brain in healthy and diseased states. A critical step in the development of marmosets for such models is to characterize functional network topologies of frontal cortex in healthy, normally functioning marmosets, that is, how these circuitries are functionally divided and how those topologies compare to human circuitry. To our knowledge, this is the first study to demonstrate functional boundaries of the lateral frontal cortex and the corresponding network topologies in marmoset monkeys.

Looming and receding visual networks in awake marmosets investigated with fMRI.

An object that is looming toward a subject or receding away contains important information for determining if this object is dangerous, beneficial or harmless. This information (motion, direction, identity, time-to-collision, size, velocity) is analyzed by the brain in order to execute the appropriate behavioral responses depending on the context: fleeing, freezing, grasping, eating, exploring. In the current study, we performed ultra-high-field functional MRI (fMRI) at 9.4T in awake marmosets to explore the patterns of brain activation elicited by visual stimuli looming toward or receding away from the monkey. We found that looming and receding visual stimuli activated a large cortical network in frontal, parietal, temporal and occipital cortex in areas involved in the analysis of motion, shape, identity and features of the objects. Looming stimuli strongly activated a network composed of portions of the pulvinar, superior colliculus, putamen, parietal, prefrontal and temporal cortical areas. These activations suggest the existence of a network that processes visual stimuli looming toward peripersonal space to predict the consequence of these stimuli. Together with previous studies in macaque monkeys, these findings indicate that this network is preserved across Old and New World primates.

Comparison of resting-state functional connectivity in marmosets with tracer-based cellular connectivity.

Resting-state functional MRI (RS-fMRI) is widely used to assess how strongly different brain areas are connected. However, this connection obtained by RS-fMRI, which is called functional connectivity (FC), simply refers to the correlation of blood oxygen level-dependent (BOLD) signals across time it has yet to be quantified how accurately FC reflects cellular connectivity (CC). In this study, we elucidated this relationship using RS-fMRI and quantitative tracer data in marmosets. In addition, we also elucidated the effects of distance between two brain regions on the relationship between FC and CC across seed region. To calculate FC, we used full correlation approach that is considered to reflect not only direct (monosynaptic connections) but also indirect pathways (polysynaptic connections). Our main findings are that: (1) overall FC obtained by RS-fMRI was highly correlated with tracer-based CC, but correlation coefficients varied remarkably across seed regions; (2) the strength of FC decreased with increase in the distance between two regions; (3) correlation coefficients between FC and CC after regressing out the effects of the distance between two regions still varied across seed regions, but some regions have strong correlations. These findings suggest that although FC reflects the strength of monosynaptic pathways, it is strongly affected by the distance between regions.

Whole brain mapping of somatosensory responses in awake marmosets investigated with ultra-high-field fMRI.

The common marmoset (Callithrix jacchus) is a small-bodied New World primate that is becoming an important model to study brain functions. Despite several studies exploring the somatosensory system of marmosets, all results have come from anesthetized animals using invasive techniques and postmortem analyses. Here, we demonstrate the feasibility for getting high-quality and reproducible somatosensory mapping in awake marmosets with functional magnetic resonance imaging (fMRI). We acquired fMRI sequences in four animals, while they received tactile stimulation (via air-puffs), delivered to the face, arm, or leg. We found a topographic body representation with the leg representation in the most medial part, the face representation in the most lateral part, and the arm representation between leg and face representation within areas 3a, 3b, and 1/2. A similar sequence from leg to face from caudal to rostral sites was identified in areas S2 and PV. By generating functional connectivity maps of seeds defined in the primary and second somatosensory regions, we identified two clusters of tactile representation within the posterior and midcingulate cortex. However, unlike humans and macaques, no clear somatotopic maps were observed. At the subcortical level, we found a somatotopic body representation in the thalamus and, for the first time in marmosets, in the putamen. These maps have similar organizations, as those previously found in Old World macaque monkeys and humans, suggesting that these subcortical somatotopic organizations were already established before Old and New World primates diverged. Our results show the first whole brain mapping of somatosensory responses acquired in a noninvasive way in awake marmosets.NEW & NOTEWORTHY We used somatosensory stimulation combined with functional MRI (fMRI) in awake marmosets to reveal the topographic body representation in areas S1, S2, thalamus, and putamen. We showed the existence of a body representation organization within the thalamus and the cingulate cortex by computing functional connectivity maps from seeds defined in S1/S2, using resting-state fMRI data. This noninvasive approach will be essential for chronic studies by guiding invasive recording and manipulation techniques.

Elimination of low-inversion-efficiency induced artifacts in whole-brain MP2RAGE using multiple RF-shim configurations at 7 T.

The magnetization-prepared two-rapid-gradient-echo (MP2RAGE) sequence is used for structural T1 -weighted imaging and T1 mapping of the human brain. In this sequence, adiabatic inversion RF pulses are commonly used, which require the B1+ magnitude to be above a certain threshold. Achieving this threshold in the whole brain may not be possible at ultra-high fields because of the short RF wavelength. This results in low-inversion regions especially in the inferior brain (eg cerebellum and temporal lobes), which is reflected as regions of bright signal in MP2RAGE images. This study aims at eliminating the low-inversion-efficiency induced artifacts in MP2RAGE images at 7 T. The proposed technique takes advantage of parallel RF transmission systems by splitting the brain into two overlapping slabs and calculating the complex weights of transmit channels (ie RF shims) on these slabs for excitation and inversion independently. RF shims were calculated using fast methods implemented in the standard workflow. The excitation RF pulse was designed to obtain slabs with flat plateaus and sharp edges. These slabs were joined into a single volume during the online image reconstruction. The two-slab strategy naturally results in a signal-to-noise ratio loss; however, it allowed the use of independent shims to make the B1+ field exceed the adiabatic threshold in the inferior brain, eliminating regions of low inversion efficiency. Accordingly, the normalized root-mean-square errors in the inversion were reduced to below 2%. The two-slab strategy was found to outperform subject-specific kT -point inversion RF pulses in terms of inversion error. The proposed strategy is a simple yet effective method to eliminate low-inversion-efficiency artifacts; consequently, MP2RAGE-based, artifact-free T1 -weighted structural images were obtained in the whole brain at 7 T.

Integrated radiofrequency array and animal holder design for minimizing head motion during awake marmoset functional magnetic resonance imaging.

Marmosets are small New World primates that are posited to become an important preclinical animal model for studying intractable human brain diseases. A critical step in the development of marmosets as a viable model for human brain dysfunction is to characterize brain networks that are homologous with human network topologies. In this regard, the use of functional magnetic resonance imaging (fMRI) holds tremendous potential for functional brain mapping in marmosets. Although possible, implementation of hardware for fMRI in awake marmosets (free of the confounding effects of anesthesia) is not trivial due to the technical challenges associated with developing specialized imaging hardware. Here, we describe the design and implementation of a marmoset holder and head-fixation system with an integrated receive coil for awake marmoset fMRI. This design minimized head motion, with less than 100  µm of translation and 0.5 degrees of rotation over 15 consecutive resting state fMRI runs (at 15 min each) across 3 different marmosets. The fMRI data was of sufficient quality to reliably extract 8 resting state networks from each animal with only 60-90 min of resting state fMRI acquisition per animal. The restraint system proved to be an efficient and practical solution for securing an awake marmoset and positioning a receive array within minutes, limiting stress to the animal. This design is also amenable for multimodal imaging, allowing for electrode or lens placement above the skull via the open chamber design. All computer-aided-design (CAD) files and engineering drawings are provided as an open resource, with the majority of the parts designed to be 3D printed.

Exploring the limits of network topology estimation using diffusion-based tractography and tracer studies in the macaque cortex.

Reconstructing the anatomical pathways of the brain to study the human connectome has become an important endeavour for understanding brain function and dynamics. Reconstruction of the cortico-cortical connectivity matrix in vivo often relies on noninvasive diffusion-weighted imaging (DWI) techniques but the extent to which they can accurately represent the topological characteristics of structural connectomes remains unknown. We addressed this question by constructing connectomes using DWI data collected from macaque monkeys in vivo and with data from published invasive tracer studies. We found the strength of fiber tracts was well estimated from DWI and topological properties like degree and modularity were captured by tractography-based connectomes. Rich-club/core-periphery type architecture could also be detected but the classification of hubs using betweenness centrality, participation coefficient and core-periphery identification techniques was inaccurate. Our findings indicate that certain aspects of cortical topology can be faithfully represented in noninvasively-obtained connectomes while other network analytic measures warrant cautionary interpretations.

Intrinsic functional clustering of anterior cingulate cortex in the common marmoset.

The common marmoset (Callithrix jacchus) has garnered recent attention as a potentially powerful preclinical model and complement to other canonical mammalian models of human brain diseases (e.g., rodents and Old World non-human primates). With a granular frontal cortex and the advent of transgenic modifications, marmosets are well positioned to serve as neuropsychiatric models of prefrontal cortex dysfunction. A critical step in the development of marmosets for such models is to characterize functional network topologies of frontal cortex in healthy, normally functioning marmosets. Here, we sought to characterize the intrinsic functional connectivity of anterior cingulate cortex (ACC) in marmosets using resting state functional magnetic resonance imaging (RS-fMRI). Seven lightly anesthetized marmosets were imaged at ultra-high field (9.4 T) and hierarchical clustering was employed to extract functional clusters of ACC from the RS-fMRI data. The data demonstrated three functionally discrete clusters within ACC. The functional connectivity between these clusters with the rest of the brain was also found to be distinct, supporting the hypothesis that ACC subregions serve different circuits and their concomitant functions. In a separate seed-based analysis, we also sought to delineate finer-grained patterns of ACC connectivity between marmoset primary motor area 4ab and putative eye movement areas (8aD and 8aV). This analysis demonstrated distinct patterns of ACC functional connectivity between motor and eye movement regions that overlapped well with what has been shown in humans and macaques. Overall, these results demonstrate that marmosets have a network topology of ACC that resembles that of Old World primates, giving further credence to the use of marmosets for preclinical studies of intractable human brain diseases.

Task-based fMRI of a free-viewing visuo-saccadic network in the marmoset monkey.

Saccadic tasks are often used to index aberrations of cognitive function in patient populations, with several neuropsychiatric and neurologic disorders characterized by saccadic dysfunction. The common marmoset (Callithrix jacchus) has received recent attention as an additional primate model for studying the neural basis of these dysfunctions - marmosets are amenable to a host of genetic manipulation techniques and have a lissencephalic cortex, which is well suited for a variety of recording techniques (e.g., calcium imaging, laminar electrophysiology). Because the marmoset cortex is mostly lissencephalic, however, the locations of frontal saccade-related regions (e.g., frontal eye fields (FEF)) are less readily identified than in Old World macaque monkeys. Further, although high quality histology-based atlases do exist for marmosets, identifying these regions based on histology alone is not always accurate, with the cytoarchitectonic boundaries often inconsonant with functional boundaries. As such, there is a need to map the functional location of these regions directly. Task-based functional magnetic resonance imaging (fMRI) is of utility in this regard, allowing for detection of whole-brain signal changes in response to moving stimuli. Here, we conducted task-based fMRI in marmosets at ultra-high field (9.4 T) during a free-viewing visuo-saccadic task. We also conducted the same task in humans at ultra-high field (7 T) to validate that our simple task was indeed evoking the visuo-saccadic circuitry we expected (as defined by a meta-analysis of fMRI saccade studies). In the marmosets, we found that the task evoked a robust visuo-saccadic topology, with visual cortex (V1, V2, V3, V4) activation extending ventrally to MT, MST, FST and dorsally into V6, 19M, 23V. This topology also included putative cingulate eye field (area 32 and 24d), posterior parietal cortex (with strongest activation in lateral intraparietal area (LIP)), and a frontolateral peak in area 8 aV in marmosets, extending into 45, 46, 8aD, 6DR, 8c, 6 aV, 6DC. Overall, these results support the view that marmosets are a promising preclinical modelling species for studying saccadic dysfunction related to neuropsychiatric or neurodegenerative human brain diseases.

In vivo manganese tract tracing of frontal eye fields in rhesus macaques with ultra-high field MRI: Comparison with DWI tractography.

The saccadic eye movement system has emerged as a valuable model for studying neural circuitry related to flexible control of behavior. Although connections of the saccadic circuitry are well documented via histochemical tracers, these methods require fixed tissue and thus cannot provide longitudinal assessments of connectivity. To circumvent this, diffusion weighted imaging (DWI) is often used as a proxy for connectivity in vivo, allowing for the tracing of connections longitudinally and noninvasively. DWI, however, has certain limitations in its ability to estimate the paths of fiber tracts. Here, we demonstrate the use of manganese, in an animal model, as an MRI-based in vivo labeling technique for saccadic circuitry that allows for direct tract tracing without the need to sacrifice the animal. Manganese is a strong paramagnetic contrast agent used for T1-relaxation enhancement in MRI. Here, we locally injected MnCl2 into the frontal eye fields (FEF), a key saccadic node, of two male rhesus macaques and collected ultra-high field MRI data at 7 T (T1, DWI). The results demonstrate that MnCl2-traced FEF connections parallel those established by histochemical tracing (albeit at a lower spatial resolution) and suggest that DWI underestimates FEF connectivity, likely due to crossing fibers and small tract size. These results highlight the lack of DWI sensitivity for tracing subcortical FEF fibers, but also suggest MnCl2-based tracing as a powerful alternative for assessing these connections in vivo.

BOLD activation of the ventromedial prefrontal cortex in patients with late life depression and comparison participants.

ABSTRACTThe ventromedial prefrontal cortex's (vMPFC) role in regulating emotions in late life depression (LLD) remains unclarified. We assessed vMPFC activation in an emotional valence blood oxygenation level-dependent (BOLD) functional magnetic neuroimaging (fMRI) task and related the findings to extent of white matter hyperintensities (WMH). Sixteen participants with mild to moderate LLD were compared to 14 similar aged comparison participants. Participants in the scanner viewed words matched for length and arousal, indicated the perceived valence by pressing one of the three buttons i.e. "positive, negative, or neutral." WMH volume was greater in LLD participants than comparison participants. There were no differences in activations between groups to any valence contrast. Female LLD participants showed greater activation for negative versus positive and negative versus neutral words as compared to female comparison participants. Female LLD participants respond differently to emotionally laden words compared to comparison participants. WMH could play a role in etiopathology of emotional perception in female LLD participants.