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Primary sensory systems are classically considered to be separate units, however there is current evidence that there are notable interactions between them. We examined the cross-sensory interplay by applying a quiet and motion-tolerant zero echo time functional magnetic resonance imaging (fMRI) technique to elucidate the evoked brain-wide responses to whisker pad stimulation in awake and anesthetized rats. Specifically, characterized the brain-wide responses in core and non-core regions to whisker pad stimulation by the varying stimulation-frequency, and determined whether isoflurane-medetomidine anesthesia, traditionally used in preclinical imaging, confounded investigations related to sensory integration. We demonstrated that unilateral whisker pad stimulation not only elicited robust activity along the whisker-mediated tactile system, but also in auditory, visual, high-order, and cerebellar regions, indicative of brain-wide cross-sensory and associative activity. By inspecting the response profiles to different stimulation frequencies and temporal signal characteristics, we observed that the non-core regions responded to stimulation in a very different way compared to the primary sensory system, likely reflecting different encoding modes between the primary sensory, cross-sensory, and integrative processing. Lastly, while the activity evoked in low-order sensory structures could be reliably detected under anesthesia, the activity in high-order processing and the complex differences between primary, cross-sensory, and associative systems were visible only in the awake state. We conclude that our study reveals novel aspects of the cross-sensory interplay of whisker-mediated tactile system, and importantly, that these would be difficult to observe in anesthetized rats.

Introduction: Deep brain stimulation (DBS) is a rapidly developing therapeutic intervention with constantly expanding neurological and psychiatric indications. A major challenge for the approach is the precise targeting and limitation of the effect on the desired neural pathways. We have introduced a new approach, orientation selective stimulation (OSS) that allows free rotation of the induced electric field on a plane when using a probe with three parallel electrodes forming an equilateral triangle at the tip. Here, we expand the technique by introducing a tetrahedral stimulation probe that enables adjustment of the primary electric field direction freely at any angle in a 3D space around the stimulating probe. OSS in 3D will enable better targeting of the electric field according to the local brain anatomy. We tested its utility in a rat model of DBS for treatment-resistant depression. The stimulation directed to the subgenual anterior cingulate cortex (sgACC) has yielded dramatic improvement in individual patients suffering from therapy resistant depression, but no consistent benefit in larger series. This failure has been ascribed to the challenging anatomy of sgACC with several crossing neural tracts and individual differences in the local anatomy., Methods: We stimulated infralimbic cortex (IL), the rat analog of sgACC, and recorded local electrical responses in amygdala (AMG) that is monosynaptically connected to IL and plays a central role in emotional states. We further traced AMG-IL connections using a viral vector and tractography using diffusion magnetic resonance imaging (MRI). Finally, we mimicked the clinical situation by delivering sustained 130 Hz stimulation at IL at the most effective field orientation and followed changes in resting-state functional connectivity with IL using functional MRI. To help interpretation of responses in functional connectivity, we stimulated only the left IL, which we did not expect to evoke measurable changes in the rat behavior., Results: The AMG evoked responses depended systematically on the IL stimulation field orientation and yielded the maximum response in near vertical field orientation in accordance with tractography. Sustained 130 Hz stimulation at a field orientation yielding the strongest AMG evoked responses increased functional connectivity between IL and AMG on the stimulation side., Conclusion: These findings suggest that OSS in 3D provides a new approach to optimize the DBS for every individual patient with a single stimulation probe implantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gureviciene, Laakso, Narvaez, Paasonen, Lehto, Gurevicius, Mangia, Michaeli, Gröhn, Sierra and Tanila.)

Traditionally, preclinical resting state functional magnetic resonance imaging (fMRI) studies have been performed in anesthetized animals. Nevertheless, as anesthesia affects the functional connectivity (FC) in the brain, there has been a growing interest in imaging in the awake state. Obviously, awake imaging requires resource- and time-consuming habituation prior to data acquisition to reduce the stress and motion of the animals. Light sedation has been a less widely exploited alternative for awake imaging, requiring shorter habituation times, while still reducing the effect of anesthesia. Here, we imaged 102 rats under light sedation and 10 awake animals to conduct an FC analysis. We established an automated data-processing pipeline suitable for both groups. Additionally, the same pipeline was used on data obtained from an openly available awake rat database (289 measurements in 90 rats). The FC pattern in the light sedation measurements closely resembled the corresponding patterns in both onsite and offsite awake datasets. However, fewer datasets had to be excluded due to movement in rats with light sedation. The temporal analysis of FC in the lightly sedated group indicated a lingering effect of anesthesia that stabilized after the first 5 min. In summary, our results indicate that the light sedation protocol is a valid alternative for large-scale studies where awake protocols may become prohibitively resource-demanding, as it provides similar results to awake imaging, preserves more scans, and requires shorter habituation times. The large amount of fMRI data obtained in this work are openly available for further analyses., (© 2021 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Purpose: To develop a high temporal resolution functional MRI method for tracking repeating events in the brain., Methods: We developed a novel functional MRI method using multiband sweep imaging with Fourier transformation (SWIFT), termed event-recurring SWIFT (EVER-SWIFT). The method is able to image similar repeating events with subsecond temporal resolution. Here, we demonstrate the use of EVER-SWIFT for detecting functional MRI responses during deep brain stimulation of the medial septal nucleus and during spontaneous isoflurane-induced burst suppression in the rat brain at 9.4 T with 200-ms temporal resolution., Results: The EVER-SWIFT approach showed that the shapes and time-to-peak values of the response curves to deep brain stimulation significantly differed between downstream brain regions connected to the medial septal nucleus, resembling findings obtained with traditional 2-second temporal resolution. In contrast, EVER-SWIFT allowed for detailed temporal measurement of a spontaneous isoflurane-induced bursting activity pattern, which was not achieved with traditional temporal resolution., Conclusion: The EVER-SWIFT technique enables subsecond 3D imaging of both stimulated and spontaneously recurring brain activities, and thus holds great potential for studying the mechanisms of neuromodulation and spontaneous brain activity., (© 2022 International Society for Magnetic Resonance in Medicine.)

Understanding the link between the brain activity and behavior is a key challenge in modern neuroscience. Behavioral neuroscience, however, lacks tools to record whole-brain activity in complex behavioral settings. Here we demonstrate that a novel Multi-Band SWeep Imaging with Fourier Transformation (MB-SWIFT) functional magnetic resonance imaging (fMRI) approach enables whole-brain studies in spontaneously behaving head-fixed rats. First, we show anatomically relevant functional parcellation. Second, we show sensory, motor, exploration, and stress-related brain activity in relevant networks during corresponding spontaneous behavior. Third, we show odor-induced activation of olfactory system with high correlation between the fMRI and behavioral responses. We conclude that the applied methodology enables novel behavioral study designs in rodents focusing on tasks, cognition, emotions, physical exercise, and social interaction. Importantly, novel zero echo time and large bandwidth approaches, such as MB-SWIFT, can be applied for human behavioral studies, allowing more freedom as body movement is dramatically less restricting factor., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Temporal lobe epilepsy (TLE) is the most prevalent type of epilepsy in adults; it often starts in infancy or early childhood. Although TLE is primarily considered to be a grey matter pathology, a growing body of evidence links this disease with white matter abnormalities. In this study, we explore the impact of TLE onset and progression in the immature brain on white matter integrity and development utilising the rat model of Li-pilocarpine-induced TLE at the 12th postnatal day (P). Diffusion tensor imaging (DTI) and Black-Gold II histology uncovered disruptions in major white matter tracks (corpus callosum, internal and external capsules, and deep cerebral white matter) spreading through the whole brain at P28. These abnormalities were mostly not present any longer at three months after TLE induction, with only limited abnormalities detectable in the external capsule and deep cerebral white matter. Relaxation Along a Fictitious Field in the rotating frame of rank 4 indicated that white matter changes observed at both timepoints, P28 and P72, are consistent with decreased myelin content. The animals affected by TLE-induced white matter abnormalities exhibited increased functional connectivity between the thalamus and medial prefrontal and somatosensory cortex in adulthood. Furthermore, histological analyses of additional animal groups at P15 and P18 showed only mild changes in white matter integrity, suggesting a gradual age-dependent impact of TLE progression. Taken together, TLE progression in the immature brain distorts white matter development with a peak around postnatal day 28, followed by substantial recovery in adulthood. This developmental delay might give rise to cognitive and behavioural comorbidities typical for early-onset TLE., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Isoflurane, the most commonly used preclinical anesthetic, induces brain plasticity and long-term cellular and molecular changes leading to behavioral and/or cognitive consequences. These changes are most likely associated with network-level changes in brain function. To elucidate the mechanisms underlying long-term effects of isoflurane, we investigated the influence of a single isoflurane exposure on functional connectivity, brain electrical activity, and gene expression. Male Wistar rats (n = 22) were exposed to 1.8% isoflurane for 3 h. Control rats (n = 22) spent 3 h in the same room without exposure to anesthesia. After 1 month, functional connectivity was evaluated with resting-state functional magnetic resonance imaging (fMRI; n = 6 + 6) and local field potential measurements (n = 6 + 6) in anesthetized animals. A whole genome expression analysis (n = 10+10) was also conducted with mRNA-sequencing from cortical and hippocampal tissue samples. Isoflurane treatment strengthened thalamo-cortical and hippocampal-cortical functional connectivity. Cortical low-frequency fMRI power was also significantly increased in response to the isoflurane treatment. The local field potential results indicating strengthened hippocampal-cortical alpha and beta coherence were in good agreement with the fMRI findings. Furthermore, altered expression was found in 20 cortical genes, several of which are involved in neuronal signal transmission, but no gene expression changes were noted in the hippocampus. Isoflurane induced prolonged changes in thalamo-cortical and hippocampal-cortical function and expression of genes contributing to signal transmission in the cortex. Further studies are required to investigate whether these changes are associated with the postoperative behavioral and cognitive symptoms commonly observed in patients and animals., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)