Selective Activation of the Spinal Cord with Epidural Electrical Stimulation.

Spinal cord epidural electrical stimulation (EES) has been successfully employed to treat chronic pain and to restore lost functions after spinal cord injury. Yet, the efficacy of this approach is largely challenged by the suboptimal spatial distribution of the electrode contacts across anatomical targets, limiting the spatial selectivity of stimulation. In this study, we exploited different ESS paradigms, designed as either Spatial-Selective Stimulation (SSES) or Orientation-Selective Epidural Stimulation (OSES), and compared them to Conventional Monopolar Epidural Stimulation (CMES). SSES, OSES, and CMES were delivered with a 3- or 4-contact electrode array. Amplitudes and latencies of the Spinally Evoked Motor Potentials (SEMPs) were evaluated with different EES modalities. The results demonstrate that the amplitudes of SEMPs in hindlimb muscles depend on the orientation of the electrical field and vary between stimulation modalities. These findings show that the electric field applied with SSES or OSES provides more selective control of amplitudes of the SEMPs as compared to CMES. We demonstrate that spinal cord epidural stimulation applied with SSES or OSES paradigms in the rodent model could be tailored to the functional spinal cord neuroanatomy and can be tuned to specific target fibers and their orientation, optimizing the effect of neuromodulation.

Distance from main arteries influences microstructural and functional brain tissue characteristics.

Given the substantial dependence of neurons on continuous supply of energy, the distribution of major cerebral arteries opens a question whether the distance from the main supply arteries constitutes a modulating factor for the microstructural and functional properties of brain tissue. To tackle this question, multimodal MRI acquisitions of 102 healthy volunteers over the full adult age span were utilised. Relaxation along a fictitious field in the rotating frame of rank n = 4 (RAFF4), adiabatic T1ρ, T2ρ,  and intracellular volume fraction (fICVF) derived from diffusion-weighted imaging were implemented to quantify microstructural (cellularity, myelin density, iron concentration) tissue characteristics and degree centrality and fractional amplitude of low-frequency fluctuations to probe for functional metrics. Inverse correlation of arterial distance with robust homogeneity was detected for T1ρ, T2ρ and RAFF4 for cortical grey matter and white matter, showing substantial complex microstructural differences between brain tissue close and farther from main arterial trunks. Albeit with wider variability, functional metrics pointed to increased connectivity and neuronal activity in areas farther from main arteries. Surprisingly, multiple of these microstructural and functional distance-based gradients diminished with higher age, pointing to uniformization of brain tissue with ageing. All in all, this pilot study provides a novel insight on brain regionalisation based on artery distance, which merits further investigation to validate its biological underpinnings.

On the geometric phases during radio frequency pulses with sine and cosine amplitude and frequency modulation.

In this work, we describe the formation of geometric phases during nonadiabatic frequency swept (FS) radio frequency (RF) pulses with sine amplitude modulation and cosine frequency modulation functions. The geometric phases during the FS pulse were analyzed using a Schrödinger equation formalism, and the unified analytical expression for the geometric phase was derived. We present the solutions for sub-geometric phase components incorporated in spinor wavefunctions for the RF Hamiltonian of spin ½ nuclei. We demonstrate that the geometric phases during sine/cosine RF pulses are opposite in signs for different initial conditions of the spinor and that geometric phases can accumulate in correspondence to different magnetization trajectories. The derived formalism could be extended for the evaluation of the geometric phases during a wide class of amplitude- and frequency-modulated pulses used in MRI and in high-resolution NMR.

Orientation selective stimulation with tetrahedral electrodes of the rat infralimbic cortex to indirectly target the amygdala.

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.

Neurovascular coupling is optimized to compensate for the increase in proton production from nonoxidative glycolysis and glycogenolysis during brain activation and maintain homeostasis of pH, pCO2 , and pO2.

During transient brain activation cerebral blood flow (CBF) increases substantially more than cerebral metabolic rate of oxygen consumption (CMRO2 ) resulting in blood hyperoxygenation, the basis of BOLD fMRI contrast. Explanations for the high CBF vs. CMRO2 slope, termed neurovascular coupling (NVC) constant, focused on maintainenance of tissue oxygenation to support mitochondrial ATP production. However, paradoxically the brain has a 3-fold lower oxygen extraction fraction (OEF) than other organs with high energy requirements, like heart and muscle during exercise. Here, we hypothesize that the NVC constant and the capillary oxygen mass transfer coefficient (which in combination determine OEF) are co-regulated during activation to maintain simultaneous homeostasis of pH and partial pressure of CO2 and O2 (pCO2 and pO2 ). To test our hypothesis, we developed an arteriovenous flux balance model for calculating blood and brain pH, pCO2 , and pO2 as a function of baseline OEF (OEF0 ), CBF, CMRO2 , and proton production by nonoxidative metabolism coupled to ATP hydrolysis. Our model was validated against published brain arteriovenous difference studies and then used to calculate pH, pCO2, and pO2 in activated human cortex from published calibrated fMRI and PET measurements. In agreement with our hypothesis, calculated pH, pCO2, and pO2 remained close to constant independently of CMRO2 in correspondence to experimental measurements of NVC and OEF0 . We also found that the optimum values of the NVC constant and OEF0 that ensure simultaneous homeostasis of pH, pCO2, and pO2 were remarkably similar to their experimental values. Thus, the high NVC constant is overall determined by proton removal by CBF due to increases in nonoxidative glycolysis and glycogenolysis. These findings resolve the paradox of the brain's high CBF yet low OEF during activation, and may contribute to explaining the vulnerability of brain function to reductions in blood flow and capillary density with aging and neurovascular disease.

Utility of quantitative MRI metrics in brain ageing research.

The advent of new, advanced quantitative MRI metrics allows for in vivo evaluation of multiple biological processes highly relevant for ageing. The presented study combines several MRI parameters hypothesised to detect distinct biological characteristics as myelin density, cellularity, cellular membrane integrity and iron concentration. 116 healthy volunteers, continuously distributed over the whole adult age span, underwent a multi-modal MRI protocol acquisition. Scatterplots of individual MRI metrics revealed that certain MRI protocols offer much higher sensitivity to early adulthood changes while plateauing in higher age (e.g., global functional connectivity in cerebral cortex or orientation dispersion index in white matter), while other MRI metrics provided reverse ability-stable levels in young adulthood with sharp changes with rising age (e.g., T1ρ and T2ρ). Nonetheless, despite the previously published validations of specificity towards microstructural biology based on cytoarchitectonic maps in healthy population or alterations in certain pathologies, several metrics previously hypothesised to be selective to common measures failed to show similar scatterplot distributions, pointing to further confounding factors directly related to age. Furthermore, other metrics, previously shown to detect different biological characteristics, exhibited substantial intercorrelations, be it due to the nature of the MRI protocol itself or co-dependence of relevant biological microstructural processes. All in all, the presented study provides a unique basis for the design and choice of relevant MRI parameters depending on the age group of interest. Furthermore, it calls for caution in simplistic biological inferences in ageing based on one simple MRI metric, even though previously validated under other conditions. Complex multi-modal approaches combining several metrics to extract the shared subcomponent will be necessary to achieve the desired goal of histological MRI.

Orientation selective DBS of entorhinal cortex and medial septal nucleus modulates activity of rat brain areas involved in memory and cognition.

The recently introduced orientation selective deep brain stimulation (OS-DBS) technique freely controls the direction of the electric field's spatial gradient by using multiple contacts with independent current sources within a multielectrode array. The goal of OS-DBS is to align the electrical field along the axonal track of interest passing through the stimulation site. Here we utilized OS-DBS with a planar 3-channel electrode for stimulating the rat entorhinal cortex (EC) and medial septal nucleus (MSN), two promising areas for DBS treatment of Alzheimer's disease. The brain responses to OS-DBS were monitored by whole brain functional magnetic resonance imaging (fMRI) at 9.4 T with Multi-Band Sweep Imaging with Fourier Transformation (MB-SWIFT). Varying the in-plane OS-DBS stimulation angle in the EC resulted in activity modulation of multiple downstream brain areas involved in memory and cognition. Contrary to that, no angle dependence of brain activations was observed when stimulating the MSN, consistent with predictions based on the electrode configuration and on the main axonal directions of the targets derived from diffusion MRI tractography and histology. We conclude that tuning the OS-DBS stimulation angle modulates the activation of brain areas relevant to Alzheimer's disease, thus holding great promise in the DBS treatment of the disease.

Event-recurring multiband SWIFT functional MRI with 200-ms temporal resolution during deep brain stimulation and isoflurane-induced burst suppression in rat.

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.

Whole-brain studies of spontaneous behavior in head-fixed rats enabled by zero echo time MB-SWIFT fMRI.

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.

Tremor associated with similar structural networks in Parkinson's disease and essential tremor.

INTRODUCTION: Despite substantial clinical and pathophysiological differences, the characteristics of tremor in Parkinson's disease (PD) and essential tremor (ET) patients bear certain similarities. The presented study delineates tremor-related structural networks in these two disorders. METHODS: 42 non-advanced PD patients (18 tremor-dominant, 24 without substantial tremor), 17 ET, and 45 healthy controls underwent high-angular resolution diffusion-weighted imaging acquisition to reconstruct their structural motor connectomes as a proxy of the anatomical interconnections between motor network regions, implementing state-of-the-art globally optimised probabilistic tractography. RESULTS: When compared to healthy controls, ET patients exhibited higher structural connectivity in the cerebello-thalamo-cortical network. Interestingly, the comparison of tremor-dominant PD patients and PD patients without tremor yielded very similar results - higher structural connectivity in tremor-dominant PD sharing multiple nodes with the tremor network detected in ET, despite the generally lower structural connectivity between basal ganglia and frontal cortex in the whole PD group when compared to healthy controls. CONCLUSION: The higher structural connectivity of the cerebello-thalamo-cortical network seems to be the dominant tremor driver in both PD and ET. While it appears to be the only tremor-related network in ET, its combination with large scale hypoconnectivity in the frontal cortico-subcortical network in PD may explain different clinical features of tremor in these two disorders.

Infantile status epilepticus disrupts myelin development.

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.

Alterations in Sensorimotor and Mesiotemporal Cortices and Diffuse White Matter Changes in Primary Progressive Multiple Sclerosis Detected by Adiabatic Relaxometry.

Background: The research of primary progressive multiple sclerosis (PPMS) has not been able to capitalize on recent progresses in advanced magnetic resonance imaging (MRI) protocols. Objective: The presented cross-sectional study evaluated the utility of four different MRI relaxation metrics and diffusion-weighted imaging in PPMS. Methods: Conventional free precession T1 and T2, and rotating frame adiabatic T1ρ and T2ρ in combination with diffusion-weighted parameters were acquired in 13 PPMS patients and 13 age- and sex-matched controls. Results: T1ρ, a marker of crucial relevance for PPMS due to its sensitivity to neuronal loss, revealed large-scale changes in mesiotemporal structures, the sensorimotor cortex, and the cingulate, in combination with diffuse alterations in the white matter and cerebellum. T2ρ, particularly sensitive to local tissue background gradients and thus an indicator of iron accumulation, concurred with similar topography of damage, but of lower extent. Moreover, these adiabatic protocols outperformed both conventional T1 and T2 maps and diffusion tensor/kurtosis approaches, methods previously used in the MRI research of PPMS. Conclusion: This study introduces adiabatic T1ρ and T2ρ as elegant markers confirming large-scale cortical gray matter, cerebellar, and white matter alterations in PPMS invisible to other in vivo biomarkers.

Corrigendum: RAFF-4, Magnetization Transfer and Diffusion Tensor MRI of Lysophosphatidylcholine Induced Demyelination and Remyelination in Rats.

[This corrects the article DOI: 10.3389/fnins.2021.625167.].

Spinal cord fMRI with MB-SWIFT for assessing epidural spinal cord stimulation in rats.

PURPOSE: Electrical epidural spinal cord stimulation (SCS) is used as a treatment for chronic pain as well as to partially restore motor function after a spinal cord injury. Monitoring the spinal cord activity during SCS with fMRI could provide important and objective measures of integrative responses to treatment. Unfortunately, spinal cord fMRI is severely challenged by motion and susceptibility artifacts induced by the implanted electrode and bones. This pilot study introduces multi-band sweep imaging with Fourier transformation (MB-SWIFT) technique for spinal cord fMRI during SCS in rats. Given the close to zero acquisition delay and high bandwidth in 3 dimensions, MB-SWIFT is demonstrated to be highly tolerant to motion and susceptibility-induced artifacts and thus holds promise for fMRI during SCS. METHODS: MB-SWIFT with 0.78 × 0.78 × 1.50 mm3 spatial resolution and 3-s temporal resolution was used at 9.4 Tesla in rats undergoing epidural SCS at different frequencies. Its performance was compared with spin echo EPI. The origin of the functional contrast was also explored using suppression bands. RESULTS: MB-SWIFT was tolerant to electrode-induced artifacts and respiratory motion, leading to substantially higher fMRI sensitivity than spin echo fMRI. Clear stimulation frequency-dependent responses to SCS were detected in the rat spinal cord close to the stimulation site. The origin of MB-SWIFT fMRI signals was consistent with dominant inflow effects. CONCLUSION: fMRI of the rat spinal cord during SCS can be consistently achieved with MB-SWIFT, thus providing a valuable experimental framework for assessing the effects of SCS on the central nervous system.

RAFF-4, Magnetization Transfer and Diffusion Tensor MRI of Lysophosphatidylcholine Induced Demyelination and Remyelination in Rats.

Remyelination is a naturally occurring response to demyelination and has a central role in the pathophysiology of multiple sclerosis and traumatic brain injury. Recently we demonstrated that a novel MRI technique entitled Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank n (RAFFn) achieved exceptional sensitivity in detecting the demyelination processes induced by lysophosphatidylcholine (LPC) in rat brain. In the present work, our aim was to test whether RAFF4, along with magnetization transfer (MT) and diffusion tensor imaging (DTI), would be capable of detecting the changes in the myelin content and microstructure caused by modifications of myelin sheets around axons or by gliosis during the remyelination phase after LPC-induced demyelination in the corpus callosum of rats. We collected MRI data with RAFF4, MT and DTI at 3 days after injection (demyelination stage) and at 38 days after injection (remyelination stage) of LPC (n = 12) or vehicle (n = 9). Cell density and myelin content were assessed by histology. All MRI metrics detected differences between LPC-injected and control groups of animals in the demyelination stage, on day 3. In the remyelination phase (day 38), RAFF4, MT parameters, fractional anisotropy, and axial diffusivity detected signs of a partial recovery consistent with the remyelination evident in histology. Radial diffusivity had undergone a further increase from day 3 to 38 and mean diffusivity revealed a complete recovery correlating with the histological assessment of cell density attributed to gliosis. The combination of RAFF4, MT and DTI has the potential to differentiate between normal, demyelinated and remyelinated axons and gliosis and thus it may be able to provide a more detailed assessment of white matter pathologies in several neurological diseases.

Brain fMRI during orientation selective epidural spinal cord stimulation.

Epidural spinal cord stimulation (ESCS) is widely used for chronic pain treatment, and is also a promising tool for restoring motor function after spinal cord injury. Despite significant positive impact of ESCS, currently available protocols provide limited specificity and efficiency partially due to the limited number of contacts of the leads and to the limited flexibility to vary the spatial distribution of the stimulation field in respect to the spinal cord. Recently, we introduced Orientation Selective (OS) stimulation strategies for deep brain stimulation, and demonstrated their selectivity in rats using functional MRI (fMRI). The method achieves orientation selectivity by controlling the main direction of the electric field gradients using individually driven channels. Here, we introduced a similar OS approach for ESCS, and demonstrated orientation dependent brain activations as detected by brain fMRI. The fMRI activation patterns during spinal cord stimulation demonstrated the complexity of brain networks stimulated by OS-ESCS paradigms, involving brain areas responsible for the transmission of the motor and sensory information. The OS approach may allow targeting ESCS to spinal fibers of different orientations, ultimately making stimulation less dependent on the precision of the electrode implantation.

Orientation-selective and directional deep brain stimulation in swine assessed by functional MRI at 3T.

Functional MRI (fMRI) has become an important tool for probing network-level effects of deep brain stimulation (DBS). Previous DBS-fMRI studies have shown that electrical stimulation of the ventrolateral (VL) thalamus can modulate sensorimotor cortices in a frequency and amplitude dependent manner. Here, we investigated, using a swine animal model, how the direction and orientation of the electric field, induced by VL-thalamus DBS, affects activity in the sensorimotor cortex. Adult swine underwent implantation of a novel 16-electrode (4 rows x 4 columns) directional DBS lead in the VL thalamus. A within-subject design was used to compare fMRI responses for (1) directional stimulation consisting of monopolar stimulation in four radial directions around the DBS lead, and (2) orientation-selective stimulation where an electric field dipole was rotated 0°-360° around a quadrangle of electrodes. Functional responses were quantified in the premotor, primary motor, and somatosensory cortices. High frequency electrical stimulation through leads implanted in the VL thalamus induced directional tuning in cortical response patterns to varying degrees depending on DBS lead position. Orientation-selective stimulation showed maximal functional response when the electric field was oriented approximately parallel to the DBS lead, which is consistent with known axonal orientations of the cortico-thalamocortical pathway. These results demonstrate that directional and orientation-selective stimulation paradigms in the VL thalamus can tune network-level modulation patterns in the sensorimotor cortex, which may have translational utility in improving functional outcomes of DBS therapy.

Differential diagnosis of tremor syndromes using MRI relaxometry.

Differential diagnosis of the most common tremor syndromes - essential tremor (ET) and Parkinson's disease (PD) is burdened with high error rate. However, diagnostic MRI biomarkers applicable in this clinically highly relevant scenario remain an unfulfilled objective. The presented study was designed in search for possible candidate MRI protocols relevant for differential diagnostic process in tremor syndromes.10 non-advanced tremor-dominant PD patients meeting diagnostic criteria for clinically established PD, 12 isolated ET patients and 16 healthy controls were enrolled into this study. The study focused on relaxation MRI protocols - T1, T2, adiabatic T1ρ and adiabatic T2ρ due to their relatively low post-processing requirements enabling implementation into routine clinical practice. Compared to ET, PD patients had significantly longer T2 relaxation times in striata with dominant findings in the putamen contralateral to the clinically more affected body side. This difference was driven by alterations in the PD group as confirmed in the complementary comparison with healthy controls. According to the receiver operating characteristic analysis, this region provided a reasonable sensitivity of 0.91 and specificity of 0.89 in the differential diagnosis of PD and ET. In PD patients, we further found prolonged T1ρ in the substantia nigra compared to ET and healthy controls, and shorter T2 and T2ρ in the cerebellum compared to healthy controls. T2 relaxation time in the putamen contralateral to the clinically more affected body side is a plausible candidate diagnostic marker for the differentiation of PD and ET.

Rotating frame MRI relaxations as markers of diffuse white matter abnormalities in multiple sclerosis.

Even though MRI visualization of white matter lesions is pivotal for the diagnosis and management of multiple sclerosis (MS), the issue of detecting diffuse brain tissue damage beyond the apparent T2-hyperintense lesions continues to spark considerable interest. Motivated by the notion that rotating frame MRI methods are sensitive to slow motional regimes critical for tissue characterization, here we utilized novel imaging protocols of rotating frame MRI on a clinical 3 Tesla platform, including adiabatic longitudinal, T1ρ, and transverse, T2ρ, relaxation methods, and Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank 4 (RAFF4), in 10 relapsing-remitting multiple sclerosis patients and 10 sex- and age-matched healthy controls. T1ρ, T2ρ and RAFF4 relaxograms extracted from the whole white matter exhibited a significant shift towards longer relaxation time constants in MS patients as compared to controls. T1ρ and RAFF4 detected alterations even when considering only regions of normally appearing white matter (NAWM), while other MRI metrics such as T1w/T2w ratio and diffusion tensor imaging measures failed to find group differences. In addition, RAFF4, T2ρ and, to a lesser extent, T1ρ showed differences in subcortical grey matter structures, mainly hippocampus, whereas no functional changes in this region were detected in resting-state functional MRI metrics. We conclude that rotating frame MRI techniques are exceptionally sensitive methods for the detection of subtle abnormalities not only in NAWM, but also in deep grey matter in MS, where they surpass even highly sensitive measures of functional changes, which are often suggested to precede detectable structural alterations. Such abnormalities are consistent with a wide spectrum of different, but interconnected pathological features of MS, including the loss of neuronal cells and their axons, decreased levels of myelin even in NAWM, and altered iron content.

Orientation selective deep brain stimulation of the subthalamic nucleus in rats.

Deep brain stimulation (DBS) has become an important tool in the management of a wide spectrum of diseases in neurology and psychiatry. Target selection is a vital aspect of DBS so that only the desired areas are stimulated. Segmented leads and current steering have been shown to be promising additions to DBS technology enabling better control of the stimulating electric field. Recently introduced orientation selective DBS (OS-DBS) is a related development permitting sensitization of the stimulus to axonal pathways with different orientations by freely controlling the primary direction of the electric field using multiple contacts. Here, we used OS-DBS to stimulate the subthalamic nucleus (STN) in healthy rats while simultaneously monitoring the induced brain activity with fMRI. Maximal activation of the sensorimotor and basal ganglia-thalamocortical networks was observed when the electric field was aligned mediolaterally in the STN pointing in the lateral direction, while no cortical activation was observed with the electric field pointing medially to the opposite direction. Such findings are consistent with mediolateral main direction of the STN fibers, as seen with high resolution diffusion imaging and histology. The asymmetry of the OS-DBS dipolar field distribution using three contacts along with the potential stimulation of the internal capsule, are also discussed. We conclude that OS-DBS offers an additional degree of flexibility for optimization of DBS of the STN which may enable a better treatment response.