Shalom Michaeli

Purpose Functional assessments of the central nervous system (CNS) are essential for many areas of research. Functional MRI (fMRI) typically targets either the brain or the spinal cord, but usually not both, due to the obstacles associated with simultaneous image acquisitions from distant fields of view (FOVs) with conventional MRI. In this work, we establish a novel MRI approach that enables artefact-free, quiet, simultaneous fMRI of both brain and spinal cord, avoiding the need for dynamic shimming procedures. Methods We utilized zero echo time (TE) Multi-Band-SWeep Imaging with Fourier Transformation (MB-SWIFT) technique at 9.4T in a simultaneous dual-FOV configuration and two separate radio frequency (RF) transmit-receive surface coils. The first coil covered the rat brain, while the second was positioned approximately at the T13-L1 level of the rat”s spinal cord with copper shielding to minimize the coupling between the RF coils. Eight Sprague–Dawley rats were used for hindlimb stimulation fMRI studies. Results Robust and specific activations were detected in both the brain and spinal cord during hind paw stimulation at individual and group levels. The results established the feasibility of the novel approach for simultaneous functional assessment of the lumbar spinal cord and brain in rats. Conclusion This study demonstrated the feasibility of a novel dual-FOV fMRI approach based on zero-TE MB-SWIFT and set the stage for translation to humans. The methodology enables comprehensive functional CNS evaluations of great value in different conditions such as pain, spinal cord injury, neurodegenerative diseases, and aging.

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.

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.

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 versus CMRO₂ slope, termed neurovascular coupling (NVC) constant, focused on maintenance 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. image

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.