Recent demonstrations of correlated low-frequency MRI signal variations between subregions of the spinal cord at rest in humans, similar to those found in the brain, suggest that such resting-state functional connectivity constitutes a common feature of the intrinsic organization of the entire central nervous system. We report our detection of functional connectivity within the spinal cords of anesthetized squirrel monkeys at rest and show that the strength of connectivity within these networks is altered by the effects of injuries. By quantifying the low-frequency MRI signal correlations between different horns within spinal cord gray matter, we found distinct functional connectivity relationships between the different sensory and motor horns, a pattern that was similar to activation patterns evoked by nociceptive heat or tactile stimulation of digits. All horns within a single spinal segment were functionally connected, with the strongest connectivity occurring between ipsilateral dorsal and ventral horns. Each horn was strongly connected to the same horn on neighboring segments, but this connectivity reduced drastically along the spinal cord. Unilateral injury to the spinal cord significantly weakened the strength of the intrasegment horn-to-horn connectivity only on the injury side and in slices below the lesion. These findings suggest resting-state functional connectivity may be a useful biomarker of functional integrity in injured and recovering spinal cords.hand | spinal cord injury | resting state fMRI | monkey | cervical spinal cord R esting-state functional connectivity (rsFC) has been widely used to identify and characterize neural circuits in the brain (1-3), and its presentation at various spatial scales and its changes with specific physiological conditions confirm its fundamental role in maintaining normal brain function (4, 5). More importantly, alterations of rsFC networks in various disease conditions have altered our view about the functional significance of spontaneous baseline neural activity (3). Two very recent reports of success in detecting intrinsic functional circuits in human spines using resting-state fMRI once more suggest that rsFC is a fundamental, common feature of the entire nervous system (6, 7).Despite these exciting findings in human subjects, the functional and behavioral relevance of the intrinsic functional networks within the spine gray matter remains largely obscure, and there have been no previous reports attempting to understand their significance. One way to address this question is to manipulate the network and then examine how the network reacts to the manipulation. This type of approach is impossible to execute in humans but can be performed in nonhuman primates in a very well-controlled manner. Thus, this study aimed to better understand the functional and behavioral relevance of newly identified rsFC in the spinal cord by first determining whether similar intrinsic rsFC networks can be detected in the spinal cords of anesthetized monkeys. We also sought to determ...

The current knowledge about heat nociception is mainly confined to the thermosensors, including the transient receptor potential cation channel V1 expressed in the nociceptive neurons of dorsal root ganglion (DRG). However, the loss of thermosensors only partially impairs heat nociception, suggesting the existence of undiscovered mechanisms. We found that the loss of an intracellular fibroblast growth factor (FGF), FGF13, in the mouse DRG neurons selectively abolished heat nociception. The noxious heat stimuli could not evoke the sustained action potential firing in FGF13-deficient DRG neurons. Furthermore, FGF13 interacted with the sodium channel Na1.7 in a heat-facilitated manner. FGF13 increased Na1.7 sodium currents and maintained the membrane localization of Na1.7 during noxious heat stimulation, enabling the sustained firing of action potentials. Disrupting the FGF13/Na1.7 interaction reduced the heat-evoked action potential firing and nociceptive behavior. Thus, beyond the thermosensors, the FGF13/Na1.7 complex is essential for sustaining the transmission of noxious heat signals.

Focused ultrasound (FUS) has gained recognition as a technique for non-invasive neuromodulation with high spatial precision and the ability to both excite and inhibit neural activity. Here we demonstrate that MRI-guided FUS is capable of exciting precise targets within areas 3a/3b in the monkey brain, causing downstream activations in off-target somatosensory and associated brain regions which are simultaneously detected by functional MRI. The similarity between natural tactile stimulation-and FUS- evoked fMRI activation patterns suggests that FUS likely can excite populations of neurons and produce associated spiking activities that may be subsequently transmitted to other functionally related touch regions. The across-region differences in fMRI signal changes relative to area 3a/3b between tactile and FUS conditions also indicate that FUS modulated the tactile network differently. The significantly faster rising (>1 sec) fMRI signals elicited by direct FUS stimulation at the targeted cortical region suggest that a different neural hemodynamic coupling mechanism may be involved in generating fMRI signals. This is the first demonstration of imaging neural excitation effects of FUS with BOLD fMRI on a specific functional circuit in non-human primates.

Transcranial focused ultrasound (FUS) stimulation under MRI guidance, coupled with functional MRI (fMRI) monitoring of effects, offers a precise, noninvasive technology to dissect functional brain circuits and to modulate altered brain functional networks in neurological and psychiatric disorders. Here we show that ultrasound at moderate intensities modulated neural activity bi-directionally. Concurrent sonication of somatosensory areas 3a/3b with 250 kHz FUS suppressed the fMRI signals produced there by peripheral tactile stimulation, while at the same time eliciting fMRI activation at inter-connected, off-target brain regions. Direct FUS stimulation of the cortex resulted in different degrees of BOLD signal changes across all five off-target regions, indicating that its modulatory effects on active and resting neurons differed. This is the first demonstration of the dual suppressive and excitative modulations of FUS on a specific functional circuit and of ability of concurrent FUS and MRI to evaluate causal interactions between functional circuits with neuron-class selectivity.