Target For Neuromodulation Research Articles

Brain Activation of Patients With Obsessive-Compulsive Disorder During a Mental Rotation Task: A Functional MRI Study.

Functional neuroimaging studies have implicated alterations in frontostriatal and frontoparietal circuits in obsessive-compulsive disorder (OCD) during various tasks. To date, however, brain activation for visuospatial function in conjunction with symptoms in OCD has not been comprehensively evaluated. To elucidate the relationship between neural activity, cognitive function, and obsessive-compulsive symptoms, we investigated regional brain activation during the performance of a visuospatial task in patients with OCD using functional magnetic resonance imaging (fMRI). Seventeen medication-free patients with OCD and 21 age-, sex-, and IQ-matched healthy controls participated in this study. Functional magnetic resonance imaging data were obtained while the subjects performed a mental rotation (MR) task. Brain activation during the task was compared between the two groups using a two-sample t-test. Voxel-wise whole-brain multiple regression analyses were also performed to examine the relationship between obsessive-compulsive symptom severity and neural activity during the task. The two groups did not differ in MR task performance. Both groups also showed similar task-related activation patterns in frontoparietal regions with no significant differences. Activation in the right dorsolateral prefrontal cortex in patients with OCD during the MR task was positively associated with their total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores. This study identified the specific brain areas associated with the interaction between symptom severity and visuospatial cognitive function during an MR task in medication-free patients with OCD. These findings may serve as potential neuromodulation targets for OCD treatment.

Stimulation of zona incerta selectively modulates pain in humans

Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. Sensory changes observed in Parkinsonian patients with subthalamic deep brain stimulation suggest that this effect is translatable to humans. Here, we utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. We found that stimulation at 20 Hz, the physiological firing frequency of zona incerta, reduces experimental heat pain by a modest but significant amount, achieving a 30% reduction in one fifth of implants. Stimulation at higher frequencies did not modulate heat pain. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain.

A Unified Functional Network Target for Deep Brain Stimulation in Obsessive-Compulsive Disorder

BackgroundMultiple deep brain stimulation (DBS) targets have been proposed for treating intractable obsessive-compulsive disorder (OCD). Here, we investigated whether stimulation effects of different target sites would be mediated by one common or several segregated functional brain networks. MethodsFirst, seeding from active electrodes of 4 OCD patient cohorts (N = 50) receiving DBS to anterior limb of the internal capsule or subthalamic nucleus zones, optimal functional connectivity profiles for maximal Yale-Brown Obsessive Compulsive Scale improvements were calculated and cross-validated in leave-one-cohort-out and leave-one-patient-out designs. Second, we derived optimal target-specific connectivity patterns to determine brain regions mutually predictive of clinical outcome for both targets and others predictive for either target alone. Functional connectivity was defined using resting-state functional magnetic resonance imaging data acquired in 1000 healthy participants. ResultsWhile optimal functional connectivity profiles showed both commonalities and differences between target sites, robust cross-predictions of clinical improvements across OCD cohorts and targets suggested a shared network. Connectivity to the anterior cingulate cortex, insula, and precuneus, among other regions, was predictive regardless of stimulation target. Regions with maximal connectivity to these commonly predictive areas included the insula, superior frontal gyrus, anterior cingulate cortex, and anterior thalamus, as well as the original stereotactic targets. ConclusionsPinpointing the network modulated by DBS for OCD from different target sites identified a set of brain regions to which DBS electrodes associated with optimal outcomes were functionally connected—regardless of target choice. On these grounds, we establish potential brain areas that could prospectively inform additional or alternative neuromodulation targets for obsessive-compulsive disorder.

Functional connectivity of dorsolateral prefrontal cortex predicts cocaine relapse: implications for neuromodulation treatment.

Relapse is one of the most perplexing problems of addiction. The dorsolateral prefrontal cortex is crucially involved in numerous cognitive and affective processes that are implicated in the phenotypes of both substance use disorders and other neuropsychiatric diseases and has become the principal site to deliver transcranial magnetic stimulation for their treatment. However, the dorsolateral prefrontal cortex is an anatomically large and functionally heterogeneous region, and the specific dorsolateral prefrontal cortex locus and dorsolateral prefrontal cortex-based functional circuits that contribute to drug relapse and/or treatment outcome remain unknown. We systematically investigated the relationship of cocaine relapse with functional circuits from 98 dorsolateral prefrontal cortex regions-of-interest defined by evenly sampling the entire surface of bilateral dorsolateral prefrontal cortex in a cohort of cocaine dependent patients (n = 43, 5 Fr) following a psychosocial treatment intervention. Cox regression models were utilized to predict relapse likelihood based on dorsolateral prefrontal cortex functional connectivity strength. Functional connectivity from only 3 of the 98 dorsolateral prefrontal cortex loci, one in the left and two in the right hemisphere, significantly predicted cocaine relapse with an accuracy of 83.9%, 84.6% and 85.4%, respectively. Combining all three loci significantly improved prediction validity to 87.5%. Protective and risk circuits related to these dorsolateral prefrontal cortex loci were identified that have previously been implicated to support ‘bottom up’ drive to use drug and ‘top down’ control over behaviour together with social emotional, learning and memory processing. Three dorsolateral prefrontal cortex-centric circuits were identified that predict relapse to cocaine use with high accuracy. These functionally distinct dorsolateral prefrontal cortex-based circuits provide insights into the multiple roles played by the dorsolateral prefrontal cortex in cognitive and affective functioning that affects treatment outcome. The identified dorsolateral prefrontal cortex loci may serve as potential neuromodulation targets to be tested in subsequent clinical studies for addiction treatment and as clinically relevant biomarkers of its efficacy. Zhai et al. identify three dorsolateral prefrontal cortex (dlPFC)-centric circuits that predict cocaine relapse with high accuracy, providing insights into the multiple roles of the dlPFC in brain functioning that affects treatment outcome and suggesting the dlPFC loci as potential neuromodulation targets for addiction treatment.

Migraine chronification is associated with beta-band connectivity within the pain-related cortical regions: a magnetoencephalographic study.

Pain disorders are associated with aberrant oscillations in the pain-related cortical regions; however, few studies have investigated the relationship between the functional cortical network and migraine chronification through direct neural signals. Magnetoencephalography was used to record the resting-state brain activity of healthy controls as well as patients with episodic migraine (EM) and chronic migraine (CM). The source-based oscillatory dynamics of the pain-related cortical regions, which comprises 10 node regions (the bilateral primary [SI] and secondary somatosensory cortices, insula, medial frontal cortex, and anterior cingulate cortex [ACC]), were calculated to determine the intrinsic connectivity and node strength at 1 to 40 Hz. The total node strength within the pain-related cortical regions was smaller in the beta band in patients with migraine (70 EM and 80 CM) than in controls (n = 65). In the beta band, the node strength and functional connectivity values of patients with CM and patients with EM differed from those of controls in specific cortical areas, notably the left SI (EM < control) and bilateral ACC (CM < control); moreover, the node strength was lower in patients with CM than in those with EM. In all patients with migraine, negative correlations were observed between headache frequency and node strength in the bilateral ACC. In conclusion, migraine is characterized by reduced beta oscillatory connectivity within the pain-related cortical regions. Reduced beta connectivity in the ACC is linked to migraine chronification. Longitudinal studies should verify whether this oscillation change is a brain signature and a potential neuromodulation target for migraine.

Abstract 54: Bilateral Developmental Alterations in Cortical Morphology in Children With Perinatal Stroke

Perinatal stroke (PS) causes hemiparetic cerebral palsy (CP) and lifelong disability. Compensatory changes in the nonlesioned hemisphere may mediate residual function and represent targets for neuromodulation. Region-based approaches may reveal relationships between cortical thickness of nonlesioned primary motor/sensory cortices and motor function. This study uses surface-based morphometry to explore cortical alterations in the nonlesioned hemisphere in children after perinatal stroke. Children aged 6-19 with MRI-confirmed unilateral perinatal stroke and CP underwent T1-weighted anatomical imaging. Participants were classified as arterial ischemic stroke (AIS; n=36), periventricular venous infarction (PVI; n=38), or typically developing controls (TDC; n=53). Group differences in cortical thickness (distance between grey/white matter boundary and pial surface), grey matter volume, gyrification and sulcal depth and relationships between these morphology metrics and validated measures of motor/executive function were explored. Group comparisons revealed less cortical thickness, greater gyrification, and greater surface area in the nonlesioned hemisphere in both AIS and PVI as compared to TDC. Greater volume and sulcal depth were observed in the nonlesioned hemisphere for AIS. The PVI group showed greater volume in the cingulate cortex and less volume in the precuneus relative to TDC. The AIS group showed more widespread differences than the PVI group in volume and other cortical surface parameters when compared with TDC. Only modest correlations were observed between morphometric changes and clinical function. We suggest that broad differences in structural developmental plasticity occur in the nonlesioned hemisphere after perinatal stroke, particularly the larger lesions seen with AIS, and may represent novel targets for therapeutic neuromodulation.

21813 Changes in Electrophysiologic Activity in the Rat Visual Cortex following Traumatic Brain Injury (TBI)

ABSTRACT IMPACT: This research aims to identify changes in visual network function after TBI as a way to define potential therapeutic targets for neuromodulation or neural tissue substrates. OBJECTIVES/GOALS: The objectives of this study are to compare neural activity in the visual cortex following TBI with cortical activity in the uninjured brain. This study aims to characterize functional changes in single neuron activity, spike-field relationships and oscillatory activity. METHODS/STUDY POPULATION: The effects of TBI will be studied by comparing electrophysiologic recordings from Long-Evans rats with a fluid percussion injury (FPI) to rats with a sham injury. Four days after the injury or sham procedure, a laminar probe with multiple electrode contacts will be chronically implanted in the ipsilesional primary visual cortex (V1). Afterwards, rats will be anesthetized weekly for 3 weeks (up to 4 weeks post-injury) to assess visual processing in response to drifting grating visual stimulation. To assess behavioral correlates, neural activity will also be recorded while rats perform a visual discrimination task in an operant, touchscreen chamber twice weekly. Recordings will be analyzed for visually evoked units, unit entrainment to local field potentials (LFPs) and evoked oscillatory activity. RESULTS/ANTICIPATED RESULTS: Consistent with other studies, our preliminary evidence from V1 recordings in naive rats has shown that individual neurons are responsive to visual stimuli, visual stimuli are associated with evoked oscillations and unit activity is correlated with LFPs. While activity of individual V1 neurons in injured animals is expected to recover to resemble activity in uninjured animals over time, patterns of functional organization in the two groups are expected to diverge over time. We anticipate that TBI-associated axonal damage, neuronal loss and changes in synaptic weights will lead to disruptions in the timing of neural activity in V1. These perturbations of neural communication within the visual system are expected to be associated with behavioral deficits in the awake, visual discrimination task. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study helps define how cortical network disruption after TBI. These changes are potential targets for novel TBI therapeutics, including neuromodulation and neural tissue transplantation. Thus, this work lays the groundwork for future studies aimed at mitigating the effects of TBI with rationally designed experimental therapeutics.

Role of the Anterior Cingulate Cortex in Translational Pain Research.

As the most common symptomatic reason to seek medical consultation, pain is a complex experience that has been classified into different categories and stages. In pain processing, noxious stimuli may activate the anterior cingulate cortex (ACC). But the function of ACC in the different pain conditions is not well discussed. In this review, we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain, neuropathic pain, and cancer pain in the ACC, and discuss the cellular receptors and signaling molecules from animal studies. We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management. The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.

Longitudinal Changes After Amygdala Surgery for Intractable Aggressive Behavior: Clinical, Imaging Genetics, and Deformation-Based Morphometry Study-A Case Series.

Intractable aggressive behavior (iAB) is a devastating behavioral disorder that may affect psychiatric patients. These patients have reduced quality of life, are more challenging to treat as they impose a high caregiver burden and require specialized care. Neuromodulatory interventions targeting the amygdala, a key hub in the circuitry of aggressive behavior (AB), may provide symptom alleviation. To Report clinical and imaging findings from a case series of iAB patients treated with bilateral amygdala ablation. This series included 4 cases (3 males, 19-32 years old) who underwent bilateral amygdala radiofrequency ablation for iAB hallmarked by life-threatening self-injury and social aggression. Pre- and postassessments involved full clinical, psychiatric, and neurosurgical evaluations, including scales quantifying AB, general agitation, quality of life, and magnetic resonance imaging (MRI). Postsurgery assessments revealed decreased aggression and agitation and improved quality of life. AB was correlated with testosterone levels and testosterone/cortisol ratio in males. No clinically significant side effects were observed. Imaging analyses showed preoperative amygdala volumes within normal populational range and confirmed lesion locations. The reductions in aggressive symptoms were accompanied by significant postsurgical volumetric reductions in brain areas classically associated with AB and increases in regions related to somatosensation. The local volumetric reductions are found in areas that in a normal brain show high expression levels of genes related to AB (eg, aminergic transmission) using gene expression data provided by the Allen brain atlas. These findings provide new insight into the whole brain neurocircuitry of aggression and suggest a role of altered somatosensation and possible novel neuromodulation targets.

The Neurocircuitry Underlying Additive Effects of Safety Instruction on Extinction Learning.

Extinction learning is the dominant laboratory model for exposure therapy, a treatment involving both experience of safety near the feared object, and safety instructions relayed by a therapist. While the experiential aspect of extinction learning is well researched, less is known about instructed extinction learning and its neurocircuitry. Here, in 14 healthy participants we examined the neural correlates of, and the network interactions evoked by instructed extinction learning. Following fear conditioning to two CS+ stimuli, participants were instructed about the absence of the aversive unconditioned stimulus (US) for one of the CS+s (instructed CS; CS+I) but not the second CS+ (uninstructed CS+; CS+U). Early during extinction learning, greater activation was observed for the CS+I > CS+U contrast in regions including the vmPFC, dmPFC, vlPFC, and right parahippocampus. Subsequently, psychophysiological interaction (PPI) was applied to investigate functional connectivity of a seed in the vmPFC. This analyses revealed significant modulation of the dmPFC, parahippocampus, amygdala, and insula. Our findings suggest that the addition of cognitive instruction yields greater activation of emotion regulation and reappraisal networks during extinction learning. This work is a step in advancing laboratory paradigms that more accurately model exposure therapy and identifies regions which may be potential targets for neuromodulation to enhance psychotherapy effects.

The Oscillatory Basis of Working Memory Function and Dysfunction in Epilepsy.

Working memory (WM) deficits are pervasive co-morbidities of epilepsy. Although the pathophysiological mechanisms underpinning these impairments remain elusive, it is thought that WM depends on oscillatory interactions within and between nodes of large-scale functional networks. These include the hippocampus and default mode network as well as the prefrontal cortex and frontoparietal central executive network. Here, we review the functional roles of neural oscillations in subserving WM and the putative mechanisms by which epilepsy disrupts normative activity, leading to aberrant oscillatory signatures. We highlight the particular role of interictal epileptic activity, including interictal epileptiform discharges and high frequency oscillations (HFOs) in WM deficits. We also discuss the translational opportunities presented by greater understanding of the oscillatory basis of WM function and dysfunction in epilepsy, including potential targets for neuromodulation.

The role of gap junctions in cell death and neuromodulation in the retina.

Vision altering diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, myopia, retinal vascular disease, traumatic brain injuries and others cripple many lives and are projected to continue to cause anguish in the foreseeable future. Gap junctions serve as an emerging target for neuromodulation and possible regeneration as they directly connect healthy and/or diseased cells, thereby playing a crucial role in pathophysiology. Since they are permeable for macromolecules, able to cross the cellular barriers, they show duality in illness as a cause and as a therapeutic target. In this review, we take recent advancements in gap junction neuromodulation (pharmacological blockade, gene therapy, electrical and light stimulation) into account, to show the gap junction’s role in neuronal cell death and the possible routes of rescuing neuronal and glial cells in the retina succeeding illness or injury.

Deep Brain Stimulation for Stroke: Continuous Stimulation of the Pedunculopontine Tegmental Nucleus has no Impact on Skilled Walking in Rats After Photothrombotic Stroke.

Gait impairment after stroke is considered as a loss of cerebral function but is also the result of dysfunctional cerebral signals travelling to the spinal motor centres. A therapeutic option to restore disturbed cerebral network activity is deep brain stimulation (DBS). A promising target for neuromodulation might be the pedunculopontine tegmental nucleus (PPTg), which contributes to the initiation and control of gait. To test this hypothesis, we trained eighteen rats to cross a horizontal ladder and a wooden beam before inflicting a photothrombosis in the right sensorimotor cortex and implanting a stimulating electrode in the ipsilateral PPTg. Continuous high-frequency DBS (130 Hz; amplitude 55 ± 5 μA) of rats for 10 days yielded no significant improvement of skilled walking when examined with the ladder rung walking test and beam walking test compared to sham-stimulation. In contrast to DBS of the cuneiform nucleus, PPTg-stimulation improves neither control of gait nor balance after stroke.

Integration of Convergent Sensorimotor Inputs Within Spinal Reflex Circuits in Healthy Adults

The output from motor neuron pools is influenced by the integration of synaptic inputs originating from descending corticomotor and spinal reflex pathways. In this study, using paired non-invasive brain and peripheral nerve stimulation, we investigated how descending corticomotor pathways influence the physiologic recruitment order of the soleus Hoffmann (H-) reflex. Eleven neurologically unimpaired adults (9 females; mean age 25 ± 3 years) completed an assessment of transcranial magnetic stimulation (TMS)-conditioning of the soleus H-reflex over a range of peripheral nerve stimulation (PNS) intensities. Unconditioned H-reflex recruitment curves were obtained by delivering PNS pulses to the posterior tibial nerve. Subsequently, TMS-conditioned H-reflex recruitment curves were obtained by pairing PNS with subthreshold TMS at short (−1.5 ms) and long (+10 ms) intervals. We evaluated unconditioned and TMS-conditioned H-reflex amplitudes along the ascending limb, peak, and descending limb of the H-reflex recruitment curve. Our results revealed that, for long-interval facilitation, TMS-conditioned H-reflex amplitudes were significantly larger than unconditioned H-reflex amplitudes along the ascending limb and peak of the H-reflex recruitment curve. Additionally, significantly lower PNS intensities were needed to elicit peak H-reflex amplitude (Hmax) for long-interval facilitation compared to unconditioned. These findings suggest that the influence of descending corticomotor pathways, particularly those mediating long-interval facilitation, contribute to changing the recruitment gain of the motor neuron pool, and can inform future methodological protocols for TMS-conditioning of H-reflexes. By characterizing and inducing short-term plasticity in circuitry mediating short- and long-interval TMS-conditioning of H-reflex amplitudes, future studies can investigate supraspinal and spinal circuit contributions to abnormal motor control, as well as develop novel therapeutic targets for neuromodulation.

Aryl hydrocarbon receptors as potential therapeutic targets

Aryl hydrocarbon receptors (AhR) are regulators of the expression of cytochrome P-450 isoforms, mediating a wide variety of the effects of substances from the endogenous or exogenous origin, including those produced from the microbiome. An exciting new aspect of their activity is their localization in the brain and their potential to modulate the action of the immune system. AhR is emerging as an essential toxicological and therapeutic target for neuromodulation. Further studies are needed for elucidating their utility as drug-targets.

What is the role of the cingulate cortex in pain?

Pain is a complex experience that is perceived as signaling potential danger and has sensory-discriminative, emotional, motivational, and behavioral components. Consistent with its complexity, pain activates several brain areas that form part of distributed networks. The cingulate cortex is a major hub in many of these networks and has a critical role in several aspects of pain processing.1 Functional neuroimaging studies in humans indicate that emotional, cognitive, and motor responses to pain involve different portions of the cingulate cortex.2–4 Studies in mouse models show that areas of the cingulate cortex undergo profound plastic changes in structure and synaptic function in the setting of acute and chronic pain.5,6 The cingulate cortex thus provides a target for neuromodulation using deep brain stimulation (DBS).7

Neuropeptide FF receptor 2 inhibits capsaicin-induced CGRP Upregulation in mouse trigeminal ganglion

BackgroundStimulation of trigeminovascular pathway is widely used to establish the headache animal model. Headache is a common neurological disorder, in which symptomatic attacks are mediated by calcitonin-gene-related peptide (CGRP). CGRP is synthesized and released from the trigeminal ganglion to transmit pain signals under stimulation. On the other hand, Neuropeptide FF (NPFF) is a candidate transmitter/modulator for migraine, and stimulation of its receptor, NPFFR2, increases the expression and release of CGRP in mice sensory neurons. Here, we investigate the impact of NPFFR2 on trigeminal CGRP level in a capsaicin-induced headache mouse model.MethodsMice were intracisternally injected with capsaicin into the cisterna magna to activate the trigeminovascular pathway and induce headache symptoms. Mice pretreated with Npffr2-shRNA or NPFFR2 knockouts were adopted to test the impact of NPFFR2 on capsaicin-induced CGRP upregulation in trigeminal ganglion. The gene silencing effect of Npffr2-shRNA in trigeminal ganglion was confirmed by real-time PCR. Trigeminal CGRP level was determined by immunofluorescence staining, and the percentage of CGRP-positive cell was calculated after setting the signal intensity threshold by Image J software. Amount of trigeminal CGRP in NPFFR2 overexpressed mice was also measured by CGRP ELISA.FindingsInfusion of capsaicin into the cisterna magna upregulated the CGRP in trigeminal ganglion and induced spontaneous pain behaviors including the reduction of locomotor activity and the increase of freezing behavior. Intracisternal injection of Npffr2-shRNA reduced the mRNA of Npffr2 in trigeminal ganglion. Mice pretreatment with Npffr2-shRNA prevented capsaicin-induced CGRP upregulation in trigeminal ganglion. Similarly, CGRP upregulation was also reduced in NPFFR2 knockout mice. On the contrary, trigeminal CGRP was increased in NPFFR2 overexpressed mice.ConclusionsReducing the level of NPFFR2 leads to the downregulation of capsaicin-induced CGRP in trigeminal ganglion, which would consequently attenuate the activation of trigeminovascular pathway. Thus, NPFFR2 could serve as a potential target for neuromodulation of cephalic pain.

Effects of Transcutaneous Electric Nerve Stimulation on Upper Extremity Proprioceptive Function.

Electrical stimulation of the vagus nerve has been shown to enhance cortical plasticity and may benefit upper extremity rehabilitation following stroke. As an initial step towards assessing the potential of other craniocervical nerves as neuromodulation targets during rehabilitation, we explored the ability of non-invasive stimulation of cervical spine afferents, paired with a proprioceptive discrimination task, to improve sensory function in neurologically intact human subjects. On each trial, subjects' arms were moved by a robot from a test position, along a random path, to a judgment position located 1-4 cm away. Subjects responded 'same' if the judgment position was the same as the test or 'different' if it was not. These responses were used to compute proprioceptive sensitivity and bias. Three groups of 20 subjects received transcutaneous electric nerve stimulation to the C3/C4 cervical spine at one of three frequencies (30 Hz, 300 Hz, 3 kHz) for 10 minutes prior to task performance. A fourth group served as a sham. We found a statistically significant interaction between stimulation frequency and displacement distance on proprioceptive sensitivity. In summary, stimulation of cervical spine afferents may enhance arm proprioceptive function, though in unimpaired subjects these gains depend on both stimulation frequency and discrimination distance.Clinical Relevance- This study provides preliminary data on the potential for non-invasive stimulation of cervical spine afferents to enhance recovery of function following stroke and other neurological disorders.

Functional segregation within the pelvic nerve of male rats: a meso- and microscopic analysis.

The pelvic splanchnic nerves are essential for pelvic organ function and have been proposed as targets for neuromodulation. We have focused on the rodent homologue of these nerves, the pelvic nerves. Our goal was to define within the pelvic nerve the projections of organ‐specific sensory axons labelled by microinjection of neural tracer (cholera toxin, subunit B) into the bladder, urethra or rectum. We also examined the location of peptidergic sensory axons within the pelvic nerves to determine whether they aggregated separately from sacral preganglionic and paravertebral sympathetic postganglionic axons travelling in the same nerve. To address these aims, microscopy was performed on the major pelvic ganglion (MPG) with attached pelvic nerves, microdissected from young adult male Sprague–Dawley rats (6–8 weeks old) and processed as whole mounts for fluorescence immunohistochemistry. The pelvic nerves were typically composed of five discrete fascicles. Each fascicle contained peptidergic sensory, cholinergic preganglionic and noradrenergic postganglionic axons. Sensory axons innervating the lower urinary tract (LUT) consistently projected in specific fascicles within the pelvic nerves, whereas sensory axons innervating the rectum projected in a complementary group of fascicles. These discrete aggregations of organ‐specific sensory projections could be followed along the full length of the pelvic nerves. From the junction of the pelvic nerve with the MPG, sensory axons immunoreactive for calcitonin gene‐related peptide (CGRP) showed several distinct patterns of projection: some projected directly to the cavernous nerve, others projected directly across the surface of the MPG to the accessory nerves and a third class entered the MPG, encircling specific cholinergic neurons projecting to the LUT. A subpopulation of preganglionic inputs to noradrenergic MPG neurons also showed CGRP immunoreactivity. Together, these studies reveal new molecular and structural features of the pelvic nerves and suggest functional targets of sensory nerves in the MPG. These anatomical data will facilitate the design of experimental bioengineering strategies to specifically modulate each axon class.

Impaired mesocorticolimbic connectivity underlies increased pain sensitivity in chronic low back pain

Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC)/and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP.