Intrinsic brain activity is increasingly complex and develops asymmetrically during childhood and early adolescence.

A large body of evidence suggests that brain signal complexity (BSC) may be an important indicator of healthy brain functioning or alternately, a harbinger of disease and dysfunction. However, despite recent progress our current understanding of how BSC emerges and evolves in large-scale networks, and the factors that shape these dynamics, remains limited. Here, we utilized resting-state functional near-infrared spectroscopy (rs-fNIRS) to capture and characterize the nature and time course of BSC dynamics within large-scale functional networks in 107 healthy participants ranging from 6-13 years of age. Age-dependent increases in spontaneous BSC were observed predominantly in higher-order association areas including the default mode (DMN) and attentional (ATN) networks. Our results also revealed asymmetrical developmental patterns in BSC that were specific to the dorsal and ventral ATN networks, with the former showing a left-lateralized and the latter demonstrating a right-lateralized increase in BSC. These age-dependent laterality shifts appeared to be more pronounced in females compared to males. Lastly, using a machine-learning model, we showed that BSC is a reliable predictor of chronological age. Higher-order association networks such as the DMN and dorsal ATN demonstrated the most robust prognostic power for predicting ages of previously unseen individuals. Taken together, our findings offer new insights into the spatiotemporal patterns of BSC dynamics in large-scale intrinsic networks that evolve over the course of childhood and adolescence, suggesting that a network-based measure of BSC represents a promising approach for tracking normative brain development and may potentially aid in the early detection of atypical developmental trajectories.

Robust dynamic brain coactivation states estimated in individuals.

A confluence of evidence indicates that brain functional connectivity is not static but rather dynamic. Capturing transient network interactions in the individual brain requires a technology that offers sufficient within-subject reliability. Here, we introduce an individualized network-based dynamic analysis technique and demonstrate that it is reliable in detecting subject-specific brain states during both resting state and a cognitively challenging language task. We evaluate the extent to which brain states show hemispheric asymmetries and how various phenotypic factors such as handedness and gender might influence network dynamics, discovering a right-lateralized brain state that occurred more frequently in men than in women and more frequently in right-handed versus left-handed individuals. Longitudinal brain state changes were also shown in 42 patients with subcortical stroke over 6 months. Our approach could quantify subject-specific dynamic brain states and has potential for use in both basic and clinical neuroscience research.

Individualized functional connectome identified generalizable biomarkers for psychiatric symptoms in transdiagnostic patients.

Substantial clinical heterogeneity and comorbidity inherent amongst mental disorders limit the identification of neuroimaging biomarkers that can reliably track clinical symptoms. Strategies that enable generation of meaningful and replicable neurobiological markers at the individual level will push the field of neuropsychiatry forward in developing efficacious personalized treatment. The current study included 142 adult patients with a primary diagnosis of schizophrenia (SCZ), bipolar (BP), or attention deficit/hyperactivity disorder (ADHD), and 67 patient ratings across four behavioral measures. Using functional connectivity derived from a personalized fMRI approach, we identified several candidate imaging markers related to dimensional phenotypes across disorders, assessed the internal and external generalizability of these markers, and compared the probability of replicating findings across datasets using individual and group-averaged defined functional regions. We identified subject-specific connections related to three different clinical domains (attention deficit, appetite-energy, psychosis-positive) in a discovery dataset. Importantly, these connectivity biomarkers were robust and were reproduced in an independent validation dataset. For markers related to neurovegetative symptoms (attention deficit, appetite-energy symptoms), the brain connections involved showed similar connectivity patterns across the different diagnoses. However, psychosis-positive symptoms were associated with connections of varying strength across disorders. Finally, we found that markers for symptom domains were replicable for individually-specified connections, but not for group template-derived connections. Our personalized strategies allowed us to identify meaningful and generalizable imaging markers for symptom domains in patients who exhibit high levels of heterogeneity. These biomarkers may shed new light on the connectivity underpinnings of psychiatric symptoms and lead to personalized interventions.

Fast cortical surface reconstruction from MRI using deep learning.

Reconstructing cortical surfaces from structural magnetic resonance imaging (MRI) is a prerequisite for surface-based functional and anatomical image analyses. Conventional algorithms for cortical surface reconstruction are computationally inefficient and typically take several hours for each subject, causing a bottleneck in applications when a fast turnaround time is needed. To address this challenge, we propose a fast cortical surface reconstruction (FastCSR) pipeline by leveraging deep machine learning. We trained our model to learn an implicit representation of the cortical surface in volumetric space, termed the "level set representation". A fast volumetric topology correction method and a topology-preserving surface mesh extraction procedure were employed to reconstruct the cortical surface based on the level set representation. Using 1-mm isotropic T1-weighted images, the FastCSR pipeline was able to reconstruct a subject's cortical surfaces within 5 min with comparable surface quality, which is approximately 47 times faster than the traditional FreeSurfer pipeline. The advantage of FastCSR becomes even more apparent when processing high-resolution images. Importantly, the model demonstrated good generalizability in previously unseen data and showed high test-retest reliability in cortical morphometrics and anatomical parcellations. Finally, FastCSR was robust to images with compromised quality or with distortions caused by lesions. This fast and robust pipeline for cortical surface reconstruction may facilitate large-scale neuroimaging studies and has potential in clinical applications wherein brain images may be compromised.

Personalized fMRI Delineates Functional Regions Preserved within Brain Tumors.

OBJECTIVE: Accumulating evidence from invasive cortical stimulation mapping and noninvasive neuroimaging studies indicates that brain function may be preserved within brain tumors. However, a noninvasive approach to accurately and comprehensively delineate individual-specific functional networks in the whole brain, especially in brain tissues within and surrounding tumors, is still lacking. The purpose of the study is to develop a clinically useful technique that can map functional regions within tumoral brains. METHODS: We developed an individual-specific functional network parcellation approach using resting state functional magnetic resonance imaging (rsfMRI) that effectively captured functional networks within and nearby tumors in 20 patients. We examined the accuracy of the functional maps using invasive cortical stimulation and task response. RESULTS: We found that approximately 33.2% of the tumoral mass appeared to be functionally active and demonstrated robust functional connectivity with non-tumoral brain regions. Functional networks nearby tumors were validated by invasive cortical stimulation mapping. Intratumoral sensorimotor networks mapped by our technique could be distinguished by their distinct cortico-cerebellar connectivity patterns and were consistent with hand movement evoked fMRI task activations. Furthermore, in some patients, cognitive networks that were detected in the tumor mass showed long-distance and distributed functional connectivity. INTERPRETATION: Our noninvasive approach to mapping individual-specific functional networks using rsfMRI represents a promising new tool for identifying regions with preserved functional connectivity within and surrounding brain tumors, and could be used as a complement to presurgical planning for patients undergoing tumor resection surgery. ANN NEUROL 2022;91:353-366.

Dissociable Auditory Cortico-Cerebellar Pathways in the Human Brain Estimated by Intrinsic Functional Connectivity.

The cerebellum, a structure historically associated with motor control, has more recently been implicated in several higher-order auditory-cognitive functions. However, the exact functional pathways that mediate cerebellar influences on auditory cortex (AC) remain unclear. Here, we sought to identify auditory cortico-cerebellar pathways based on intrinsic functional connectivity magnetic resonance imaging. In contrast to previous connectivity studies that principally consider the AC as a single functionally homogenous unit, we mapped the cerebellar connectivity across different parts of the AC. Our results reveal that auditory subareas demonstrating different levels of interindividual functional variability are functionally coupled with distinct cerebellar regions. Moreover, auditory and sensorimotor areas show divergent cortico-cerebellar connectivity patterns, although sensorimotor areas proximal to the AC are often functionally grouped with the AC in previous connectivity-based network analyses. Lastly, we found that the AC can be functionally segmented into highly similar subareas based on either cortico-cerebellar or cortico-cortical functional connectivity, suggesting the existence of multiple parallel auditory cortico-cerebellar circuits that involve different subareas of the AC. Overall, the present study revealed multiple auditory cortico-cerebellar pathways and provided a fine-grained map of AC subareas, indicative of the critical role of the cerebellum in auditory processing and multisensory integration.

Subthalamic Nucleus Deep Brain Stimulation Modulates 2 Distinct Neurocircuits.

OBJECTIVE: Current understanding of the neuromodulatory effects of deep brain stimulation (DBS) on large-scale brain networks remains elusive, largely due to the lack of techniques that can reveal DBS-induced activity at the whole-brain level. Using a novel 3T magnetic resonance imaging (MRI)-compatible stimulator, we investigated whole-brain effects of subthalamic nucleus (STN) stimulation in patients with Parkinson disease. METHODS: Fourteen patients received STN-DBS treatment and participated in a block-design functional MRI (fMRI) experiment, wherein stimulations were delivered during "ON" blocks interleaved with "OFF" blocks. fMRI responses to low-frequency (60Hz) and high-frequency(130Hz) STN-DBS were measured 1, 3, 6, and 12 months postsurgery. To ensure reliability, multiple runs (48 minutes) of fMRI data were acquired at each postsurgical visit. Presurgical resting-state fMRI (30 minutes) data were also acquired. RESULTS: Two neurocircuits showed highly replicable, but distinct responses to STN-DBS. A circuit involving the globus pallidus internus (GPi), thalamus, and deep cerebellar nuclei was significantly activated, whereas another circuit involving the primary motor cortex (M1), putamen, and cerebellum showed DBS-induced deactivation. These 2 circuits were dissociable in terms of their DBS-induced responses and resting-state functional connectivity. The GPi circuit was frequency-dependent, selectively responding to high-frequency stimulation, whereas the M1 circuit was responsive in a time-dependent manner, showing enhanced deactivation over time. Finally, activation of the GPi circuit was associated with overall motor improvement, whereas M1 circuit deactivation was related to reduced bradykinesia. INTERPRETATION: Concurrent DBS-fMRI using 3T revealed 2 distinct circuits that responded differentially to STN-DBS and were related to divergent symptoms, a finding that may provide novel insights into the neural mechanisms underlying DBS. ANN NEUROL 2020;88:1178-1193.

Aberrant Salience? Brain Hyperactivation in Response to Pain Onset and Offset in Fibromyalgia.

OBJECTIVE: While much brain research on fibromyalgia (FM) focuses on the study of hyperresponsiveness to painful stimuli, some studies suggest that the increased pain-related brain activity often reported in FM studies may be partially explained by stronger responses to salient aspects of the stimulation rather than, or in addition to, the stimulation's painfulness. Therefore, this study was undertaken to test our hypothesis that FM patients would demonstrate elevated brain responses to both pain onset and offset-2 salient sensory events of opposing valences. METHODS: Thirty-eight FM patients (mean ± SD age 46.1 ± 13.4 years; 33 women) and 15 healthy controls (mean ± SD age 45.5 ± 12.4; 10 women) received a moderately painful pressure stimulus to the leg during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Stimulus onset and offset transients were analyzed using a general linear model as stick functions. RESULTS: During pain onset, higher BOLD signal response was observed in FM patients compared to healthy controls in dorsolateral and ventrolateral prefrontal cortices (DLPFC and VLPFC, respectively), orbitofrontal cortex (OFC), frontal pole, and precentral gyrus (PrCG). During pain offset, higher and more widespread BOLD signal response was demonstrated in FM patients compared to controls in frontal regions significantly hyperactivated in response to onset. In FM patients, some of these responses were positively correlated with pain unpleasantness ratings (VLPFC, onset; r = 0.35, P = 0.03), pain catastrophizing scores (DLPFC, offset; r = 0.33, P = 0.04), or negatively correlated with stimulus intensity (OFC, offset; r = -0.35, P = 0.03) (PrCG, offset; r = -0.39, P = 0.02). CONCLUSION: Our results suggest that the increased sensitivity exhibited by FM patients in response to the onset and offset of painful stimuli may reflect a more generalized hypersensitivity to salient sensory events, and that brain hyperactivation may be a mechanism potentially involved in the generalized hypervigilance to salient stimuli in FM.

The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study.

BACKGROUND: Brainstem-focused mechanisms supporting transcutaneous auricular VNS (taVNS) effects are not well understood, particularly in humans. We employed ultrahigh field (7T) fMRI and evaluated the influence of respiratory phase for optimal targeting, applying our respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique. HYPOTHESIS: We proposed that targeting of nucleus tractus solitarii (NTS) and cardiovagal modulation in response to taVNS stimuli would be enhanced when stimulation is delivered during a more receptive state, i.e. exhalation. METHODS: Brainstem fMRI response to auricular taVNS (cymba conchae) was assessed for stimulation delivered during exhalation (eRAVANS) or inhalation (iRAVANS), while exhalation-gated stimulation over the greater auricular nerve (GANctrl, i.e. earlobe) was included as control. Furthermore, we evaluated cardiovagal response to stimulation by calculating instantaneous HF-HRV from cardiac data recorded during fMRI. RESULTS: Our findings demonstrated that eRAVANS evoked fMRI signal increase in ipsilateral pontomedullary junction in a cluster including purported NTS. Brainstem response to GANctrl localized a partially-overlapping cluster, more ventrolateral, consistent with spinal trigeminal nucleus. A region-of-interest analysis also found eRAVANS activation in monoaminergic source nuclei including locus coeruleus (LC, noradrenergic) and both dorsal and median raphe (serotonergic) nuclei. Response to eRAVANS was significantly greater than iRAVANS for all nuclei, and greater than GANctrl in LC and raphe nuclei. Furthermore, eRAVANS, but not iRAVANS, enhanced cardiovagal modulation, confirming enhanced eRAVANS response on both central and peripheral neurophysiological levels. CONCLUSION: 7T fMRI localized brainstem response to taVNS, linked such response with autonomic outflow, and demonstrated that taVNS applied during exhalation enhanced NTS targeting.

Microstructural White Matter Abnormalities in the Dorsal Cingulum of Adolescents with IBS.

Alterations in fractional anisotropy (FA) have been considered to reflect microstructural white matter (WM) changes in disease conditions; however, no study to date has examined WM changes using diffusion tensor imaging (DTI) in adolescents with irritable bowel syndrome (IBS). The objective of the present study was two-fold: (1) to determine whether differences in FA, and other non-FA metrics, were present in adolescents with IBS compared to healthy controls using whole-brain, region of interest (ROI)-restricted tract-based spatial statistics (TBSS) and canonical ROI DTI analyses for the cingulum bundle, and (2) to determine whether these metrics were related to clinical measures of disease duration and pain intensity in the IBS group. A total of 16 adolescents with a Rome III diagnosis of IBS (females = 12; mean age = 16.29, age range: 11.96-18.5 years) and 16 age- and gender-matched healthy controls (females = 12; mean age = 16.24; age range: 11.71-20.32 years) participated in this study. Diffusion-weighted images were acquired using a Siemens 3-T Trio Tim Syngo MRI scanner with a 32-channel head coil. The ROI-restricted TBSS and canonical ROI-based DTI analyses revealed that adolescents with IBS showed decreased FA in the right dorsal cingulum bundle compared to controls. No relationship between FA and disease severity measures was found. Microstructural WM alterations in the right dorsal cingulum bundle in adolescents with IBS may reflect a premorbid brain state or the emergence of a disease-driven process that results from complex changes in pain- and affect-related processing via spinothalamic and corticolimbic pathways.

High Frequency Migraine Is Associated with Lower Acute Pain Sensitivity and Abnormal Insula Activity Related to Migraine Pain Intensity, Attack Frequency, and Pain Catastrophizing.

Migraine is a pain disorder associated with abnormal brain structure and function, yet the effect of migraine on acute pain processing remains unclear. It also remains unclear whether altered pain-related brain responses and related structural changes are associated with clinical migraine characteristics. Using fMRI and three levels of thermal stimuli (non-painful, mildly painful, and moderately painful), we compared whole-brain activity between 14 migraine patients and 14 matched controls. Although, there were no significant differences in pain thresholds nor in pre-scan pain ratings to mildly painful thermal stimuli, patients did have aberrant suprathreshold nociceptive processing. Brain imaging showed that, compared to controls, patients had reduced activity in pain modulatory regions including left dorsolateral prefrontal, posterior parietal, and middle temporal cortices and, at a lower-threshold, greater activation in the right mid-insula to moderate pain vs. mild pain. We also found that pain-related activity in the insula was associated with clinical variables in patients, including associations between: bilateral anterior insula and pain catastrophizing (PCS); bilateral anterior insula and contralateral posterior insula and migraine pain intensity; and bilateral posterior insula and migraine frequency at a lower-threshold. PCS and migraine pain intensity were also negatively associated with activity in midline regions including posterior cingulate and medial prefrontal cortices. Diffusion tensor imaging revealed a negative correlation between fractional anisotropy (a measure of white matter integrity; FA) and migraine duration in the right mid-insula and a positive correlation between left mid-insula FA and PCS. In sum, while patients showed lower sensitivity to acute noxious stimuli, the neuroimaging findings suggest enhanced nociceptive processing and significantly disrupted modulatory networks, particularly involving the insula, associated with indices of disease severity in migraine.

Brain Changes in Responders vs. Non-Responders in Chronic Migraine: Markers of Disease Reversal.

The aim of this study was to identify structural and functional brain changes that accompanied the transition from chronic (CM; ≥15 headache days/month) to episodic (EM; <15 headache days/month) migraine following prophylactic treatment with onabotulinumtoxinA (BoNT-A). Specifically, we examined whether CM patients responsive to prophylaxis (responders; n = 11), as evidenced by a reversal in disease status (defined by at least a 50% reduction in migraine frequency and <15 headache days/month), compared to CM patients whose migraine frequency remained unchanged (non-responders; n = 12), showed differences in cortical thickness using surface-based morphometry. We also investigated whether areas showing group differences in cortical thickness displayed altered resting-state functional connectivity (RS-FC) using seed-to-voxel analyses. Migraine characteristics measured across groups included disease duration, pain intensity and headache frequency. Patient reports of headache frequency over the 4 weeks prior to (pre-treatment) and following (post-treatment) prophylaxis were compared (post minus pre) and this measure served as the clinical endpoint that determined group assignment. All patients were scanned within 2 weeks of the post-treatment visit. Results revealed that responders showed significant cortical thickening in the right primary somatosensory cortex (SI) and anterior insula (aINS), and left superior temporal gyrus (STG) and pars opercularis (ParsOp) compared to non-responders. In addition, disease duration was negatively correlated with cortical thickness in fronto-parietal and temporo-occipital regions in responders but not non-responders, with the exception of the primary motor cortex (MI) that showed the opposite pattern; disease duration was positively associated with MI cortical thickness in responders versus non-responders. Our seed-based RS-FC analyses revealed anti-correlations between the SI seed and lateral occipital (LOC) and dorsomedial prefrontal cortices (DMPFC) in responders, whereas non-responders showed increased connectivity between the ParsOp seed and LOC. Overall, our findings revealed distinct morphometric and functional brain changes in CM patients that reverted to EM following prophylactic treatment compared to CM patients that showed no change in disease status. Elucidating the CNS changes involved in disease reversal may be critical to discovering interventions that prevent or slow the progression of CM. Such changes may aid in the evaluation of treatments as well as provide markers for disease "de-chronification".

Abdominal Pain, the Adolescent and Altered Brain Structure and Function.

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder of unknown etiology. Although relatively common in children, how this condition affects brain structure and function in a pediatric population remains unclear. Here, we investigate brain changes in adolescents with IBS and healthy controls. Imaging was performed with a Siemens 3 Tesla Trio Tim MRI scanner equipped with a 32-channel head coil. A high-resolution T1-weighted anatomical scan was acquired followed by a T2-weighted functional scan. We used a surface-based morphometric approach along with a seed-based resting-state functional connectivity (RS-FC) analysis to determine if groups differed in cortical thickness and whether areas showing structural differences also showed abnormal RS-FC patterns. Patients completed the Abdominal Pain Index and the GI Module of the Pediatric Quality of Life Inventory to assess abdominal pain severity and impact of GI symptoms on health-related quality of life (HRQOL). Disease duration and pain intensity were also assessed. Pediatric IBS patients, relative to controls, showed cortical thickening in the posterior cingulate (PCC), whereas cortical thinning in posterior parietal and prefrontal areas were found, including the dorsolateral prefrontal cortex (DLPFC). In patients, abdominal pain severity was related to cortical thickening in the intra-abdominal area of the primary somatosensory cortex (SI), whereas HRQOL was associated with insular cortical thinning. Disease severity measures correlated with cortical thickness in bilateral DLPFC and orbitofrontal cortex. Patients also showed reduced anti-correlations between PCC and DLPFC compared to controls, a finding that may reflect aberrant connectivity between default mode and cognitive control networks. We are the first to demonstrate concomitant structural and functional brain changes associated with abdominal pain severity, HRQOL related to GI-specific symptoms, and disease-specific measures in adolescents with IBS. It is possible such changes will be responsive to therapeutic intervention and may be useful as potential markers of disease progression or reversal.

Estrogen-dependent visceral hypersensitivity following stress in rats: An fMRI study.

We used functional MRI and a longitudinal design to investigate the brain mechanisms in a previously reported estrogen-dependent visceral hypersensitivity model. We hypothesized that noxious visceral stimulation would be associated with activation of the insula, anterior cingulate cortex, and amygdala, and that estrogen-dependent, stress-induced visceral hypersensitivity would both enhance activation of these regions and recruit activation of other brain areas mediating affect and reward processing. Ovariectomized rats were treated with estrogen (17 ß-estradiol, E2) or vehicle (n = 5 per group) and scanned in a 7T MRI at three different time points: pre-stress (baseline), 2 days post-stress, and 18 days post-stress. Stress was induced via a forced-swim paradigm. In a separate group of ovariectomized rats, E2 treatment induced visceral hypersensitivity at the 2 days post-stress time point, and this hypersensitivity returned to baseline at the 18 days post-stress time point. Vehicle-treated rats show no hypersensitivity following stress. During the MRI scans, rats were exposed to noxious colorectal distention. Across groups and time points, noxious visceral stimulation led to activations in the insula, anterior cingulate, and left amygdala, parabrachial nuclei, and cerebellum. A group-by-time interaction was seen in the right amygdala, ventral striatum-pallidum, cerebellum, hippocampus, mediodorsal thalamus, and pontine nuclei. Closer inspection of the data revealed that vehicle-treated rats showed consistent activations and deactivations across time, whereas estrogen-treated animals showed minimal deactivation with noxious visceral stimulation. This unexpected finding suggests that E2 may dramatically alter visceral nociceptive processing in the brain following an acute stressor. This study is the first to examine estrogen-stress dependent interactions in response to noxious visceral stimulation using functional MRI. Future studies that include other control groups and larger sample sizes are needed to fully understand the interactions between sex hormones, stress, and noxious stimulation on brain activity.

Altered cognition-related brain activity and interactions with acute pain in migraine.

Little is known about the effect of migraine on neural cognitive networks. However, cognitive dysfunction is increasingly being recognized as a comorbidity of chronic pain. Pain appears to affect cognitive ability and the function of cognitive networks over time, and decrements in cognitive function can exacerbate affective and sensory components of pain. We investigated differences in cognitive processing and pain-cognition interactions between 14 migraine patients and 14 matched healthy controls using an fMRI block-design with two levels of task difficulty and concurrent heat (painful and not painful) stimuli. Across groups, cognitive networks were recruited in response to a difficult cognitive task, and a pain-task interaction was found in the right (contralateral to pain stimulus) posterior insula (pINS), such that activity was modulated by decreasing the thermal pain stimulus or by engaging the difficult cognitive task. Migraine patients had less task-related deactivation within the left dorsolateral prefrontal cortex (DLPFC) and left dorsal anterior midcingulate cortex (aMCC) compared to controls. These regions have been reported to have decreased cortical thickness and cognitive-related deactivation within other pain populations, and are also associated with pain regulation, suggesting that the current findings may reflect altered cognitive function and top-down regulation of pain. During pain conditions, patients had decreased task-related activity, but more widespread task-related reductions in pain-related activity, compared to controls, suggesting cognitive resources may be diverted from task-related to pain-reduction-related processes in migraine. Overall, these findings suggest that migraine is associated with altered cognitive-related neural activity, which may reflect altered pain regulatory processes as well as broader functional restructuring.

Behavioral, metabolic and functional brain changes in a rat model of chronic neuropathic pain: a longitudinal MRI study.

Peripheral neuropathy often manifests clinically with symptoms of mechanical and cold allodynia. However, the neuroplastic changes associated with peripheral neuropathic pain and the onset and progression of allodynic symptoms remain unclear. Here, we used a chronic neuropathic pain model (spared nerve injury; SNI) to examine functional and metabolic brain changes associated with the development and maintenance of mechanical and cold hypersensitivity, the latter which we assessed both behaviorally and during a novel acetone application paradigm using functional MRI (fMRI). Female Sprague-Dawley rats underwent SNI (n=7) or sham (n=5) surgery to the left hindpaw. Rats were anesthetized and scanned using a 7 T MRI scanner 1 week prior to (pre-injury) and 4 (early/subchronic) and 20 weeks (late/chronic) post-injury. Functional scans were acquired during acetone application to the left hindpaw. (1)H magnetic resonance spectroscopy was also performed to assess SNI-induced metabolic changes in the anterior cingulate cortex (ACC) pre- and 4 weeks post-injury. Mechanical and cold sensitivity, as well as anxiety-like behaviors, were assessed 2 weeks pre-injury, and 2, 5, 9, 14, and 19 weeks post-injury. Stimulus-evoked brain responses (acetone application to the left hindpaw) were analyzed across the pre- and post-injury time points. In response to acetone application during fMRI, SNI rats showed widespread and functionally diverse changes within pain-related brain regions including somatosensory and cingulate cortices and subcortically within the thalamus and the periaqueductal gray. These functional brain changes temporally coincided with early and sustained increases in both mechanical and cold sensitivity. SNI rats also showed increased glutamate within the ACC that correlated with behavioral measures of cold hypersensitivity. Together, our findings suggest that extensive functional reorganization within pain-related brain regions may underlie the development and chronification of allodynic-like behaviors.

Corticosterone suppresses vasotocin-enhanced clasping behavior in male rough-skinned newts by novel mechanisms interfering with V1a receptor availability and receptor-mediated endocytosis.

In rough-skinned newts, Taricha granulosa, exposure to an acute stressor results in the rapid release of corticosterone (CORT), which suppresses the ability of vasotocin (VT) to enhance clasping behavior. CORT also suppresses VT-induced spontaneous activity and sensory responsiveness of clasp-controlling neurons in the rostromedial reticular formation (Rf). The cellular mechanisms underlying this interaction remain unclear. We hypothesized that CORT blocks VT-enhanced clasping by interfering with V1a receptor availability and/or VT-induced endocytosis. We administered a physiologically active fluorescent VT conjugated to Oregon Green (VT-OG) to the fourth ventricle 9 min after an intraperitoneal injection of CORT (0, 10, 40 µg/0.1mL amphibian Ringers). The brains were collected 30 min post-VT-OG, fixed, and imaged with confocal microscopy. CORT diminished the number of endocytosed vesicles, percent area containing VT-OG, sum intensity of VT-OG, and the amount of VT-V1a within each vesicle; indicating that CORT was interfering with V1a receptor availability and VT-V1a receptor-mediated endocytosis. CORT actions were brain location-specific and season-dependent in a manner that is consistent with the natural and context-dependent expression of clasping behavior. Furthermore, the sensitivity of the Rf to CORT was much higher in animals during the breeding season, arguing for ethologically appropriate seasonal variation in CORT's ability to prevent VT-induced endocytosis. Our data are consistent with the time course and interaction effects of CORT and VT on clasping behavior and neurophysiology. CORT interference with VT-induced endocytosis may be a common mechanism employed by hormones across taxa for mediating rapid context- and season-specific behavioral responses.

Altered Brain Structure and Function Correlate with Disease Severity and Pain Catastrophizing in Migraine Patients.

To investigate the neuroanatomical and functional brain changes in migraine patients relative to healthy controls, we used a combined analytical approach including voxel- and surface-based morphometry along with resting-state functional connectivity to determine whether areas showing structural alterations in patients also showed abnormal functional connectivity. Additionally, we wanted to assess whether these structural and functional changes were associated with group differences in pain catastrophizing and migraine-related disease variables in patients. We acquired T1-weighted anatomical and functional magnetic resonance imaging scans during rest in human subjects with a diagnosis of migraine and healthy controls. Structural analyses revealed greater left hippocampal gray matter volume and reduced cortical thickness in the left anterior midcingulate in patients compared with controls. We also observed negative associations between pain catastrophizing and migraine disease variables and gray matter in areas implicated in processing the sensory, affective, and cognitive aspects of pain in patients. Functional connectivity analyses showed that migraine patients displayed disrupted connectivity between default mode, salience, cognitive, visuospatial, and sensorimotor networks, which was associated with group differences in pain catastrophizing and migraine-related disease variables in patients. Together, our findings show widespread morphological and functional brain abnormalities in migraineurs in affective, cognitive, visual, and pain-related brain areas, which are associated with increased pain catastrophizing, disease chronicity, and severity of symptoms, suggesting that these structural and functional changes may be a consequence of repeated, long-term nociceptive signaling leading to increased pain sensitivity, mood disturbances, and maladaptive coping strategies to deal with unrelenting pain.