Non-additive effects of electrical stimulation of the dorsolateral prefrontal cortex and the vestibular system on muscle sympathetic nerve activity in humans.

Sinusoidal galvanic vestibular stimulation (sGVS) induces robust modulation of muscle sympathetic nerve activity (MSNA) alongside perceptions of side-to-side movement, sometimes with an accompanying feeling of nausea. We recently showed that transcranial alternating current stimulation (tACS) of the dorsolateral prefrontal cortex (dlPFC) also modulates MSNA, but does not generate any perceptions. Here, we tested the hypothesis that when the two stimuli are given concurrently, the modulation of MSNA would be additive. MSNA was recorded from 11 awake participants via a tungsten microelectrode inserted percutaneously into the right common peroneal nerve at the fibular head. Sinusoidal stimuli (± 2 mA, 0.08 Hz, 100 cycles) were applied in randomised order as follows: (i) tACS of the dlPFC at electroencephalogram (EEG) site F4 and referenced to the nasion; (ii) bilateral sGVS applied to the vestibular apparatuses via the mastoid processes; and (iii) tACS and sGVS together. Previously obtained data from 12 participants supplemented the data for stimulation protocols (i) and (ii). Cross-correlation analysis revealed that each stimulation protocol caused significant modulation of MSNA (modulation index (paired data): 35.2 ± 19.4% for sGVS; 27.8 ± 15.2% for tACS), but there were no additive effects when tACS and sGVS were delivered concurrently (32.1 ± 18.5%). This implies that the vestibulosympathetic reflexes are attenuated with concurrent dlPFC stimulation. These results suggest that the dlPFC is capable of blocking the processing of vestibular inputs through the brainstem and, hence, the generation of vestibulosympathetic reflexes.

The effects of electrical stimulation of ventromedial prefrontal cortex on skin sympathetic nerve activity.

Skin sympathetic nerve activity (SSNA) is primarily involved in thermoregulation and emotional expression; however, the brain regions involved in the generation of SSNA are not completely understood. In recent years, our laboratory has shown that blood-oxygen-level-dependent signal intensity in the ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) are positively correlated with bursts of SSNA during emotional arousal and increases in signal intensity in the vmPFC occurring with increases in spontaneous bursts of SSNA even in the resting state. We have recently shown that unilateral transcranial alternating current stimulation (tACS) of the dlPFC causes modulation of SSNA but given that the current was delivered between electrodes over the dlPFC and the nasion, it is possible that the effects were due to current acting on the vmPFC. To test this, we delivered tACS to target the right vmPFC or dlPFC and nasion and recorded SSNA in 11 healthy participants by inserting a tungsten microelectrode into the right common peroneal nerve. The similarity in SSNA modulation between ipsilateral vmPFC and dlPFC suggests that the ipsilateral vmPFC, rather than the dlPFC, may be causing the modulation of SSNA during ipsilateral dlPFC stimulation.

Recent developments and challenges in positron emission tomography imaging of gliosis in chronic neuropathic pain.

ABSTRACT: Understanding the mechanisms that underpin the transition from acute to chronic pain is critical for the development of more effective and targeted treatments. There is growing interest in the contribution of glial cells to this process, with cross-sectional preclinical studies demonstrating specific changes in these cell types capturing targeted timepoints from the acute phase and the chronic phase. In vivo longitudinal assessment of the development and evolution of these changes in experimental animals and humans has presented a significant challenge. Recent technological advances in preclinical and clinical positron emission tomography, including the development of specific radiotracers for gliosis, offer great promise for the field. These advances now permit tracking of glial changes over time and provide the ability to relate these changes to pain-relevant symptomology, comorbid psychiatric conditions, and treatment outcomes at both a group and an individual level. In this article, we summarize evidence for gliosis in the transition from acute to chronic pain and provide an overview of the specific radiotracers available to measure this process, highlighting their potential, particularly when combined with ex vivo/in vitro techniques, to understand the pathophysiology of chronic neuropathic pain. These complementary investigations can be used to bridge the existing gap in the field concerning the contribution of gliosis to neuropathic pain and identify potential targets for interventions.

Re-examining the Mysterious Role of the Cerebellum in Pain.

Pain is considered a multidimensional experience that embodies not merely sensation, but also emotion and perception. As is appropriate for this complexity, pain is represented and processed by an extensive matrix of cortical and subcortical structures. Of these structures, the cerebellum is gaining increasing attention. Although association between the cerebellum and both acute and chronic pain have been extensively detailed in electrophysiological and neuroimaging studies, a deep understanding of what functions are mediated by these associations is lacking. Nevertheless, the available evidence implies that lobules IV-VI and Crus I are especially pertinent to pain processing, and anatomical studies reveal that these regions connect with higher-order structures of sensorimotor, emotional, and cognitive function. Therefore, we speculate that the cerebellum exerts a modulatory role in pain via its communication with sites of sensorimotor, executive, reward, and limbic function. On this basis, in this review, we propose numerous ways in which the cerebellum might contribute to both acute and chronic pain, drawing particular attention to emotional and cognitive elements of pain. In addition, we emphasise the importance of advancing our knowledge about the relationship between the cerebellum and pain by discussing novel therapeutic opportunities that capitalize on this association.

Infraorbital nerve injury triggers sex-specific neuroimmune responses in the peripheral trigeminal pathway and common pain behaviours.

Trigeminal neuropathic pain is emotionally distressing and disabling. It presents with allodynia, hyperalgesia and dysaesthesia. In preclinical models it has been assumed that cephalic nerve constriction injury shows identical molecular, cellular, and sex dependent neuroimmune changes as observed in extra-cephalic injury models. This study sought empirical evidence for such assumptions using the infraorbital nerve chronic constriction model (ION-CCI). We compared the behavioural consequences of nerve constriction with: (i) the temporal patterns of recruitment of macrophages and T-lymphocytes at the site of nerve injury and in the trigeminal ganglion; and (ii) the degree of demyelination and axonal reorganisation in the injured nerve. Our data demonstrated that simply testing for allodynia and hyperalgesia as is done in extra-cephalic neuropathic pain models does not provide access to the range of injury-specific nociceptive responses and behaviours reflective of the experience of trigeminal neuropathic pain. Similarly, trigeminal neuroimmune changes evoked by nerve injury are not the same as those identified in models of extra-cephalic neuropathy. Specifically, the timing, magnitude, and pattern of ION-CCI evoked macrophage and T-lymphocyte activity differs between the sexes.

Electrical stimulation of the ventromedial prefrontal cortex modulates muscle sympathetic nerve activity and blood pressure.

We recently showed that transcranial alternating current stimulation of the dorsolateral prefrontal cortex modulates spontaneous bursts of muscle sympathetic nerve activity, heart rate, and blood pressure (Sesa-Ashton G, Wong R, McCarthy B, Datta S, Henderson LA, Dawood T, Macefield VG. Stimulation of the dorsolateral prefrontal cortex modulates muscle sympathetic nerve activity and blood pressure in humans. Cereb Cortex Comm. 2022:3:2tgac017.). Stimulation was delivered between scalp electrodes placed over the nasion and electroencephalogram (EEG) electrode site F3 (left dorsolateral prefrontal cortex) or F4 (right dorsolateral prefrontal cortex), and therefore the current passed within the anatomical locations underlying the left and right ventromedial prefrontal cortices. Accordingly, we tested the hypothesis that stimulation of the left and right ventromedial prefrontal cortices would also modulate muscle sympathetic nerve activity, although we predicted that this would be weaker than that seen during dorsolateral prefrontal cortex stimulation. We further tested whether stimulation of the right ventromedial prefrontal cortices would cause greater modulation of muscle sympathetic nerve activity, than stimulation of the left ventromedial prefrontal cortices. In 11 individuals, muscle sympathetic nerve activity was recorded via microelectrodes inserted into the right common peroneal nerve, together with continuous blood pressure, electrocardiogram, and respiration. Stimulation was achieved using transcranial alternating current stimulation, +2 to -2 mA, 0.08 Hz, 100 cycles, applied between electrodes placed over the nasion, and EEG electrode site FP1, (left ventromedial prefrontal cortices) or FP2 (right ventromedial prefrontal cortices); for comparison, stimulation was also applied over F4 (right dorsolateral prefrontal cortex). Stimulation of all three cortical sites caused partial entrainment of muscle sympathetic nerve activity to the sinusoidal stimulation, together with modulation of blood pressure and heart rate. We found a significant fall in mean blood pressure of ~6 mmHg (P = 0.039) during stimulation of the left ventromedial prefrontal cortices, as compared with stimulation of the right. We have shown, for the first time, that transcranial alternating current stimulation of the ventromedial prefrontal cortices modulates muscle sympathetic nerve activity and blood pressure in awake humans at rest. However, it is unclear if this modulation occurred through the same brain pathways activated during transcranial alternating current stimulation of the dorsolateral prefrontal cortex.

Top-down control of vestibular inputs by the dorsolateral prefrontal cortex.

The vestibular apparatus provides spatial information on the position of the head in space and with respect to gravity. Low-frequency sinusoidal galvanic vestibular stimulation (sGVS), a means of selectively changing the firing of vestibular afferents, induces a frequency-dependent perception of sway and, in some individuals, induces nausea. Given that vestibular afferents project to the insular cortex-which forms part of the vestibular cortex-and that the insula receives inputs from the dorsolateral prefrontal cortex (dlPFC), we tested the hypothesis that electrical stimulation of the dlPFC can modulate vestibular inputs. Sinusoidal electrical stimulation (± 2 mA, 0.08 Hz, 100 cycles) was delivered via surface electrodes over (1) the mastoid processes alone (sGVS), (2) electroencephalogram (EEG) site F4 (right dlPFC) and the nasion or (3) to each site concurrently (sGVS + dlPFC) in 23 participants. The same stimulation protocol was used in a separate study to investigate EEG site F3 (left dlPFC) instead of F4 in 13 participants. During sGVS, all participants reported perceptions of sway and 13 participants also reported nausea, neither sensation of which occurred as a result of dlPFC stimulation. Interestingly, when sGVS and dlPFC stimulations were delivered concurrently, vestibular perceptions and sensations of nausea were almost completely abolished. We conclude that the dlPFC provides top-down control of vestibular inputs and further suggests that dlPFC stimulation may provide a novel means of controlling nausea.

Function and biochemistry of the dorsolateral prefrontal cortex during placebo analgesia: how the certainty of prior experiences shapes endogenous pain relief.

Prior experiences, conditioning cues, and expectations of improvement are essential for placebo analgesia expression. The dorsolateral prefrontal cortex is considered a key region for converting these factors into placebo responses. Since dorsolateral prefrontal cortex neuromodulation can attenuate or amplify placebo, we sought to investigate dorsolateral prefrontal cortex biochemistry and function in 38 healthy individuals during placebo analgesia. After conditioning participants to expect pain relief from a placebo "lidocaine" cream, we collected baseline magnetic resonance spectroscopy (1H-MRS) at 7 Tesla over the right dorsolateral prefrontal cortex. Following this, functional magnetic resonance imaging scans were collected during which identical noxious heat stimuli were delivered to the control and placebo-treated forearm sites. There was no significant difference in the concentration of gamma-aminobutyric acid, glutamate, Myo-inositol, or N-acetylaspartate at the level of the right dorsolateral prefrontal cortex between placebo responders and nonresponders. However, we identified a significant inverse relationship between the excitatory neurotransmitter glutamate and pain rating variability during conditioning. Moreover, we found placebo-related activation within the right dorsolateral prefrontal cortex and altered functional magnetic resonance imaging coupling between the dorsolateral prefrontal cortex and the midbrain periaqueductal gray, which also correlated with dorsolateral prefrontal cortex glutamate. These data suggest that the dorsolateral prefrontal cortex formulates stimulus-response relationships during conditioning, which are then translated to altered cortico-brainstem functional relationships and placebo analgesia expression.

The Central Network Involved in the Processing of Vestibular Inputs and the Generation of Vestibulosympathetic Reflexes Controlling Blood Pressure in Humans.

The vestibular apparatus is highly specialized for detecting linear and angular acceleration, contributing importantly to perception of our position in the gravitational field and to motion in the three spatial axes. Beginning in the inner ear, spatial information is relayed toward higher cortical regions for processing, though the specific locations at which this action takes place remain somewhat ambiguous. This article aims to highlight brain regions known to be involved in the processing of spatial information, as well as those that contribute to a less widely documented function of the vestibular system-its capacity to regulate blood pressure via vestibulosympathetic reflexes. As we go from lying to standing, there is a proportional increase in muscle sympathetic nerve activity (MSNA) to the legs that prevents the fall in blood pressure associated with the pooling of blood toward the feet. While feedback from baroreceptors is partially responsible, vestibulosympathetic reflexes operate in a feed-forward manner to compensate for postural changes in the gravitational field. The cortical and subcortical network comprising the central sympathetic connectome shares certain elements with the vestibular system, and it is known that vestibular afferents project via the vestibular nuclei to the rostral ventrolateral medulla (RVLM)-the final output nucleus for generating MSNA. Here we consider how vestibular afferents interact with other components of the central sympathetic connectome, with particular emphasis on the potential roles of the insula and dorsolateral prefrontal cortex (dlPFC) as possible core integrative sites for vestibular and higher cortical processes. © 2023 American Physiological Society. Compr Physiol 13:4811-4832, 2023.

Stimulus-independent and stimulus-dependent neural networks underpin placebo analgesia responsiveness in humans.

The neural circuits that regulate placebo analgesia responsivity are unknown, although engagement of brainstem pain modulatory regions is likely critical. Here we show in 47 participants that differences are present in neural circuit connectivity's in placebo responders versus non-responders. We distinguish stimulus-independent and stimulus-dependent neural networks that display altered connections between the hypothalamus, anterior cingulate cortex and midbrain periaqueductal gray matter. This dual regulatory system underpins an individual's ability to mount placebo analgesia.

The role of the dorsolateral prefrontal cortex in control of skin sympathetic nerve activity in humans.

The dorsolateral prefrontal cortex (dlPFC) is primarily involved in higher order executive functions, with there being evidence of lateralization. Brain imaging studies have revealed its link to the generation of skin sympathetic nerve activity (SSNA), which is elevated in states of emotional arousal or anxiety. However, no studies have directly explored dlPFC influences on SSNA. Transcranial alternating current stimulation (-2 to 2 mA, 0.08 Hz, 100 cycles) was applied between the left or right dlPFC and nasion via surface electrodes. Spontaneous bursts of SSNA were recorded from the common peroneal nerve via a tungsten microelectrode in 21 healthy participants. The modulation index was calculated for each stimulation paradigm by constructing cross-correlation histograms between SSNA and the sinusoidal stimulus. Stimulation of the dlPFC caused significant modulation of SSNA, but there was no significant difference in the median modulation index across sides. Stimulation also caused cyclic modulation of skin blood flow and sweat release. We have shown for the first time that stimulation of the dlPFC causes modulation of SSNA, also reflected in the effector-organ responses. This supports a role for the dlPFC in the control of SSNA, which likely contributes to the ability of emotions to bring about cutaneous vasoconstriction and sweat release.

Detailed organisation of the human midbrain periaqueductal grey revealed using ultra-high field magnetic resonance imaging.

The midbrain periaqueductal grey (PAG) is a critical region for the mediation of pain-related behavioural responses. Neuronal tract tracing techniques in experimental animal studies have demonstrated that the lateral column of the PAG (lPAG) displays a crude somatotopy, which is thought to be critical for the selection of contextually appropriate behavioural responses, without the need for higher brain input. In addition to the different behavioural responses to cutaneous and muscle pain - active withdrawal versus passive coping - there is evidence that cutaneous pain is processed in the region of the lPAG and muscle pain in the adjacent ventrolateral PAG (vlPAG). Given the fundamental nature of these behavioural responses to cutaneous and muscle pain, these PAG circuits are assumed to have been preserved, though yet to be definitively documented in humans. Using ultra-high field (7-Tesla) functional magnetic resonance imaging we determined the locations of signal intensity changes in the PAG during noxious cutaneous heat stimuli and muscle pain in healthy control participants. Images were processed and blood oxygen level dependant (BOLD) signal changes within the PAG determined. It was observed that noxious cutaneous stimulation of the lip, cheek, and ear evoked maximal increases in BOLD activation in the rostral contralateral PAG, whereas noxious cutaneous stimulation of the thumb and toe evoked increases in the caudal contralateral PAG. Analysis of individual participants demonstrated that these activations were located in the lPAG. Furthermore, we found that deep muscular pain evoked the greatest increases in signal intensity in the vlPAG. These data suggest that the crude somatotopic organization of the PAG may be phyletically preserved between experimental animals and humans, with a body-face delineation capable of producing an appropriate behavioural response based on the location and tissue origin of a noxious stimulus.

Brain and cardiovascular-related changes are associated with aging, hypertension, and atrial fibrillation.

PURPOSE: The neural pathways in which the brain regulates the cardiovascular system is via sympathetic and parasympathetic control of the heart and sympathetic control of the systemic vasculature. Various cortical and sub-cortical sites are involved, but how these critical brain regions for cardiovascular control are altered in healthy aging and other risk conditions that may contribute to cardiovascular disease is uncertain. METHODS: Here we review the functional and structural brain changes in healthy aging, hypertension, and atrial fibrillation - noting their potential influence on the autonomic nervous system and hence on cardiovascular control. RESULTS: Evidence suggests that aging, hypertension, and atrial fibrillation are each associated with functional and structural changes in specific areas of the central nervous system involved in autonomic control. Increased muscle sympathetic nerve activity (MSNA) and significant alterations in the brain regions involved in the default mode network are commonly reported in aging, hypertension, and atrial fibrillation. CONCLUSIONS: Further studies using functional and structural magnetic resonance imaging (MRI) coupled with autonomic nerve activity in healthy aging, hypertension, and atrial fibrillation promise to reveal the underlying brain circuitry modulating the abnormal sympathetic nerve activity in these conditions. This understanding will guide future therapies to rectify dysregulation of autonomic and cardiovascular control by the brain.

Alterations in brain structure associated with trigeminal nerve anatomy in episodic migraine.

The pathophysiology of migraine remains to be elucidated. We have recently shown that interictal migraineurs exhibit reduced fractional anisotropy (FA) in the root entry zone of the trigeminal nerve when compared to controls, but it is not known if this altered nerve anatomy is associated with changes within the brainstem or higher cortical brain regions. Diffusion tensor imaging of the brain was used to calculate regional measures of structure, including mean diffusivity (MD), axial diffusivity (AX) and radial diffusivity (RD) in addition to voxel-based morphometry of T1-weighted anatomical images. Linear relationships between trigeminal nerve anatomy (FA) and MD throughout the brainstem and/or higher cortical regions were determined in both controls (n = 31, brainstem; n = 38, wholebrain) and interictal migraineurs (n = 32, brainstem; n = 38, wholebrain). Additionally, within the same brain areas, relationships of AX and RD with nerve FA were determined. We found that in both interictal migraine and control participants, decreasing trigeminal nerve FA was associated with significantly increased MD in brainstem regions including the spinal trigeminal nucleus and midbrain periaqueductal gray matter (PAG), and in higher brain regions such as the hypothalamus, insula, posterior cingulate, primary somatosensory and primary visual (V1) cortices. Whereas, both control and migraineur groups individually displayed significant inverse correlations between nerve FA and MD, in migraineurs this pattern was disrupted in the areas of the PAG and V1, with only the control group displaying a significant linear relationship (PAG controls r = -0.58, p = 0.003; migraineurs r = -0.25, p = 0.17 and V1 controls r = -0.52, p = 0.002; migraineurs r = -0.10, p = 0.55). Contrastingly, we found no gray matter volume changes in brainstem or wholebrain areas. These data show that overall, trigeminal nerve anatomy is significantly related to regional brain structure in both controls and migraineurs. Importantly, the PAG showed a disruption of this relationship in migraineurs suggesting that the anatomy and possibly the function of the PAG is uniquely altered in episodic migraine, which may contribute to altered orofacial pain processing in migraine.

Baroreflex sensitivity during rest and pressor challenges in obstructive sleep apnea patients with and without CPAP.

INTRODUCTION: Obstructive sleep apnea (OSA) increases sympathetic vasoconstrictor drive and reduces baroreflex sensitivity (BRS), the degree to which blood pressure changes modify cardiac output. Whether nighttime continuous positive airway pressure (CPAP) corrects BRS in the awake state in OSA remains unclear. We assessed spontaneous BRS using non-invasive continuous BP and ECG recordings at rest and during handgrip and Valsalva challenges, maneuvers that increase vasoconstrictor drive with progressively higher BP, in untreated OSA (unOSA), CPAP-treated OSA (cpOSA) and healthy (CON) participants. METHODS: In a cross-sectional study of 104 participants, 34 unOSA (age mean±std, 50.6±14.1years; Respiratory Event Index [REI] 21.0±15.3 events/hour; 22male), 31 cpOSA (49.6±14.5years; REI 23.0±14.2 events/hour; 22male; self-report 4+hours/night,5+days/week,6months), and 39 CON (42.2±15.0years; 17male), we calculated BRS at rest and during handgrip and Valsalva. Additionally, we correlated BP variability (BPV) with BRS during these protocols. RESULTS: BRS in unOSA, cpOSA and CON was, respectively (mean±sdv in ms/mmHg), at rest: 14.8±11.8, 15.8±17.0, 16.1±11.3; during handgrip 13.3±7.6, 12.7±8.4, 16.4±8.7; and during Valsalva 12.7±8.0, 11.5±6.6, 15.1±8.9. BRS was lower in cpOSA than CON for handgrip (p=0.04) and Valsalva (p=0.03). BRS was negatively correlated with BPV in unOSA during Valsalva and handgrip for cpOSA, both R=-0.4 (p=0.02). BRS was negatively correlated with OSA severity (levels: none, mild, moderate, severe) at R=-0.2 (p=0.04,n=104). CONCLUSIONS: As expected, BRS was lower and BPV higher in OSA during the pressor challenges, and disease severity negatively correlated with BRS. In this cross-sectional study, both CPAP-treated (self-reported) and untreated OSA showed reduced BRS, leaving open whether within-person CPAP improves BRS.

Regional hypothalamic, amygdala, and midbrain periaqueductal gray matter recruitment during acute pain in awake humans: A 7-Tesla functional magnetic resonance imaging study.

Over the past two decades, magnetic resonance imaging (MRI) studies have explored brain activation patterns during acute noxious stimuli. Whilst these human investigations have detailed changes in primarily cortical regions, they have generally not explored discrete changes within small brain areas that are critical in driving behavioural, autonomic, and endocrine responses to pain, such as within subregions of the hypothalamus, amygdala, and midbrain periaqueductal gray matter (PAG). Ultra-high field (7-Tesla) MRI provides enough signal-to-noise at high spatial resolutions to investigate activation patterns within these small brain regions during acute noxious stimulation in awake humans. In this study we used 7T functional MRI to concentrate on hypothalamic, amygdala, and PAG signal changes during acute noxious orofacial stimuli. Noxious heat stimuli were applied in three separate fMRI scans to three adjacent sites on the face in 16 healthy control participants (7 females). Images were processed using SPM12 and custom software, and blood oxygen level dependent signal changes within the hypothalamus, amygdala, and PAG assessed. We identified altered activity within eight unique subregions of the hypothalamus, four unique subregions of the amygdala, and a single region in the lateral PAG. Specifically, within the hypothalamus and amygdala, signal intensity largely decreased during noxious stimulation, and increased in the lateral PAG. Furthermore, we found sex-related differences in discrete regions of the hypothalamus and amygdala. This study reveals that the activity of discrete nuclei during acute noxious thermal stimulation in awake humans.

The pain conductor: brainstem modulation in acute and chronic pain.

PURPOSE OF REVIEW: It is well established in experimental settings that brainstem circuits powerfully modulate the multidimensional experience of pain. This review summarizes current understanding of the roles of brainstem nuclei in modulating the intensity of pain, and how these circuits might be recruited therapeutically for pain relief in chronic and palliative settings. RECENT FINDINGS: The development of ultra-high field magnetic resonance imaging and more robust statistical analyses has led to a more integrated understanding of brainstem function during pain. It is clear that a number of brainstem nuclei and their overlapping pathways are recruited to either enhance or inhibit incoming nociceptive signals. This review reflects on early preclinical research, which identified in detail brainstem analgesic function, putting into context contemporary investigations in humans that have identified the role of specific brainstem circuits in modulating pain, their contribution to pain chronicity, and even the alleviation of palliative comorbidities. SUMMARY: The brainstem is an integral component of the circuitry underpinning pain perception. Enhanced understanding of its circuitry in experimental studies in humans has, in recent years, increased the possibility for better optimized pain-relief strategies and the identification of vulnerabilities to postsurgical pain problems. When integrated into the clinical landscape, these experimental findings of brainstem modulation of pain signalling have the potential to contribute to the optimization of pain management and patient care from acute, to chronic, to palliative states.

Stimulation of the dorsolateral prefrontal cortex modulates muscle sympathetic nerve activity and blood pressure in humans.

Introduction: Muscle sympathetic nerve activity (MSNA) controls the diameter of arterioles in skeletalmuscle, contributing importantly to the beat-to-beat regulation of blood pressure (BP). Although brain imaging studies have shown that bursts of MSNA originate in the rostral ventrolateral medulla, other subcortical and cortical structures-including the dorsolateral prefrontal cortex (dlPFC)-contribute. Hypothesis: We tested the hypothesis that MSNA and BP could be modulated by stimulating the dlPFC. Method: dlPFC. In 22 individuals MSNA was recorded via microelectrodes inserted into the common peroneal nerve, together with continuous BP, electrocardiographic, and respiration.Stimulation of the right (n=22) or left dlPFC (n=10) was achieved using transcranial alternating current (tcACS; +2 to -2mA, 0.08 Hz,100 cycles), applied between the nasion and electrodes over the F3 or F4 EEG sites on the scalp. Results: Sinusoidal stimulation of either dlPFC caused cyclicmodulation of MSNA, BP and heart rate, and a significant increase in BP. Conclusion: We have shown, for the first time, that tcACS of the dlPFC in awake humans causes partial entrainment of MSNA, heart rate and BP, arguing for an important role of this higher-level cortical area in the control of cardiovascular function.

Altered basal ganglia infraslow oscillation and resting functional connectivity in complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a painful condition commonly accompanied by movement disturbances and often affects the upper limbs. The basal ganglia motor loop is central to movement, however, non-motor basal ganglia loops are involved in pain, sensory integration, visual processing, cognition, and emotion. Systematic evaluation of each basal ganglia functional loop and its relation to motor and non-motor disturbances in CRPS has not been investigated. We recruited 15 upper limb CRPS and 45 matched healthy control subjects. Using functional magnetic resonance imaging, infraslow oscillations (ISO) and resting-state functional connectivity in motor and non-motor basal ganglia loops were investigated using putamen and caudate seeds. Compared to controls, CRPS subjects displayed increased ISO power in the putamen contralateral to the CRPS affected limb, specifically, in contralateral putamen areas representing the supplementary motor area hand, motor hand, and motor tongue. Furthermore, compared to controls, CRPS subjects displayed increased resting connectivity between these putaminal areas as well as from the caudate body to cortical areas such as the primary motor cortex, supplementary and cingulate motor areas, parietal association areas, and the orbitofrontal cortex. These findings demonstrate changes in basal ganglia loop function in CRPS subjects and may underpin motor disturbances of CRPS.