Stimulation Of Anterior Cingulate Cortex Research Articles

Maturation of a cortical-amygdala circuit limits sociability in male rats.

Prefrontal cortical maturation coincides with adolescent transitions in social engagement, suggesting that it influences social development. The anterior cingulate cortex (ACC) is important for social interaction, including ACC outputs to the basolateral amygdala (BLA). However, little is known about ACC-BLA sensitivity to the social environment and if this changes during maturation. Here, we used brief (2-hour) isolation to test the immediate impact of changing the social environment on the ACC-BLA circuit and subsequent shifts in social behavior of adolescent and adult rats. We found that optogenetic inhibition of the ACC during brief isolation reduced isolation-driven facilitation of social interaction across ages. Isolation increased activity of ACC-BLA neurons across ages, but altered the influence of ACC on BLA activity in an age-dependent manner. Isolation reduced the inhibitory impact of ACC stimulation on BLA neurons in a frequency-dependent manner in adults, but uniformly suppressed ACC-driven BLA activity in adolescents. This work identifies isolation-driven alterations in an ACC-BLA circuit, and the ACC itself as an essential region sensitive to social environment and regulates its impact on social behavior in both adults and adolescents.

Frequency Dependent Electrical Stimulation of PFC and ACC for Acute Pain Treatment in Rats.

As pain consists of both sensory and affective components, its management by pharmaceutical agents remains difficult. Alternative forms of neuromodulation, such as electrical stimulation, have been studied in recent years as potential pain treatment options. Although electrical stimulation of the brain has shown promise, more research into stimulation frequency and targets is required to support its clinical applications. Here, we studied the effect that stimulation frequency has on pain modulation in the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC) in acute pain models in rats. We found that low-frequency stimulation in the prelimbic region of the PFC (PL-PFC) provides reduction of sensory and affective pain components. Meanwhile, high-frequency stimulation of the ACC, a region involved in processing pain affect, reduces pain aversive behaviors. Our results demonstrate that frequency-dependent neuromodulation of the PFC or ACC has the potential for pain modulation.

Participation of the Anterior Cingulate Cortex in Sodium Salicylate-induced Tinnitus.

The anterior cingulate cortex (ACC) participates in sodium salicylate (SS)-induced tinnitus through alteration of the disordered neural activity and modulates the neuronal changes in the auditory cortex (AC). Although the mechanism underlying tinnitus remains unclear, the crucial roles of the auditory center and limbic system in this process have been elucidated. Recent reports suggest that dysfunction of the ACC, an important component of the limbic system that regulates and controls the conduction of multiple sensations, is involved in tinnitus. Although altered functional connectivity between the ACC and the auditory system has been observed in humans with tinnitus, the underlying neuronal mechanism remains unexplored. SS (350 mg/kg, 10%, i.p.) was used to yield tinnitus model in rats, followed by comparison of the alteration in the spontaneous firing rate (SFR), local field potential (LFP), and extracellular glutamic acid in the ACC. The responses of neurons in the AC to electrical stimulation from the ACC were also observed. We determined significant increases in the neuronal SFR and extracellular glutamate level in the ACC after SS injection (p < 0.05). These effects were accompanied by decreased alpha band activity and increased beta and gamma band activity (p < 0.05). In the majority of AC neurons, the SFR decreased in response to ACC stimulation (p < 0.05). Our results demonstrated that disordered neural activity in the ACC contributes to SS-induced tinnitus and that ACC activation can modulate AC activity.

Applying a Sensing-Enabled System for Ensuring Safe Anterior Cingulate Deep Brain Stimulation for Pain

Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) was offered to chronic pain patients who had exhausted medical and surgical options. However, several patients developed recurrent seizures. This work was conducted to assess the effect of ACC stimulation on the brain activity and to guide safe DBS programming. A sensing-enabled neurostimulator (Activa PC + S) allowing wireless recording through the stimulating electrodes was chronically implanted in three patients. Stimulation patterns with different amplitude levels and variable ramping rates were tested to investigate whether these patterns could provide pain relief without triggering after-discharges (ADs) within local field potentials (LFPs) recorded in the ACC. In the absence of ramping, AD activity was detected following stimulation at amplitude levels below those used in chronic therapy. Adjustment of stimulus cycling patterns, by slowly ramping on/off (8-s ramp duration), was able to prevent ADs at higher amplitude levels while maintaining effective pain relief. The absence of AD activity confirmed from the implant was correlated with the absence of clinical seizures. We propose that AD activity in the ACC could be a biomarker for the likelihood of seizures in these patients, and the application of sensing-enabled techniques has the potential to advance safer brain stimulation therapies, especially in novel targets.

Anterior cingulate cortex and its input to the basolateral amygdala control innate fear response

Prefrontal brain areas are implicated in the control of fear behavior. However, how prefrontal circuits control fear response to innate threat is poorly understood. Here, we show that the anterior cingulate cortex (ACC) and its input to the basolateral nucleus of amygdala (BLA) contribute to innate fear response to a predator odor in mice. Optogenetic inactivation of the ACC enhances freezing response to fox urine without affecting conditioned freezing. Conversely, ACC stimulation robustly inhibits both innate and conditioned freezing. Circuit tracing and slice patch recordings demonstrate a monosynaptic glutamatergic connectivity of ACC-BLA but no or very sparse ACC input to the central amygdala. Finally, our optogenetic manipulations of the ACC-BLA projection suggest its inhibitory control of innate freezing response to predator odors. Together, our results reveal the role of the ACC and its projection to BLA in innate fear response to olfactory threat stimulus.

Top-down descending facilitation of spinal sensory excitatory transmission from the anterior cingulate cortex

Spinal sensory transmission is under descending biphasic modulation, and descending facilitation is believed to contribute to chronic pain. Descending modulation from the brainstem rostral ventromedial medulla (RVM) has been the most studied, whereas little is known about direct corticospinal modulation. Here, we found that stimulation in the anterior cingulate cortex (ACC) potentiated spinal excitatory synaptic transmission and this modulation is independent of the RVM. Peripheral nerve injury enhanced the spinal synaptic transmission and occluded the ACC-spinal cord facilitation. Inhibition of ACC reduced the enhanced spinal synaptic transmission caused by nerve injury. Finally, using optogenetics, we showed that selective activation of ACC-spinal cord projecting neurons caused behavioral pain sensitization, while inhibiting the projection induced analgesic effects. Our results provide strong evidence that ACC stimulation facilitates spinal sensory excitatory transmission by a RVM-independent manner, and that such top-down facilitation may contribute to the process of chronic neuropathic pain.

Heterosynaptic long-term potentiation from the anterior cingulate cortex to spinal cord in adult rats.

Spinal nociceptive transmission receives biphasic modulation from supraspinal structures. Recent studies demonstrate that the anterior cingulate cortex facilitates spinal excitatory synaptic transmission and nociceptive reflex. However, whether the top-down descending facilitation can cause long-term synaptic changes in spinal cord remains unclear. In the present study, we recorded C-fiber-evoked field potentials in spinal dorsal horn and found that the anterior cingulate cortex stimulation caused enhancement of C-fiber-mediated responses. The enhancement lasted for more than a few hours. Spinal application of N-methyl-D-aspartate (NMDA) receptor antagonist D-AP5 abolished this enhancement, suggesting that the activation of the NMDA receptor is required. Furthermore, spinal application of methysergide, a serotonin receptor antagonist, also blocked the anterior cingulate cortex-induced spinal long-term potentiation. Our results suggest that the anterior cingulate cortex stimulation can produce heterosynaptic form of long-term potentiation at the spinal cord dorsal horn, and this novel form of long-term potentiation may contribute to top-down long-term facilitation in chronic pain conditions.

Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons.

Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy. However, use of existing electrode based ACC stimulation has not significantly reduced pain, at least in part due to the lack of specificity and likely co-activation of both excitatory and inhibitory neurons. Herein, we report a dramatic reduction of pain behavior in transgenic mice by optogenetic stimulation of the inhibitory neural circuitry of the ACC expressing channelrhodopsin-2. Electrophysiological measurements confirmed that stimulation of ACC inhibitory neurons is associated with decreased neural activity in the ACC. Further, a distinct optogenetic stimulation intensity and frequency-dependent inhibition of spiking activity in the ACC was observed. Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons. These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

Stress prevention by modulation of autonomic nervous system (heart rate variability): A preliminary study using transcranial direct current stimulation

Introduction: Transcranial Direct Current Stimulation (tDCS) is a non-invasive, technique for brain stimulation. Anodal stimulation causes neuronal depolarisation and long-term potentiation, while cathodal stimulation causes hyperpolarisation and long-term depression. Stressors are associated with an increase in sympathetic cardiac control, a decrease in parasympathetic control, or both. Associated with these reactions is a frequently reported increase in Low Frequency (LF) Heart Rate Variability (HRV), a decrease in High Frequency (HF) power, and/or an increase in the LF/HF ratio. Objectives and aims: The present work aims to explore the tDCS potential in the modulation of the Autonomic Nervous System (ANS), through indirect stimulation of Anterior Cingulate Cortex (ACC). Methods: Two subjects, a 39 year old female and a 49 year old male, gave informed consent. Saline soaked synthetic sponges involving two, thick, metalic (stainless steel) rectangles, with an area of 25 cm2 each have been used as electrodes, connected to Iomed Phoresor II Auto device. It has been delivered a 2 mA current, for 20 minutes, over the left Dorsolateral Prefrontal Cortex (DLPFC) (Anode). Spectrum analysis (cStress software) of HRV has been performed before and after tDCS administration. Results: The female/male subject results of LF power, HF power and LF/HF ratio, before tDCS administration, were, respectively: 50.1 nu/60 nu, 46.1 nu/21.7 nu and 1.087/2.771; and, after tDCS administration, respectively: 33.5 nu/52.7 nu, 47.6 nu/ 22.8 nu and 0.704/2.312. Conclusions: tDCS over the left DLPFC (left ACC) increased parasympathetic activity and decreased sympathetic activity, suggesting the importance of tDCS in the management of stress-related disorders.

P-1372 - Modulation of the autonomic nervous system by transcranial direct current stimulation: preliminary results of a pilot study with relevance to resilience to stress science

Introduction Transcranial Direct Current Stimulation (tDCS) is a non-invasive, technique for brain stimulation. Anodal stimulation causes neuronal depolarisation and long-term potentiation, while cathodal stimulation causes hyperpolarisation and long-term depression. Stressors are associated with an increase in sympathetic cardiac control, a decrease in parasympathetic control, or both. Associated with these reactions is a frequently reported increase in Low Frequency (LF) Heart Rate Variability (HRV), a decrease in High Frequency (HF) power, and/or an increase in the LF/HF ratio. Objectives and aims The present work aims to explore the tDCS potential in the modulation of the Autonomic Nervous System (ANS), through indirect stimulation of Anterior Cingulate Cortex (ACC). Methods Two subjects, a 39 year old female and a 49 year old male, gave informed consent. Saline soaked synthetic sponges involving two, thick, metalic (stainless steel) rectangles, with an area of 25 cm2 each have been used as electrodes, connected to Iomed Phoresor II Auto device. It has been delivered a 2 mA current, for 20 minutes, over the left Dorsolateral Prefrontal Cortex (DLPFC) (Anode). Spectrum analysis (cStress software) of HRV has been performed before and after tDCS administration. Results The female/male suject results of LF power, HF power and LF/HF ratio, before tDCS administration, were, respectively: 50,1 nu/60 nu, 46,1 nu/21,7 nu and 1,087/2,771; and, after tDCS administration, respectively: 33,5 nu/52,7 nu, 47,6 nu/22,8 nu and 0,704/2,312. Conclusions tDCS over the left DLPFC (left ACC) increased parasympathetic activity and decreased sympatethic activity, sugesting the importance of tDCS in the management of stress-related disorders.

Activation of anterior cingulate cortex produces inhibitory effects on noxious mechanical and electrical stimuli-evoked responses in rat spinal WDR neurons

In present study, in vivo electrophysiological techniques were applied to examine the effects of anterior cingulate cortex (ACC) activation on mechanical and electrical stimuli-evoked responses in rat spinal cord wide-dynamic-range (WDR) neurons. We found that bilateral ACC electrical stimulation (100 Hz, 20 V, 20 s) had different effects on neuronal responses to brush, pressure and pinch stimuli (10 s). The brush-evoked neuronal responses at baseline, post 1 min and post 5 min were 60.8 ± 15.0, 59.2 ± 15.4 and 60.0 ± 19.3 spikes/10 s, respectively ( n = 10, P > 0.05 vs. baseline). The pressure-evoked neuronal responses at baseline, post 1 min and post 5 min were 77.8 ± 11.9, 38.0 ± 7.8 and 45.8 ± 7.6 spikes/10 s, respectively ( n = 10, P < 0.05 vs. baseline). The pinch-evoked neuronal responses at baseline, post 1 min and post 5 min were 137.6 ± 16.7, 62.6 ± 17.5 and 68.8 ± 15.0 spikes/10 s, respectively ( n = 10, P < 0.05 vs. baseline). Furthermore, ACC stimulation generated distinct effects on the different components of wind-up response. The total numbers of late response (LR) and after-discharge (AD), but not early response (ER), significantly decreased. Collectively, the present study demonstrated that short-term ACC activation could generate long-term inhibitory effects on the responses of WDR neurons to noxious mechanical (pressure and pinch) and electrical stimuli. The results indicated that ACC activation could negatively regulate noxious information ascending from spinal cord with long-term effect, providing potential neuronal substrate for the modulation of ACC activation on nociception.

Biphasic effects of the anterior cingulate cortex stimulation on glabrous skin blood flow in rats

A growing body of evidence indicates that the anterior cingulate cortex (ACC) is associated with sensory, cognition and emotion processing. We have shown that electrical stimulation of rat ACC depressed the spinal cord dorsal horn neuron activity in response to noxious stimuli, possibly through a release of GABA. GABA may elicit dorsal root reflexes (DRRs) to induce peripheral vasodilatation. On the other hand, the ACC may also regulate autonomic flow via the lateral hypothalamus (LH). The goal of this work was to investigate the role of ACC in regulating autonomic activity. A laser Doppler imager was used to continuously monitor rat glabrous skin blood perfusion in both hind paws, while a simultaneous heart rate (HR) and DRRs were recorded to assess contributions of sympathetic flow and sensory afferent to the ACC-induced vascular change. Twenty-three rats were divided into three groups: a unilateral electrolytic LH lesion group ( n = 6), a sham lesion group ( n = 9), and a control group (neither lesion nor stimulation, n = 8). ACC stimulation induced a biphasic systemic vascular response, with an initial transient cutaneous vasoconstriction followed by a prolonged vasodilatation. Unilateral LH lesion did not alter this biphasic response. A short-term tachycardia occurred in response to the ACC stimulation, but did not correlate with the prolonged vasodilatation. No significant change in DRRs was found (in 35 fibers). ACC stimulation induced a biphasic vascular response in the skin. Data are consistent with sympathetic contribution. However, other mechanisms should also be involved.

Electrical Stimulation of the Anterior Cingulate Cortex Reduces Responses of Rat Dorsal Horn Neurons to Mechanical Stimuli

The anterior cingulate cortex (ACC) is involved in the affective and motivational aspect of pain perception. Behavioral studies show a decreased avoidance behavior to noxious stimuli without change in mechanical threshold after stimulation of the ACC. However, as part of the neural circuitry of behavioral reflexes, there is no evidence showing that ACC stimulation alters dorsal horn neuronal responses. We hypothesize that ACC stimulation has two phases: a short-term phase in which stimulation elicits antinociception and a long-term phase that follows stimulation to change the affective response to noxious input. To begin testing this hypothesis, the purpose of this study was to examine the response of spinal cord dorsal horn neurons during stimulation of the ACC. Fifty-eight wide dynamic range spinal cord dorsal horn neurons from adult Sprague-Dawley rats were recorded in response to graded mechanical stimuli (brush, pressure, and pinch) at their respective receptive fields, while simultaneous stepwise electrical stimulations (300 Hz, 0.1 ms, at 10, 20, and 30 V) were applied in the ACC. The responses to brush at control, 10, 20, and 30 V, and recovery were 14.2 +/- 1.4, 12.3 +/- 1.2, 10.9 +/- 1.2, 10.3 +/- 1.1, and 14.1 +/- 1.4 spikes/s, respectively. The responses to pressure at control, 10, 20, and 30 V, and recovery were 39.8 +/- 4.7, 25.6 +/- 3.0, 25.0 +/- 3.0, 21.6 +/- 2.4, and 34.2 +/- 3.7 spikes/s, respectively. The responses to pinch at control, 10, 20, and 30 V, and recovery were 40.7 +/- 3.8, 30.6 +/- 3.1, 27.8 +/- 2.8, 27.2 +/- 3.2, and 37.4 +/- 3.9 spikes/s, respectively. We conclude that electrical stimulation of the ACC induces significant inhibition of the responses of spinal cord dorsal horn neurons to noxious mechanical stimuli. The stimulation-induced inhibition begins to recover as soon as the stimulation is terminated. These results suggest differential short-term and long-term modulatory effects of the ACC stimulation on nociceptive circuits.

Attenuation of negative pain affect produced by unilateral spinal nerve injury in the rat following anterior cingulate cortex activation

The affective and the sensory dimensions of pain processing can be differentiated in humans through the use of questionnaires and verbal communication. It is difficult to dissociate these two components of pain processing in rodents, and an understanding of the underlying mechanisms for each component is unclear. The quantification of a novel behavioral response to a repeated noxious cutaneous stimulus together with a measurement of tactile allodynia in nerve-injured rats might be used to differentially explore the sensory and affective components of pain processing in the rat. The present study utilized electrical stimulation of the anterior cingulate cortex, a structure implicated in affective pain processing but not sensory processing, in nerve-injured rats (L5 spinal nerve ligation) and found that the aversive quality of noxious cutaneous hindpaw stimulation was attenuated. There were no effects on sensory processing, because anterior cingulate cortex stimulation did not produce an anti-allodynic effect in L5 spinal nerve ligation animals. Furthermore, anterior cingulate cortex stimulation in animals with bilateral ventrolateral periaqueductal gray area lesions did not affect tactile sensitivity in L5 spinal nerve ligation rats, indicating that an endogenous pain suppression system was not likely activated by anterior cingulate cortex stimulation. However, bilateral ventrolateral periaqueductal gray area lesions in L5 spinal nerve ligation rats blocked the effect produced by anterior cingulate cortex stimulation in the place escape/avoidance paradigm. Specifically, these animals avoided noxious stimulation of the allodynic paw significantly more than anterior cingulate cortex-stimulated, sham or incomplete ventrolateral periaqueductal gray area-lesioned, L5 spinal nerve ligation animals. These findings provide the first quantified report that the activation of the anterior cingulate cortex reduced the aversive quality of repeated noxious tactile stimulation in nerve-injured animals without interfering with normal sensory processing. This effect might require the presence of an intact ventrolateral periaqueductal gray area. It is concluded that the selective manipulation of the anterior cingulate cortex has different effects on pain affect and sensory processing in a rodent model of neuropathic pain.

Peripheral distribution of cutaneous sympathetic vasodilator system.

ARTICLESPeripheral distribution of cutaneous sympathetic vasodilator systemTF Rolewicz, and BG ZimmermanTF Rolewicz, and BG ZimmermanPublished Online:01 Oct 1972https://doi.org/10.1152/ajplegacy.1972.223.4.939MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByBiphasic effects of the anterior cingulate cortex stimulation on glabrous skin blood flow in ratsBrain Research, Vol. 1356Cardiovascular Adjustments to Heat Stress1 January 2011Sympathetically induced paradoxical increases of the cutaneous blood flow in chronically inflamed ratsJournal of the Autonomic Nervous System, Vol. 59, No. 3Neurogenic cutaneous vasodilation in the cat forepawJournal of the Autonomic Nervous System, Vol. 37, No. 1Interferences with DopamineNeurogenic vasodilation in the rat hairy skin measured using a laser Doppler flowmeterLife Sciences, Vol. 45, No. 1Nonadrenergic neural vasodilator mechanisms.Circulation Research, Vol. 60, No. 3Cerebrovascular projections from the sphenopalatine and otic ganglia to the middle cerebral artery of the cat.Stroke, Vol. 17, No. 3DopamineCirculation to Skeletal Muscle1 January 2011Vasodilator neurons supplying skin and skeletal muscle of the limbsJournal of the Autonomic Nervous System, Vol. 7, No. 3-4In search of mediators of skin vasodilation induced by transcutaneous nerve stimulation: I. Failure to block the response by antagonists of endogenous vasodilatorsGeneral Pharmacology: The Vascular System, Vol. 14, No. 6Absence of dopamine-β-hydroxylase in some catecholamine-containing sympathetic ganglion cells of the dog: evidence for dopaminergic autonomic neuronesNeuroscience Letters, Vol. 31, No. 1Dopaminergic neurons in sympathetic ganglia of the dog1 January 1997 | Proceedings of the Royal Society of London. Series B. Biological Sciences, Vol. 215, No. 1199Neurogenic non-adrenergic cutaneous vasodilatation elicited by hypothalamic thermal stimulation in dogsPfl�gers Archiv European Journal of Physiology, Vol. 395, No. 2The Myogenic Response1 January 2011Cholinergic and Purinergic Regulation of Blood Vessels1 January 2011Regulation of Arterial Blood Flow, Pressure and Resistance in the Systemic CirculationEVIDENCE FOR DOPAMINERGIC VASODILATOR INNERVATION OF THE CANINE PAW PAD19 July 2012 | British Journal of Pharmacology, Vol. 67, No. 3Neurogenic vasodilatationGeneral Pharmacology: The Vascular System, Vol. 9, No. 4Activation of sustained sympathetic vasodilatation in dog by spinal cord stimulationExperientia, Vol. 32, No. 11Cutaneous and muscular rasodilation in the canine hindlimb evoked by central stimulation.Circulation Research, Vol. 38, No. 6INFLUENCE OF HISTAIMINE H1 AND H2-RECEPTOR BLOCKERS ON SYMPATHETIC VASODILATOR AND VASOCONSTRICTOR RESPONSES IN CANINE PAW19 July 2012 | British Journal of Pharmacology, Vol. 53, No. 1Non-cholinergic vasodilatation in the canine hind limb evoked by hypothalamic stimulationBrain Research, Vol. 56Histaminergic vasodilatation in the hindlimb of the dogPfl�gers Archiv European Journal of Physiology, Vol. 342, No. 4 More from this issue > Volume 223Issue 4October 1972Pages 939-943 Copyright & PermissionsCopyright © 1972 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1972.223.4.939PubMed4403875History Published online 1 October 1972 Published in print 1 October 1972 Metrics