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Direct neurophysiological evidence for a role of the human anterior cingulate cortex in central command
Abstract
Introduction:
The role of the anterior cingulate cortex (ACC) is still controversial. The ACC has been implicated in such diverse functions as cognition, arousal and emotion in addition to motor and autonomic control. Therefore the ACC is the ideal candidate to orchestrate cardiovascular performance in anticipation of perceived skeletal activity. The aim of this experiment was to investigate whether the ACC forms part of the neural network of central command whereby cardiovascular performance is governed by a top-down mechanism.
Methods & results:
Direct local field potential (LFP) recordings were made using intraparenchymal electrodes in six human ACC's to measure changes in neuronal activity during performance of a motor task in which anticipation of exercise was uncoupled from skeletal activity itself. Parallel cardiovascular arousal was indexed by electrocardiographic changes in heart rate. During anticipation of exercise, ACC LFP power within the 25-60 Hz frequency band increased significantly by 21% compared to rest (from 62.7 μV2/Hz (±SE 4.94) to 76.0μV2/Hz (±SE 7.24); p = 0.004). This 25-60 Hz activity increase correlated with a simultaneous heart rate increase during anticipation (Pearson's r = 0.417, p = 0.016).
Conclusions/significance:
We provide the first invasive electrophysiological evidence to support the role of the ACC in both motor preparation and the top-down control of cardiovascular function in exercise. This further implicates the ACC in the body's response to the outside world and its possible involvement in such extreme responses as emotional syncope and hyperventilation. In addition we describe the frequency at which the neuronal ACC populations perform these tasks in the human.
... Physiologic responses to ketamine can influence cerebrovascular volume and oxygenation [37, [45][46][47], and thus pharmacoBOLD. However, preclinical studies show that the tachycardic effects of NMDAR antagonism are brain mediated [48][49][50][51][52][53][54], potentially via glutamate [49,[51][52][53][54]. Furthermore, similar NMDAR antagonism-induced effects are observed in both anesthetized, ventilated [55][56][57][58], and freely-moving animals [26,43,[59][60][61], and across multiple imaging modalities that are not affected by overall brain perfusion in humans, including 13 C MRS and PET FDG [62][63][64]. ...
... Physiologic responses to ketamine can influence cerebrovascular volume and oxygenation [37, [45][46][47], and thus pharmacoBOLD. However, preclinical studies show that the tachycardic effects of NMDAR antagonism are brain mediated [48][49][50][51][52][53][54], potentially via glutamate [49,[51][52][53][54]. Furthermore, similar NMDAR antagonism-induced effects are observed in both anesthetized, ventilated [55][56][57][58], and freely-moving animals [26,43,[59][60][61], and across multiple imaging modalities that are not affected by overall brain perfusion in humans, including 13 C MRS and PET FDG [62][63][64]. ...
Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = −0.41; p = 0.04, d = −0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = −0.36; p = 0.008, d = −0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = −0.56; p = 0.079, d = −0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.
... Nevertheless, despite the nonspecific perfusion effects, we believe our results reflect mGluR2/3 agonist target engagement, as we demonstrated moderate effect sizes of TS-134 after controlling for heartrate (d>0.4). Our interpretation is consistent with a recent report [37] showing that ketamine produces a measurable pharmacoBOLD response after correcting for the physiologic response, and preclinical studies showing that the tachycardic effects of NMDAR antagonism are brain mediated [47][48][49][50][51][52][53], potentially via glutamate [48,[50][51][52][53]. Moreover, NMDAR antagonism leads to similar pharmacoBOLD-like or CBV changes in both anesthetized, ventilated [54][55][56][57] and free-moving animals [26,[58][59][60][61] and similar ketamine-induced effects are observed in humans across multiple imaging modalities including approaches such as 13C MRS and PET FDG that are not affected by overall brain perfusion [37,[62][63][64]. ...
... Nevertheless, despite the nonspecific perfusion effects, we believe our results reflect mGluR2/3 agonist target engagement, as we demonstrated moderate effect sizes of TS-134 after controlling for heartrate (d>0.4). Our interpretation is consistent with a recent report [37] showing that ketamine produces a measurable pharmacoBOLD response after correcting for the physiologic response, and preclinical studies showing that the tachycardic effects of NMDAR antagonism are brain mediated [47][48][49][50][51][52][53], potentially via glutamate [48,[50][51][52][53]. Moreover, NMDAR antagonism leads to similar pharmacoBOLD-like or CBV changes in both anesthetized, ventilated [54][55][56][57] and free-moving animals [26,[58][59][60][61] and similar ketamine-induced effects are observed in humans across multiple imaging modalities including approaches such as 13C MRS and PET FDG that are not affected by overall brain perfusion [37,[62][63][64]. ...
We tested two metabotropic glutamate receptor 2/3 (mGluR2/3) agonist prodrugs: pomaglumetad (POMA) and TS-134 including a high-dose of POMA that was four times the dose tested in the failed phase schizophrenia III trials in two proof of mechanism, Phase Ib studies using identical pharmacoBOLD target-engagement methodology.
The POMA study was a double-blind, NIMH-sponsored, 10-day study of 80 or 320 mg/d POMA or placebo (1:1:1 ratio), designed to detect d>0.8 sd between-group effect-size differences. The TS-134 study was a single-blind, industry-sponsored, 6-day study of 20 or 60 mg/d TS-134 or placebo (5:5:2 ratio), designed to permit effect-size estimation for future studies. Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and Brief Psychiatric Rating Scale (BPRS).
95 healthy controls were randomized to POMA and 63 to TS-134. High-dose POMA had significant within and between-group reduction in ketamine-induced BPRS total symptoms (p<0.01, d=-0.41; p=0.04, d=-0.44, respectively) but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 had significant/trend level, moderate to large within and between group effects on BPRS positive symptoms (p=0.02, d=-0.36; p=0.008, d=-0.82, respectively) and dACC pharmacoBOLD (p=0.004, d=-0.56; p=0.079, d=-0.50, respectively) using pooled across-study placebo data.
High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed. TS-134 20 mg showed evidence of symptom reduction and target engagement, indicating a curvilinear dose-response curve. These results warrant further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.
... Previous studies have reported that EEG gamma-band activity is involved not only in multisensory integration (Sakowitz et al., 2001(Sakowitz et al., , 2005Senkowski et al., 2005;Kanayama et al., 2007Kanayama et al., , 2009Schneider et al., 2008), but also the prediction error (Arnal et al., 2011;Arnal and Giraud, 2012). The error-related gamma oscillations have been suggested to involve with activity of anterior cingulate cortex (ACC), superior temporal sulcus (STS) and temporoparietal junction (TPJ) (van Pelt et al., 2016;Gillies et al., 2019). Further, EEG gamma oscillations have been found to explain fluctuations in fMRI signals (Engell et al., 2012;Magri et al., 2012;Mizuhara, 2012;Tagliazucchi et al., 2012). ...
... Therefore, we suggest that the γ-ERS reflects a process relating to "prediction errors" rather than "multisensory integration." From the viewpoint of predictive coding (Friston, 2010), gamma band activity is considered to reflect prediction errors (von Stein et al., 2000;Arnal et al., 2011;Arnal and Giraud, 2012;Bastos et al., 2012;Bauer et al., 2014;van Pelt et al., 2016;Gillies et al., 2019). Arnal et al. (2011) reported that gamma activity in the STS is correlated with cross-modal inconsistency. ...
We investigated whether the inferior parietal lobule (IPL) responds in real-time to multisensory inconsistency during movement. The IPL is thought to be involved in both the detection of inconsistencies in multisensory information obtained during movement and that obtained during self-other discrimination. However, because of the limited temporal resolution of conventional neuroimaging techniques, it is difficult to distinguish IPL activity during movement from that during self-other discrimination. We simultaneously conducted electroencephalography (EEG) and near-infrared spectroscopy (NIRS) with the goal of examining IPL activity with a high spatiotemporal resolution during single reaching movements. Under a visual feedback-delay condition, gamma event-related synchronization (γ-ERS), i.e., an increase in gamma (31–47 Hz) EEG power occurred during reaching movements. This γ-ERS is considered to reflect processing of information about prediction errors. To integrate this temporal information with spatial information from the NIRS signals, we developed a new analysis technique that enabled estimation of the regions that show a hemodynamic response characterized by EEG fluctuation present in the visual feedback-delay condition. As a result, IPL activity was explained by γ-ERS specific to visual feedback delay during movements. Thus, we succeeded in demonstrating real-time activation of the IPL in response to multisensory inconsistency. However, we did not find any correlation between either IPL activity or γ-ERS with the sense of agency. Therefore, our results suggest that while the IPL is influenced by prediction error signals, it does not engage in direct processing underlying the conscious experience of making a movement, which is the foundation of self-other discrimination.
... Le cortex cingulaire antérieur (CCA) reçoit des afférences pondérées en provenance du cortex orbitofrontal et de l'insula pour orienter le comportement vers le plus grand bénéfice attendu. Le CCA détecte également les conditions dans lesquelles des erreurs peuvent survenir pour assurer la supervision de la performance(Carter et al., 1998;Gillies et al., 2019). Les informations traitées par le CCA sont ensuite transmises au noyau accumbens (NA) par les connexions corticostriatales, permettant à ce dernier d'établir le comportement approprié(Boksem & Tops, 2008). ...
... The dmPFC/dACC blood oxygen level-dependant (BOLD) activity has been consistently associated with heart-rate variability [91][92][93][94] and pupil diameter size 17,81,95-99 (see Amiez and Procyk 100 for a more exhaustive review). ...
The dorsomedial prefrontal cortex/dorsal anterior cingulate cortex (dmPFC/dACC) is a brain area subject to many theories and debates over its function(s). Even its precise anatomical borders are subject to much controversy. In the past decades, the dmPFC/dACC has been associated with more than 15 different cognitive processes, which sometimes appear quite unrelated (e.g. body perception, cognitive conflict). As a result, understanding what the dmPFC/dACC does has become a real challenge for many neuroscientists. Several theories of this brain area's function(s) have been developed, leading to successive and competitive publications bearing different models, which sometimes contradict each other. During the last two decades, the lively scientific exchanges around the dmPFC/dACC have promoted fruitful research in cognitive neuroscience.
In this review, we provide an overview of the anatomy of the dmPFC/dACC, summarize the state of the art of functions that have been associated with this brain area and present the main theories aiming at explaining the dmPFC/dACC function(s). We explore the commonalities and the arguments between the different theories.
Finally, we explain what can be learned from these debates for future investigations of the dmPFC/dACC and other brain regions' functions.
... Along with ACC and amygdala, the insula mediates interoception i.e. the awareness of internal bodily states such as cardiac palpitations in panic disorder (Craske et al. 2010;Khoury et al. 2018). The ACC (Gillies et al. 2019) connects to the hypothalamus and PAG and associates with sympathetic modulation of HR (Critchley et al. 2003). The PAG itself encapsulates the midbrain cerebral aqueduct connecting descending and ascending projections concerning emotionrelated and motor information (Vianna and Brandao 2003). ...
Neuropsychiatric diseases (NPD) represent a significant global disease burden necessitating innovative approaches to pathogenic understanding, biomarker identification and therapeutic strategy. Emerging evidence implicates heart/brain axis malfunction in NPD etiology, particularly via the autonomic nervous system (ANS) and brain central autonomic network (CAN) interaction. This heart/brain inter-relationship harbors potentially novel NPD diagnosis and treatment avenues. Nevertheless, the lack of multidisciplinary clinical approaches as well as a limited appreciation of molecular underpinnings has stymied progress. Large-scale preclinical multi-systemic functional data can therefore provide supplementary insight into CAN and ANS interaction. We here present an overview of the heart/brain axis in NPD and establish a unique rationale for utilizing a preclinical cardiovascular disease risk gene set to glean insights into heart/brain axis control in NPD. With a top-down approach focusing on genes influencing electrocardiogram ANS function, we combined hierarchical clustering of corresponding regional CAN expression data and functional enrichment analysis to reveal known and novel molecular insights into CAN and NPD. Through ‘support vector machine’ inquiries for classification and literature validation, we further pinpointed the top 32 genes highly expressed in CAN brain structures altering both heart rate/heart rate variability (HRV) and behavior. Our observations underscore the potential of HRV/hyperactivity behavior as endophenotypes for multimodal disease biomarker identification to index aberrant executive brain functioning with relevance for NPD. This work heralds the potential of large-scale preclinical functional genetic data for understanding CAN/ANS control and introduces a stepwise design leveraging preclinical data to unearth novel heart/brain axis control genes in NPD.
... Cortical areas such as mPFC and ACC have a critical role in the appropriate cognitive appraisal of negative emotions, individual's self-perception, the ability to switch between alternative emotional control strategies, as well as coordinating sympathetic and parasympathetic responses to environmental stimuli [93,104,[114][115][116][117][118]. Most of these brain structures comprise several functionally different areas. ...
Epidemiological studies have shown that a substantial proportion of acute coronary events occur in individuals who lack the traditional high-risk cardiovascular (CV) profile. Mental stress is an emerging risk and prognostic factor for coronary artery disease and stroke, independently of conventional risk factors. It is associated with an increased rate of CV events. Acute mental stress may develop as a result of anger, fear, or job strain, as well as consequence of earthquakes or hurricanes. Chronic stress may develop as a result of long-term or repetitive stress exposure, such as job-related stress, low socioeconomic status, financial problems, depression, and type A and type D personality. While the response to acute mental stress may result in acute coronary events, the relationship of chronic stress with increased risk of coronary artery disease (CAD) is mainly due to acceleration of atherosclerosis. Emotionally stressful stimuli are processed by a network of cortical and subcortical brain regions, including the prefrontal cortex, insula, amygdala, hypothalamus, and hippocampus. This system is involved in the interpretation of relevance of environmental stimuli, according to individual’s memory, past experience, and current context. The brain transduces the cognitive process of emotional stimuli into hemodynamic, neuroendocrine, and immune changes, called fight or flight response, through the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. These changes may induce transient myocardial ischemia, defined as mental stress-induced myocardial ischemia (MSIMI) in patients with and without significant coronary obstruction. The clinical consequences may be angina, myocardial infarction, arrhythmias, and left ventricular dysfunction. Although MSIMI is associated with a substantial increase in CV mortality, it is usually underestimated because it arises without pain in most cases. MSIMI occurs at lower levels of cardiac work than exercise-induced ischemia, suggesting that the impairment of myocardial blood flow is mainly due to paradoxical coronary vasoconstriction and microvascular dysfunction.
... By contrast, the NMDAR antagonist ketamine, consistently produces tachycardia and hypertension in clinical studies (1). While direct application of ketamine on in vitro cardiac tissue induces bradycardia (142), the tachycardic/hypertensive effects of in vivo ketamine are mediated through brain, with evidence for both centrally mediated top-down control (143)(144)(145) and direct effects on the baroreflex in the nucleus tractus solitarii (NTS) in the brainstem (medulla) (146)(147)(148)(149). No clinically relevant cardiovascular effects have been reported in clinical studies of D-serine. ...
Background: D-Serine, a direct, full agonist at the D-serine/glycine modulatory site of the N-methyl-D-aspartate-type glutamate receptors (NMDAR), has been assessed as a treatment for multiple psychiatric and neurological conditions. Based on studies in rats, concerns of nephrotoxicity have limited D-serine research in humans, particularly using high doses. A review of D-serine's safety is timely and pertinent, as D-serine remains under active study for schizophrenia, both directly (R61 MH116093) and indirectly through D-amino acid oxidase (DAAO) inhibitors. The principal focus is on nephrotoxicity, but safety in other physiologic and pathophysiologic systems are also reviewed.
Methods: Using the search terms “D-serine,” “D-serine and schizophrenia,” “D-serine and safety,” “D-serine and nephrotoxicity” in PubMed, we conducted a systematic review on D-serine safety. D-serine physiology, dose-response and efficacy in clinical studies and dAAO inhibitor safety is also discussed.
Results: When D-serine doses >500 mg/kg are used in rats, nephrotoxicity, manifesting as an acute tubular necrosis syndrome, seen within hours of administration is highly common, if not universal. In other species, however, D-serine induced nephrotoxicity has not been reported, even in other rodent species such as mice and rabbits. Even in rats, D--serine related toxicity is dose dependent and reversible; and does not appear to be present in rats at doses producing an acute Cmax of <2,000 nmol/mL. For comparison, the Cmax of D-serine 120 mg/kg, the highest dose tested in humans, is ~500 nmol/mL in acute dosing. Across all published human studies, only one subject has been reported to have abnormal renal values related to D-serine treatment. This abnormality did not clearly map on to the acute tubular necrosis syndrome seen in rats, and fully resolved within a few days of stopping treatment. DAAO inhibitors may be nephroprotective. D-Serine may have a physiologic role in metabolic, extra-pyramidal, cardiac and other systems, but no other clinically significant safety concerns are revealed in the literature.
Conclusions: Even before considering human to rat differences in renal physiology, using current FDA guided monitoring paradigms, D-serine appears safe at currently studied maximal doses, with potential safety in combination with DAAO inhibitors.
... The frequency of these entrained oscillations was strictly locked to the presentation frequency (n= 41 out of 41 tests) (Figures 7A, 7B, 7E and 7F) with lags ranging from -500 to + 500 ms (Figures 7C and 7D). In these strictly rhythmic trials, anticipation of the next stimulus as well as evoked activity may explain the large range in lags (see also Figure 6F) (Gillies et al., 2019;Staresina et al., 2019). ...
We lack viable explanations of how brain functions emerge from collective activities of neurons in networks. We recorded field potentials from many local networks in the human cerebral cortex during a wide variety of brain functions. The network dynamics showed that each local cortical network produced fluctuating attractor states. The state trajectories continuously stretched and contracted during all brain functions, leaving no stable patterns. Different local networks all produced this dynamic, despite different architectures. Single trial stimuli and tasks modified the stretching and contractions. These modified fluctuations cross-correlated among particular networks during specific brain functions. Spontaneous states, rest, sensory, motor and cognitive states all emerged from this dynamic. Its mathematical structure provides a general explanation of cortical dynamics that can be tested experimentally. This universal dynamic is a simple functional organizing principle for brain functions at the mm3 scale that is distinct from existing frameworks.
... Given that the MCC seems to interface the sympathetic and skeletomotor system, one could hypothesize that sympathetic output may be modulated depending on the skeletomotor system. Gillies and colleagues (Gillies et al., 2019) showed that it is indeed the case. Local field potential (LFP) and electrocardiographic variations were recorded in human MCC while subjects were performing a motor task uncoupled from skeletomotor activity. ...
The midcingulate cortex (MCC) is viewed as a central node within a large-scale system devoted to adjusting behavior in the face of changing environments. Whereas the role of the MCC in interfacing action and cognition is well established, its role in regulating the autonomic nervous system is poorly understood. Yet, adaptive reactions to novel or threatening situations induce coordinated changes in the sympathetic and the parasympathetic systems. The somatomotor maps in the MCC are organized dorsoventrally. A meta-analysis of the literature reveals that the dorsoventral organization might also concern connections with the autonomic nervous system. Activation of the dorsal and ventral parts of the MCC correlate with recruitments of the sympathetic and the parasympathetic systems, respectively. Data also suggest that, in the MCC, projections toward the sympathetic system are mapped along the sensory-motor system following the same cervico-sacral organization as projections on the spinal cord for skeletal motor control.
... The current findings in men and our previous findings in women (Keller et al. 2018a) support the role of a feedforward mechanism as demonstrated by the initial precipitous decrease in force production during approximately the first 30% of the actual time-limit (Fig. 2), which was likely reflective of a period of uncertainty and anticipation (i.e. no feedback) (Gibson et al. 2018;Gillies et al. 2019). A feedforward mechanism alone, however, does not explain the rate of change in force decline between approximately 30 and 100% of the actual time-limit. ...
The purpose of the study was to examine the fatigue-related patterns of responses for electromyography (EMG), mechanomyography (MMG), and force during a sustained isometric muscle action anchored to RPE = 5. Ten men (22.9 ± 2.0 year) performed maximal voluntary isometric contractions (MVIC) prior to and following an isometric leg extension muscle action, which was sustained for a maximal time-limit of 5 min or until it could not be maintained at RPE = 5 (actual time-limit). EMG amplitude (AMP), EMG mean power–frequency (MPF), MMG AMP, MMG MPF, and force values were determined every 5% of the actual time-limit. Regression analyses were used to examine the neuromuscular parameters and force responses, and a t test was used to examine MVIC. The pretest MVIC (62.4 ± 14.3 kg) was significantly (p < 0.001; d = 1.07) greater than posttest (47.9 ± 12.8 kg). The percent decline in force during the sustained isometric muscle action was 47.5 ± 19.6%, and there was a significant, negative force versus time relationship (p < 0.001; R = − 0.980). There was a significant, negative EMG AMP versus time relationship (p < 0.001; R = -0.789), but no significant (p > 0.05) relationships for EMG MPF, MMG AMP, or MMG MPF versus time. The findings indicated that it was necessary to reduce force and EMG AMP to maintain RPE = 5. We hypothesize that the maintenance of RPE = 5 was initially accomplished by an anticipatory feedforward mechanism and then continuous integrations of afferent feedback, which resulted in reductions of EMG AMP and force, due to reductions in neural drive, to attenuate the impact of metabolic byproducts.
In our original white paper published in the The Journal of Physiology in 2016, we set out our knowledge of the structural and functional organization of cardiac autonomic control, how it remodels during disease, and approaches to exploit such knowledge for autonomic regulation therapy. The aim of this update is to build on this original blueprint, highlighting the significant progress which has been made in the field since and major challenges and opportunities that exist with regard to translation. Imbalances in autonomic responses, while beneficial in the short term, ultimately contribute to the evolution of cardiac pathology. As our understanding emerges of where and how to target in terms of actuators (including the heart and intracardiac nervous system (ICNS), stellate ganglia, dorsal root ganglia (DRG), vagus nerve, brainstem, and even higher centres), there is also a need to develop sensor technology to respond to appropriate biomarkers (electrophysiological, mechanical, and molecular) such that closed‐loop autonomic regulation therapies can evolve. The goal is to work with endogenous control systems, rather than in opposition to them, to improve outcomes. image
Sudden cardiac death is a common cause of death during hiking activities. Since the exaggerated blood pressure (BP) response to physical activity is known to increase the risk for the development of cardiovascular events, hiking might also induce an excessive BP response and such events. The purpose of this study was to investigate the effects of hiking at around 1,200 m on the circulatory responses to isometric handgrip (IHG) exercise. Five healthy women volunteered to hike and stay at Mt. Ibuki (altitude, 1,377 m; Shiga, Japan) for 2 consecutive days. On the first day, the participants ascended to 1,220 m (Hiking study), and on the second day, they drove to an altitude of 1,260 m where they remained for about 5.5 h (Staying study). The participants performed IHG exercise before (altitude, 220 m), during (altitude, 990 m), and after (altitude, 220 m) hiking in the Hiking study, and before driving (altitude, 160 m), after staying for 5 h (altitude, 1,260 m), and after driving back from an altitude of 1,260 m (altitude, 122 m) in the Staying study. The participants performed IHG exercise at 30% maximum voluntary contraction for 2 min after seated rest. We measured systolic and diastolic BP (SBP and DBP), and pulse rate during the test, and then calculated the double product (DP) from the product of the SBP and pulse rate. In the Hiking study, SBP and DP responses to IHG exercise during hiking were significantly augmented (P < 0.05). Importantly, these responses to IHG exercise during hiking were significantly higher than those before hiking (P < 0.05). On the other hand, in the Staying study, staying at an altitude of 1,260 m for about 5.5 h did not significantly change circulatory responses to IHG exercise. In conclusion, we demonstrated that SBP and DP during IHG exercise were significantly augmented during hiking at an elevation difference of about 1,000 m. This finding suggests that transient increases in BP due to physical activity, which might trigger cardiovascular events, could be enhanced during hiking at a moderate altitude.
Complex Regional Pain Syndrome (CRPS) is a musculoskeletal pain condition that often develops after limb injury and/or immobilization. Although the exact mechanisms underlying CRPS are unknown, the syndrome is associated with central and autonomic nervous system dysregulation and peripheral hyperalgesia symptoms. These symptoms also manifest in alcoholic neuropathy, suggesting that the two conditions may be pathophysiologically accretive. Interestingly, people assigned female at birth (AFAB) appear to be more sensitive to both CRPS and alcoholic neuropathy. To better understand the biobehavioral mechanisms underlying these conditions, we investigated a model of combined CRPS and alcoholic neuropathy in female rats. Animals were pair-fed either a Lieber-DeCarli alcohol liquid diet or a control diet for ten weeks. CRPS was modeled via unilateral hind limb cast immobilization for seven days, allowing for the other limb to serve as a within-subject control for hyperalgesia measures. To investigate the role of circulating ovarian hormones on pain-related behaviors, half of the animals underwent ovariectomy (OVX). Using the von Frey procedure to record mechanical paw withdrawal thresholds, we found that cast immobilization and chronic alcohol drinking separately and additively produced mechanical hyperalgesia observed 3 days after cast removal. We then examined neuroadaptations in AMPA GluR1 and NMDA NR1 glutamate channel subunits, extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB) in bilateral motor and cingulate cortex across all groups. Consistent with increased pain-related behavior, chronic alcohol drinking increased GluR1, NR1, ERK, and CREB phosphorylation in the cingulate cortex. OVX did not alter any of the observed effects. Our results suggest accretive relationships between CRPS and alcoholic neuropathy symptoms and point to novel therapeutic targets for these conditions.
This chapter aims to provide an updated overview of whether and how sleep entails changes in the properties of the arterial baroreceptor reflex (ABR), which is arguably the most important and most amply studied cardiovascular reflex. The effects of sleep on cardiovascular control are exerted at three different time scales: at the traditional time scale of sleep macrostructure, in the order of minutes, but also at a smaller time scale in the order of seconds, which reflects sleep microstructure, and at a larger time scale in the order of hours, which reflects circadian sleep rhythms. The ABR is part of the hierarchically intermediate level of cardiovascular regulation, which modulates the local control of cardiac and vascular function and is modulated by proactive central autonomic commands. Key insights on ABR function during sleep can be gained by analyzing the relationship between arterial blood pressure, which is the variable effectively controlled by the ABR, and instrumental ABR variables such as heart rate and sympathetic nerve activity. As a working hypothesis, sleep-related cardiovascular regulation at different time scales may result from central autonomic commands that act on the cardiovascular system through multiple parallel pathways, only some of which change ABR properties. In closing, the chapter provides an overview of the evidence and hypotheses concerning the functional neuroanatomy of the ABR and central autonomic commands during sleep.
This article charts the history of deep brain stimulation (DBS) as applied to alleviate a number of neurological disorders, while in parallel mapping the electrophysiological circuits involved in generating and integrating neural signals driving the cardiorespiratory system during exercise. With the advent of improved neuroimaging techniques, neurosurgeons can place small electrodes into deep brain structures with a high degree accuracy to treat a number of neurological disorders, such as movement impairment associated with Parkinson’s disease and neuropathic pain. As well as stimulating discrete nuclei and monitoring autonomic outflow, local field potentials can also assess how the neurocircuitry responds to exercise. This technique has provided an opportunity to validate in humans putative circuits previously identified in animal models. The central autonomic network consists of multiple sites from the spinal cord to the cortex involved in autonomic control. Important areas exist at multiple evolutionary levels, which include the anterior cingulate cortex (telencephalon), hypothalamus (diencephalon), periaqueductal grey (midbrain), parabrachial nucleus and nucleus of the tractus solitaries (brainstem), and the intermediolateral column of the spinal cord. These areas receive afferent input from all over the body and provide a site for integration, resulting in a coordinated efferent autonomic (sympathetic and parasympathetic) response. In particular, emerging evidence from DBS studies have identified the basal ganglia as a major sub-cortical cognitive integrator of both higher center and peripheral afferent feedback. These circuits in the basal ganglia appear to be central in coupling movement to the cardiorespiratory motor program.
The effects of asthma on affect have been noted for some time, but little is known about associated brain processes. We therefore examined whether emotion-induced bronchoconstriction, airway inflammation, and asthma control are related to specific patterns of brain activity during processing negative affective stimuli. Fifteen adults with asthma viewed alternating blocks of distressing film clips (negative condition), affectively neutral film clips (neutral condition), and a crosshair image (baseline condition) while undergoing blood oxygenation level-dependent (BOLD) functional MRI (fMRI). Block-design fMRI analysis evaluated the BOLD response to "negative-baseline" and "neutral-baseline" contrasts. Airway response to these film clips was also assessed with impulse oscillometry in a separate session. Measures of airway inflammation [fractional exhaled nitric oxide (FENO)] and asthma control [Asthma Control Questionnaire (ACQ)] were additionally obtained. A whole brain voxel-based regression analysis of contrast maps was performed against respiratory resistance increase during negative and neutral films, FENO, and ACQ. Peak airway obstruction to negative affective stimulation was associated with stronger activation of the anterior and middle cingulate gyrus, including the dorsal anterior cingulate cortex (dACC). Stronger airway inflammation and lower asthma control were associated with reduced activation to negative stimuli in the superior frontal gyrus, middle cingulate gyrus, and supplementary motor area. Activation of the dACC in negative-affect-induced airway obstruction could be part of an integrated defensive response to critical environmental change. In addition, reduced frontal and limbic activation during processing of negative affect may reflect consequences of pathophysiological processes for CNS functioning. NEW & NOTEWORTHY This functional magnetic resonance imaging study shows, for the first time, that the degree of airway constriction due to negative affective stimuli in asthma is associated with stronger response to these stimuli in the dorsal anterior and middle cingulate cortex. Asthma patients with stronger airway inflammation and reduced asthma control also show reduced activation in a number of cortical and subcortical areas relevant for affective processing and breathing control.
The dorsal anterior cingulate cortex (dACC) is proposed to facilitate learning by signaling mismatches between the expected outcome of decisions and the actual outcomes in the form of prediction errors. The dACC is also proposed to discriminate outcome valence—whether a result has positive (either expected or desirable) or negative (either unexpected or undesirable) value. However, direct electrophysiological recordings from human dACC to validate these separate, but integrated, dimensions have not been previously performed. We hypothesized that local field potentials (LFPs) would reveal changes in the dACC related to prediction error and valence and used the unique opportunity offered by deep brain stimulation (DBS) surgery in the dACC of three human subjects to test this hypothesis. We used a cognitive task that involved the presentation of object pairs, a motor response, and audiovisual feedback to guide future object selection choices. The dACC displayed distinctly lateralized theta frequency (3–8 Hz) event-related potential responses—the left hemisphere dACC signaled outcome valence and prediction errors while the right hemisphere dACC was involved in prediction formation. Multivariate analyses provided evidence that the human dACC response to decision outcomes reflects two spatiotemporally distinct early and late systems that are consistent with both our lateralized electrophysiological results and the involvement of the theta frequency oscillatory activity in dACC cognitive processing. Further findings suggested that dACC does not respond to other phases of action-outcome-feedback tasks such as the motor response which supports the notion that dACC primarily signals information that is crucial for behavioral monitoring and not for motor control.
During face-to-face communication, listeners integrate speech with gestures. The semantic information conveyed by iconic gestures (e.g., a drinking gesture) can aid speech comprehension in adverse listening conditions. In this magnetoencephalography (MEG) study, we investigated the spatiotemporal neural oscillatory activity associated with gestural enhancement of degraded speech comprehension. Participants watched videos of an actress uttering clear or degraded speech, accompanied by a gesture or not and completed a cued-recall task after watching every video. When gestures semantically disambiguated degraded speech comprehension, an alpha and beta power suppression and a gamma power increase revealed engagement and active processing in the hand-area of the motor cortex, the extended language network (LIFG/pSTS/STG/MTG), medial temporal lobe, and occipital regions. These observed low- and high-frequency oscillatory modulations in these areas support general unification, integration and lexical access processes during online language comprehension, and simulation of and increased visual attention to manual gestures over time. All individual oscillatory power modulations associated with gestural enhancement of degraded speech comprehension predicted a listener's correct disambiguation of the degraded verb after watching the videos. Our results thus go beyond the previously proposed role of oscillatory dynamics in unimodal degraded speech comprehension and provide first evidence for the role of low- and high-frequency oscillations in predicting the integration of auditory and visual information at a semantic level.
Chronic pain is associated with autonomic disturbance. However, specific effects of chronic back pain on sympathetic regulation remain unknown. Chronic pain is also associated with structural changes in the anterior cingulate cortex (ACC), which may be linked to sympathetic dysregulation. The aim of this study was to determine whether sympathetic regulation and ACC surface and volume are affected in a rat model of chronic back pain, in which Complete Freund Adjuvant (CFA) is injected in back muscles. Sympathetic regulation was assessed with renal blood flow (RBF) changes induced by electrical stimulation of a hind paw, while ACC structure was examined by measuring cortical surface and volume. RBF changes and ACC volume were compared between control rats and rats injected with CFA in back muscles segmental (T10) to renal sympathetic innervation or not (T2). In rats with CFA, chronic inflammation was observed in the affected muscles in addition to increased nuclear factor-kappa B (NF-kB) protein expression in corresponding spinal cord segments (p=0.01) as well as decreased ACC volume (p<0.05). In addition, intensity-dependent decreases in RBF during hind paw stimulation were attenuated by chronic pain at T2 (p's<0.05) and T10 (p's<0.05), but less so at T10 compared with T2 (p's<0.05). These results indicate that chronic back pain alters sympathetic functions through non-segmental mechanisms, possibly by altering descending regulatory pathways from ACC. Yet, segmental somato-sympathetic reflexes may compete with non-segmental processes depending on the back region affected by pain and according to the segmental organization of the sympathetic nervous system.
The anterior cingulate cortex (ACC) is vital for a range of brain functions requiring cognitive control and has highly divergent inputs and outputs, thus manifesting as a hub in connectomic analyses. Studies show diverse functional interactions within the ACC are associated with network oscillations in the β (20–30 Hz) and γ (30-80 Hz) frequency range. Oscillations permit dynamic routing of information within cortex, a function that depends on bandpass filter–like behavior to selectively respond to specific inputs. However, a putative hub region such as ACC needs to be able to combine inputs from multiple sources rather than select a single input at the expense of others. To address this potential functional dichotomy, we modeled local ACC network dynamics in the rat in vitro. Modal peak oscillation frequencies in the β- and γ-frequency band corresponded to GABAAergic synaptic kinetics as seen in other regions; however, the intrinsic properties of ACC principal neurons were highly diverse. Computational modeling predicted that this neuronal response diversity broadened the bandwidth for filtering rhythmic inputs and supported combination—rather than selection—of different frequencies within the canonical γ and β electroencephalograph bands. These findings suggest that oscillating neuronal populations can support either response selection (routing) or combination, depending on the interplay between the kinetics of synaptic inhibition and the degree of heterogeneity of principal cell intrinsic conductances.
Blood-injection-injury (BII) phobia differs from other subtypes of specific phobia in that it is associated with elevated disgust-sensitivity as well as specific autonomic and brain responses during processing of phobia-relevant stimuli. To what extent these features play a role already during threat anticipation is unclear. In the current fMRI experiment, 16 female BII phobics and 16 female healthy controls anticipated the presentation of phobia-specific and neutral pictures. On the behavioral level, anxiety dominated the anticipatory period in BII phobics relative to controls, while both anxiety and disgust were elevated during picture presentation. By applying two different models for the analysis of brain responses to anticipation of phobia-specific versus neutral stimuli, we found initial and sustained increases of activation in anterior cingulate cortex (ACC), insula, lateral and medial prefrontal cortex (PFC), thalamus and visual areas, as well as initial activation in the amygdala for BII phobics as compared to healthy controls. These results suggest that BII phobia is characterized by activation of a typical neural defense network during threat anticipation, with anxiety as the predominant emotion.
In daily life, complex events are perceived in a causal manner, suggesting that the brain relies on predictive processes to
model them. Within predictive coding theory, oscillatory beta-band activity has been linked to top-down predictive signals
and gamma-band activity to bottom-up prediction-errors. However, neurocognitive evidence for predictive coding outside lower-level
sensory areas is scarce. We used magnetoencephalography to investigate neural activity during probability-dependent action
perception in three areas pivotal for causal inference, STS, TPJ, and MPFC, using bowling action animations. Within this network,
Granger-causal connectivity in the beta-band was found to be strongest for backward top-down connections, and gamma for feed-forward
bottom-up connections. Moreover, beta-band power in TPJ increased parametrically with the predictability of the action kinematics-outcome
sequences. Conversely, gamma-band power in TPJ and MPFC increased with prediction error. These findings suggest that the brain
utilizes predictive-coding-like computations for higher-order cognition such as perception of causal events.
Significance
Dysregulation of emotion is central to the etiology of mood disorders, such as depression. A causal understanding of how neural structures regulate emotion and arousal could help to improve treatments for these psychiatric disorders. Studies of patients with depression indicate that a particular part of the frontal lobe, the subgenual cingulate cortex, plays an important role in affective processing, though its precise contribution remains unclear. Here we show that, in macaque monkeys, this small part of the frontal cortex is necessary for sustaining elevated arousal in anticipation of positive emotional events. This finding suggests a mechanism for the contribution of this area to affective regulation, including an account for the lack of pleasure and passivity that characterizes mood disorders.
Deep brain stimulation (DBS) is a common therapy for treating movement disorders, such as Parkinson's disease (PD), and provides a unique opportunity to study the neural activity of various subcortical structures in human patients. Local field potential (LFP) recordings are often performed with either intraoperative microelectrodes or DBS leads and reflect oscillatory activity within nuclei of the basal ganglia. These LFP recordings have numerous clinical implications and might someday be used to optimize DBS outcomes in closed-loop systems. However, the origin of the recorded LFP is poorly understood. Therefore, the goal of this study was to theoretically analyze LFP recordings within the context of clinical DBS applications. This goal was achieved with a detailed recording model of beta oscillations (∼20 Hz) in the subthalamic nucleus. The recording model consisted of finite element models of intraoperative microelectrodes and DBS macroelectrodes implanted in the brain along with multi-compartment cable models of STN projection neurons. Model analysis permitted systematic investigation into a number of variables that can affect the composition of the recorded LFP (e.g. electrode size, electrode impedance, recording configuration, and filtering effects of the brain, electrode-electrolyte interface, and recording electronics). The results of the study suggest that the spatial reach of the LFP can extend several millimeters. Model analysis also showed that variables such as electrode geometry and recording configuration can have a significant effect on LFP amplitude and spatial reach, while the effects of other variables, such as electrode impedance, are often negligible. The results of this study provide insight into the origin of the LFP and identify variables that need to be considered when analyzing LFP recordings in clinical DBS applications.
The visceromotor nature of the rat anterior cingulate cortex was investigated by electrically stimulating this area in both anesthetized and awake animals. Initial studies demonstrated that electrical stimulation of any division of the anterior cingulate cortex elicits a significant fall in blood pressure in the sodium pentobarbital-anesthetized rat. Depressor responses were greatest (up to 50% decreases) following stimulation of the ventral third of the anterior cingulate cortex. Heart rate was not altered by cingulate cortex stimulation. In the awake animal, stimulation of previously identified depressor sites in the rostral third of the pregenual cingulate cortex elicited pressor responses. In contrast, stimulation of the caudal third of this cortex elicited depressor responses, and stimulation of the middle third elicited biphasic (pressor followed by depressor) responses. These results indicate that the anterior cingulate cortex is a visceromotor region which may provide a cortical output for the regulation of blood pressure responses associated with learning and or stress.
The arterial baroreflex is a key mechanism for the homeostatic control of blood pressure (BP). In animals and humans, psychological stressors suppress the capacity of the arterial baroreflex to control short-term fluctuations in BP, reflected by reduced baroreflex sensitivity (BRS). While animal studies have characterized the brain systems that link stressor processing to BRS suppression, comparable human studies are lacking. Here, we measured beat-to-beat BP and heart rate (HR) in 97 adults who performed a multisource interference task that evoked changes in spontaneous BRS, which were quantified by a validated sequence method. The same 97 participants also performed the task during functional magnetic resonance imaging (fMRI) of brain activity. Across participants, task performance (i) increased BP and HR and (ii) reduced BRS. Analyses of fMRI data further demonstrated that a greater task-evoked reduction in BRS covaried with greater activity in brain systems important for central autonomic and cardiovascular control, particularly the cingulate cortex, insula, amygdala, and midbrain periaqueductal gray (PAG). Moreover, task performance increased the functional connectivity of a discrete area of the anterior insula with both the cingulate cortex and amygdala. In parallel, this same insula area showed increased task-evoked functional connectivity with midbrain PAG and pons. These novel findings provide human evidence for the brain systems presumptively involved in suppressing baroreflex functionality, with relevance for understanding the neurobiological mechanisms of stressor-related cardiovascular reactivity and associated risk for essential hypertension and atherosclerotic heart disease.
Accomplishing even simple tasks depend on neuronal circuits to configure how incoming sensory stimuli map onto responses. Controlling these stimulus-response (SR) mapping rules relies on a cognitive control network comprising the anterior cingulate cortex (ACC). Single neurons within the ACC convey information about currently relevant SR mapping rules and signal unexpected action outcomes, which can be used to optimize behavioral choices. However, its functional significance and the mechanistic means of interaction with other nodes of the cognitive control network remain elusive and poorly understood. Here, we report that core aspects of cognitive control are encoded by rhythmic theta-band activity within neuronal circuits in the ACC. Throughout task performance, theta-activity predicted which of two SR mapping rules will be established before processing visual target information. Task-selective theta-activity emerged particularly early during those trials, which required the adjustment of SR rules following an erroneous rule representation in the preceding trial. These findings demonstrate a functional correlation of cognitive control processes and oscillatory theta-band activity in macaque ACC. Moreover, we report that spike output of a subset of cells in ACC is synchronized to predictive theta-activity, suggesting that the theta-cycle could serve as a temporal reference for coordinating local task selective computations across a larger network of frontal areas and the hippocampus to optimize and adjust the processing routes of sensory and motor circuits to achieve efficient sensory-motor control.
Postencounter and circa-strike defensive contexts represent two adaptive responses to potential and imminent danger. In the context of a predator, the postencounter reflects the initial detection of the potential threat, whereas the circa-strike is associated with direct predatory attack. We used functional magnetic resonance imaging to investigate the neural organization of anticipation and avoidance of artificial predators with high or low probability of capturing the subject across analogous postencounter and circa-strike contexts of threat. Consistent with defense systems models, postencounter threat elicited activity in forebrain areas, including subgenual anterior cingulate cortex (sgACC), hippocampus, and amygdala. Conversely, active avoidance during circa-strike threat increased activity in mid-dorsal ACC and midbrain areas. During the circa-strike condition, subjects showed increased coupling between the midbrain and mid-dorsal ACC and decreased coupling with the sgACC, amygdala, and hippocampus. Greater activity was observed in the right pregenual ACC for high compared with low probability of capture during circa-strike threat. This region showed decreased coupling with the amygdala, insula, and ventromedial prefrontal cortex. Finally, we found that locomotor errors correlated with subjective reports of panic for the high compared with low probability of capture during the circa-strike threat, and these panic-related locomotor errors were correlated with midbrain activity. These findings support models suggesting that higher forebrain areas are involved in early-threat responses, including the assignment and control of fear, whereas imminent danger results in fast, likely "hard-wired," defensive reactions mediated by the midbrain.
The human brain localizes mental operations of the kind posited by cognitive theories. These local computations are integrated
in the performance of cognitive tasks such as reading. To support this general hypothesis, new data from neural imaging studies
of word reading are related to results of studies on normal subjects and patients with lesions. Further support comes from
studies in mental imagery, timing, and memory.
In Experiment I 41 subjects performed one of three tasks while also hearing irrelevant tones tones. The three tasks were forewarned reaction time, vigilance and mental arithmetic and each was divided into discrete trials. The irrelevant tones either occurred during task performance (i.e., within a trial) or outside task performance (i.e., between trials). There was no difference in skin conductance OR magnitude to tones across the three tasks. Heart rate changes in contrast showed clear differences between tasks with a marked deceleration occurring during forewarned reaction time and a marked acceleration occurring during mental arithmetic. Skin conductance OR magnitude was significantly greater to tones occurring during task performance than to tones occurring outside task performance. This was interpreted as reflecting changes in the level of attention (higher during task performance) rather than direction of attention (away from tones during task performance). In Experiment II 39 subjects heard a series of irrelevant tones either while performing a forewarned reaction time task as in Experiment I or while performing no concomitant task. Rate of habituation was significantly faster for the subjects performing the concomitant task. This was interpreted as reflecting direction of attention which should be away from the tones when the subject was performing a concomitant task. Thus while rate of habituation to a class of stimuli may reflect direction of attention, short-term changes in OR amplitude probably reflect level of attention.
Thalamocortical activity exhibits two distinct states: (a) synchronized rhythmic activity in the form of delta, spindle, and other slow waves during EEG-synchronized sleep and (b) tonic activity during waking and rapid-eye-movement sleep. Spindle waves are generated largely through a cyclical interaction between thalamocortical and thalamic reticular neurons involving both the intrinsic membrane properties of these cells and their anatomical interconnections. Specific alterations in the interactions between these cells can result in the generation of paroxysmal events resembling absence seizures in children. The release of several different neurotransmitters from the brain stem, hypothalamus, basal forebrain, and cerebral cortex results in a depolarization of thalamocortical and thalamic reticular neurons and an enhanced excitability in many cortical pyramidal cells, thereby suppressing the generation of sleep rhythms and promoting a state that is conducive to sensory processing and cognition.
To identify the brain areas involved in central command, four monkeys were trained to attenuate the tachycardia of exercise while different brain sites affecting heart rate (HR) were simultaneously stimulated electrically. Among 24 brain sites located mostly in the limbic structures, we have identified four types of control systems that mediate cardiovascular and motor behavior during exercise. One system increases HR equivalently during both exercise and operantly controlled HR, whereas another increases HR during both tasks and abolishes operant HR control. In the third system, the effect of brain stimulation on HR is attenuated during exercise and during exercise with operantly controlled HR. The fourth system increases HR in both tasks, but its effect is significantly attenuated during operant HR control. We believe that this last system, which includes the mediodorsal nucleus, nucleus ventralis anterior, and cingulate cortex, plays a significant role in central command.
Brain responses to pain, assessed through positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are reviewed. Functional activation of brain regions are thought to be reflected by increases in the regional cerebral blood flow (rCBF) in PET studies, and in the blood oxygen level dependent (BOLD) signal in fMRI. rCBF increases to noxious stimuli are almost constantly observed in second somatic (SII) and insular regions, and in the anterior cingulate cortex (ACC), and with slightly less consistency in the contralateral thalamus and the primary somatic area (SI). Activation of the lateral thalamus, SI, SII and insula are thought to be related to the sensory-discriminative aspects of pain processing. SI is activated in roughly half of the studies, and the probability of obtaining SI activation appears related to the total amount of body surface stimulated (spatial summation) and probably also by temporal summation and attention to the stimulus. In a number of studies, the thalamic response was bilateral, probably reflecting generalised arousal in reaction to pain. ACC does not seem to be involved in coding stimulus intensity or location but appears to participate in both the affective and attentional concomitants of pain sensation, as well as in response selection. ACC subdivisions activated by painful stimuli partially overlap those activated in orienting and target detection tasks, but are distinct from those activated in tests involving sustained attention (Stroop, etc.). In addition to ACC, increased blood flow in the posterior parietal and prefrontal cortices is thought to reflect attentional and memory networks activated by noxious stimulation. Less noted but frequent activation concerns motor-related areas such as the striatum, cerebellum and supplementary motor area, as well as regions involved in pain control such as the periaqueductal grey. In patients, chronic spontaneous pain is associated with decreased resting rCBF in contralateral thalamus, which may be reverted by analgesic procedures. Abnormal pain evoked by innocuous stimuli (allodynia) has been associated with amplification of the thalamic, insular and SII responses, concomitant to a paradoxical CBF decrease in ACC. It is argued that imaging studies of allodynia should be encouraged in order to understand central reorganisations leading to abnormal cortical pain processing. A number of brain areas activated by acute pain, particularly the thalamus and anterior cingulate, also show increases in rCBF during analgesic procedures. Taken together, these data suggest that hemodynamic responses to pain reflect simultaneously the sensory, cognitive and affective dimensions of pain, and that the same structure may both respond to pain and participate in pain control. The precise biochemical nature of these mechanisms remains to be investigated.
The purpose of this investigation was to hypnotically manipulate effort sense during dynamic exercise and determine whether cerebral cortical structures previously implicated in the central modulation of cardiovascular responses were activated. Six healthy volunteers (4 women, 2 men) screened for high hypnotizability were studied on 3 separate days during constant-load exercise under three hypnotic conditions involving cycling on a 1) perceived level grade, 2) perceived downhill grade, and 3) perceived uphill grade. Ratings of perceived exertion (RPE), heart rate (HR), blood pressure (BP), and regional cerebral blood flow (rCBF) distributions for several sites were compared across conditions using an analysis of variance. The suggestion of downhill cycling decreased both the RPE [from 13 +/- 2 to 11 +/- 2 (SD) units; P < 0.05] and rCBF in the left insular cortex and anterior cingulate cortex, but it did not alter exercise HR or BP responses. Perceived uphill cycling elicited significant increases in RPE (from 13 +/- 2 to 14 +/- 1 units), HR (+16 beats/min), mean BP (+7 mmHg), right insular activation (+7.7 +/- 4%), and right thalamus activation (+9.2 +/- 5%). There were no differences in rCBF for leg sensorimotor regions across conditions. These findings show that an increase in effort sense during constant-load exercise can activate both insular and thalamic regions and elevate cardiovascular responses but that decreases in effort sense do not reduce cardiovascular responses below the level required to sustain metabolic needs.
The purpose of this investigation was to determine whether central command activated regions of the insular cortex, independent of muscle metaboreflex activation and blood pressure elevations. Subjects (n = 8) were studied during 1) rest with cuff occlusion, 2) static handgrip exercise (SHG) sufficient to increase mean blood pressure (MBP) by 15 mmHg, and 3) post-SHG exercise cuff occlusion (PECO) to sustain the 15-mmHg blood pressure increase. Data were collected for heart rate, MBP, ratings of perceived exertion and discomfort, and regional cerebral blood flow (rCBF) by using single-photon-emission computed tomography. When time periods were compared when MBP was matched during SHG and PECO, heart rate (7 +/- 3 beats/min; P < 0.05) and ratings of perceived exertion (15 +/- 2 units; P < 0.05) were higher for SHG. During SHG, there were significant increases in rCBF for hand sensorimotor (9 +/- 3%), right inferior posterior insula (7 +/- 3%), left inferior anterior insula (8 +/- 2%), and anterior cingluate regions (6 +/- 2%), not found during PECO. There was significant activation of the inferior (ventral) thalamus and right inferior anterior insular for both SHG and PECO. Although prior studies have shown that regions of the insular cortex can be activated independent of mechanoreflex input, it was not presently assessed. These findings provide evidence that there are rCBF changes within regions of the insular and anterior cingulate cortexes related to central command per se during handgrip exercise, independent of metaboreflex activation and blood pressure elevation.
Human anterior cingulate function has been explained primarily within a cognitive framework. We used functional MRI experiments with simultaneous electrocardiography to examine regional brain activity associated with autonomic cardiovascular control during performance of cognitive and motor tasks. Using indices of heart rate variability, and high- and low-frequency power in the cardiac rhythm, we observed activity in the dorsal anterior cingulate cortex (ACC) related to sympathetic modulation of heart rate that was dissociable from cognitive and motor-related activity. The findings predict that during effortful cognitive and motor behaviour the dorsal ACC supports the generation of associated autonomic states of cardiovascular arousal. We subsequently tested this prediction by studying three patients with focal damage involving the ACC while they performed effortful cognitive and motor tests. Each showed abnormalities in autonomic cardiovascular responses with blunted autonomic arousal to mental stress when compared with 147 normal subjects tested in identical fashion. Thus, converging neuroimaging and clinical findings suggest that ACC function mediates context-driven modulation of bodily arousal states.
Background
Deep Brain Stimulation of the Anterior Cingulate Cortex is a recent technique that has shown some promising short-term results in patients with chronic refractory neuropathic pain. Three years after the first case-series, we assessed its efficacy on a larger cohort, with longer follow-up.
Methods
24 patients (19 males; 49.1 years) with neuropathic pain underwent bilateral ACC DBS. Patient reported outcome measures were collected pre- and post-surgery, using the Numerical Rating Scale (NRS), Short-Form 36 quality of life (SF-36), McGill pain (MPQ) and EuroQol-5D questionnaires.
Results
22 patients after a trial week were fully internalized and 12 had a mean follow-up of 38.9 months. Six months post-surgery the mean NRS score dropped from 8.0 to 4.27 (P=.004). There was a significant improvement in the MPQ (mean -36%; P=.021) and EQ-5D score significantly decreased (mean -21%; P=.036). The PF domain of SF-36 was significantly improved (mean +54.2%; P=.01). Furthermore, in 83% of these patients: at 6 months NRS was improved by 60% (P<.001) and MPQ decreased by 47% (P<.01). After 1 year, NRS decreased by 43% (P< .01), EQ-5D was significantly reduced (mean -30.8; P=.05) and significant improvements were also observed for different domains of the SF-36. At longer follow-ups, efficacy was sustained up to 42 months in some patients, with a NRS as low as 3.
Conclusions
Follow-up results confirm that ACC DBS alleviates chronic neuropathic pain refractory to pharmacotherapy and improves quality of life in a significant number of patients.
Debates over the function(s) of dorsal anterior cingulate cortex (dACC) have persisted for decades. So too have demonstrations of the region's association with cognitive control. Researchers have struggled to account for this association and, simultaneously, dACC's involvement in phenomena related to evaluation and motivation. We describe a recent integrative theory that achieves this goal. It proposes that dACC serves to specify the currently optimal allocation of control by determining the overall expected value of control (EVC), thereby licensing the associated cognitive effort. The EVC theory accounts for dACC's sensitivity to a wide array of experimental variables, and their relationship to subsequent control adjustments. Finally, we contrast our theory with a recent theory proposing a primary role for dACC in foraging-like decisions. We describe why the EVC theory offers a more comprehensive and coherent account of dACC function, including dACC's particular involvement in decisions regarding foraging or otherwise altering one's behavior.
Sleep is characterized by synchronized events in billions of synaptically coupled neurons in thalamocortical systems. The activation of a series of neuromodulatory transmitter systems during awakening blocks low-frequency oscillations, induces fast rhythms, and allows the brain to recover full responsiveness. Analysis of cortical and thalamic networks at many levels, from molecules to single neurons to large neuronal assemblies, with a variety of techniques, ranging from intracellular recordings in vivo and in vitro to computer simulations, is beginning to yield insights into the mechanisms of the generation, modulation, and function of brain oscillations
Resting high-frequency heart rate variability (HF-HRV) relates to cardiac vagal control and predicts individual differences in health and longevity, but its functional neural correlates are not well defined. The medial prefrontal cortex (mPFC) encompasses visceral control regions that are components of intrinsic networks of the brain, particularly the default mode network (DMN) and the salience network (SN). Might individual differences in resting HF-HRV covary with resting state neural activity in the DMN and SN, particularly within the mPFC? This question was addressed using fMRI data from an eyes-open, 5-min rest period during which echoplanar brain imaging yielded BOLD time series. Independent component analysis yielded functional connectivity estimates defining the DMN and SN. HF-HRV was measured in a rest period outside of the scanner. Midlife (52% female) adults were assessed in two studies (Study 1, N = 107; Study 2, N = 112). Neither overall DMN nor SN connectivity strength was related to HF-HRV. However, HF-HRV related to connectivity of one region within mPFC shared by the DMN and SN, namely, the perigenual anterior cingulate cortex, an area with connectivity to other regions involved in autonomic control. In sum, HF-HRV does not seem directly related to global resting state activity of intrinsic brain networks, but rather to more localized connectivity. A mPFC region was of particular interest as connectivity related to HF-HRV was shared by the DMN and SN. These findings may indicate a functional basis for the coordination of autonomic cardiac control with engagement and disengagement from the environment.
DA - 20040628IS - 1053-8119LA - engPT - Journal ArticleSB - IM
Investigating human brain function is essential to develop models of cortical involvement during walking. Such models could advance the analysis of motor impairments following brain injuries (e.g. stroke) and may lead to novel rehabilitation approaches. In this work, we applied high-density EEG source imaging based on individual anatomy to enable neuroimaging during walking. To minimize the impact of muscular influence on EEG recordings we introduce a novel artifact correction method based on spectral decomposition. High γ oscillations (>60Hz) were previously reported to play an important role in motor control. Here, we investigate high γ amplitudes while focusing on two different aspects of a walking experiment, namely the fact that a person walks and the rhythmicity of walking. We found high γ amplitudes (60-80Hz) located focally in central sensorimotor areas were significantly increased during walking compared to standing. Moreover, high γ (70-90Hz) amplitudes in the same areas are modulated in relation to the gait cycle. Since the spectral peaks of high γ amplitude increase and modulation do not match, it is plausible that these two high γ elements represent different frequency-specific network interactions. Interestingly, we found high γ (70-90Hz) amplitudes to be coupled to low γ (24-40Hz) amplitudes, which both are modulated in relation to the gait cycle but conversely to each other. In summary, our work is a further step towards modeling cortical involvement during human upright walking.
Copyright © 2015. Published by Elsevier Inc.
An attention mechanism in the pulvinar nucleus of the thalamus appears to be involved in the filtering of a location in a cluttered visual field, according to recent PET data. The mechanism in the pulvinar is assumed to be a particular type of circuit that reciprocally connects thalamic relay cells to cortical cells. This circuit, which is characteristic of thalamic nuclei in general, appears to embody an algorithm that enhances firing in a target set of cells while inhibiting firing in the surrounding set of cells. Recent PET studies have also identified specific areas of cortex that show increased blood flow when humans expect to process particular aspects of visual objects, such as location, shape, color, and movement velocity. An expectation for a particular feature can be regarded as a peaked activity distribution across cortical synaptic space that increases the effectiveness (accuracy and speed) of the perception of that feature and features similar to that feature. The expectation process is assumed to be generated by a thalamic enhancement circuit, which in turn is driven by a cognitive procedure, apparently located in the anterior cingulate area of the cortex. The selection of a particular cognitive procedure is assumed to depend on the momentary relative motivational value associated with it by means of connections to deeper limbic structures. Under usual conditions, the procedure having the dominant motivational value is the one selected.
Pain is a multidimensional phenomenon with sensory, affective, and autonomic components. Here, we used parametric functional magnetic resonance imaging (fMRI) to correlate regional brain activity with autonomic responses to (i) painful stimuli and to (ii) anticipation of pain. The autonomic parameters used for correlation were (i) skin blood flow (SBF) and (ii) skin conductance response (SCR). During (i) experience of pain and (ii) anticipation of pain, activity in the insular cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), posterior parietal cortex (PPC), secondary somatosensory cortex (S2), thalamus, and midbrain correlated with sympathetic outflow. A conjunction analysis revealed a common central sympathetic network for (i) pain experience and (ii) pain anticipation with similar correlations between brain activity and sympathetic parameters in the anterior insula, prefrontal cortex, thalamus, midbrain, and temporoparietal junction. Therefore, we here describe shared central neural networks involved in the central autonomic processing of the experience and anticipation of pain. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
Although pain is accompanied by autonomic nervous system responses, the cerebral circuits involved in the autonomic pain dimension remain elusive. Therefore, we used functional magnetic resonance imaging (fMRI) and investigated brain processing associated with cutaneous sympathetic vasoconstrictor reflexes during noxious stimulation. When a classical fMRI analysis based on the applied block design was performed, we were able to detect activations well known to be engaged in the central processing of touch and pain. A parametric fMRI analysis in which cutaneous vasoconstrictor activity was correlated with MRI signals revealed two distinct patterns of brain activity. During (i) noxious stimulation itself, brain activity correlated with sympathetic activity in the anterior insula, ventrolateral prefrontal cortex (VLPFC), anterior cingulate cortex (ACC), and secondary somatosensory cortex (S2). During (ii) baseline, brain activity correlated with sympathetic activity in the VMPFC, dorsolateral prefrontal cortex (DLPFC), OFC, PCC, cuneus, precuneus, occipital areas, and hypothalamus. Conjunction analysis revealed significant similar responses during periods of noxious stimulation and periods of sympathetic activation in the anterior insula, ACC and VLPFC (activation) and VMPFC, OFC, PCC, cuneus and precuneus (deactivation). Therefore, we here describe a cerebral network which may be engaged in the processing of the autonomic subdimension of the human pain experience.
Increased cerebral blood flow in the anterior cingulate cortex (ACC) has been noted in a range of cognitively demanding tasks studied with PET. A PET study of 10 normal males was carried out using the bolus H2(15)O intravenous injection technique to examine the effects of anticipation on blood flow to the ACC. In a series of conditions, subjects 1) passively viewed flashing plus signs, 2) noted the occurrence of abstract patterns, 3) named animal pictures, 4) or carried out a semantic judgement on animal pictures. Anticipatory scans were carried out after the subjects were presented with the instructions but before they began the cognitive task, as they were passively viewing plus signs. Significantly increased cerebral blood flow to the ACC was found in all three cognitive tasks when compared with baseline. More importantly, a similar increase was observed in each of the anticipatory states when compared with baseline. When the anticipation scan served as the subtracted baseline for the cognitive task, the increase in blood flow was not significant. This pattern of activity suggests that receiving instructions, preparation, and anticipation of the cognitive task, rather than task-related processing itself, may be responsible for the increased blood flow in the ACC noted in many PET studies of simple cognitive tasks.
In view of conflicting neuroimaging results regarding autonomic-specific activity within the anterior cingulate cortex (ACC), we investigated autonomic responses to direct brain stimulation during stereotactic limbic surgery.
Skin conductance activity and accelerative heart rate responses to multi-voltage stimulation of the ACC (n = 7) and paralimbic subcaudate (n = 5) regions were recorded during bilateral anterior cingulotomy and bilateral subcaudate tractotomy (in patients that had previously received an adequate lesion in the ACC), respectively.
Stimulations in both groups were accompanied by increased autonomic arousal. Skin conductance activity was significantly increased during ACC stimulations compared with paralimbic targets at 2 V (2.34 +/- .68 [score in microSiemens +/- SE] vs. .34 +/- .09, p = .013) and 3 V (3.52 +/- .86 vs. 1.12 +/- .37, p = .036), exhibiting a strong "voltage-response" relationship between stimulus magnitude and response amplitude (difference from 1 to 3 V = 1.15 +/- .90 vs. 3.52 +/- .86, p = .041). Heart rate response was less indicative of between-group differences.
This is the first study of its kind aiming at seeking novel insights into the mechanisms responsible for central autonomic modulation. It supports a concept that interregional interactions account for the coordination of autonomic arousal.
Typically in neuroimaging we are looking to extract some pertinent information from imperfect, noisy images of the brain. This might be the inference of percent changes in blood flow in perfusion FMRI data, segmentation of subcortical structures from structural MRI, or inference of the probability of an anatomical connection between an area of cortex and a subthalamic nucleus using diffusion MRI. In this article we will describe how Bayesian techniques have made a significant impact in tackling problems such as these, particularly in regards to the analysis tools in the FMRIB Software Library (FSL). We shall see how Bayes provides a framework within which we can attempt to infer on models of neuroimaging data, while allowing us to incorporate our prior belief about the brain and the neuroimaging equipment in the form of biophysically informed or regularising priors. It allows us to extract probabilistic information from the data, and to probabilistically combine information from multiple modalities. Bayes can also be used to not only compare and select between models of different complexity, but also to infer on data using committees of models. Finally, we mention some analysis scenarios where Bayesian methods are impractical, and briefly discuss some practical approaches that we have taken in these cases.
The organization of projections from the macaque orbital and medial prefrontal cortex (OMPFC) to the hypothalamus and related regions of the diencephalon and midbrain was studied with retrograde and anterograde tracing techniques. Almost all of the prefrontal cortical projections to the hypothalamus arise from areas within the "medial prefrontal network," as defined previously by Carmichael and Price ([1996] J. Comp. Neurol. 371:179-207). Outside of the OMPFC, only a few neurons in the temporal pole, anterior cingulate and insular cortex project to the hypothalamus. Axons from the OMPFC also innervate the basal forebrain, zona incerta, and ventral midbrain. Within the medial prefrontal network, different regions project to distinct parts of the hypothalamus. The medial wall areas 25 and 32 send the heaviest projections to the hypothalamus; axons from these areas are especially concentrated in the anterior hypothalamic area and the ventromedial hypothalamic nucleus. Orbital areas 13a, 12o, and Iai, which are related to the medial prefrontal network, selectively innervate the lateral hypothalamic area, especially its posterior part. The cellular regions of the paraventricular, supraoptic, suprachiasmatic, arcuate, and mammillary nuclei are conspicuously devoid of cortical axons, but many axons abut the borders of these nuclei and may contact dendrites that extend from them. Areas within the orbital prefrontal network on the posterior orbital surface and agranular insula send only weak projections to the posterior lateral hypothalamic area. The rostral orbital surface does not contribute to the cortico-hypothalamic projection.
The origin and termination of prefrontal cortical projections to the periaqueductal gray (PAG) were defined with retrograde axonal tracers injected into the PAG and anterograde axonal tracers injected into the prefrontal cortex (PFC). The retrograde tracer experiments demonstrate projections to the PAG that arise primarily from the medial prefrontal areas 25, 32, and 10m, anterior cingulate, and dorsomedial areas 24b and 9, select orbital areas 14c, 13a, Iai, 12o, and caudal 12l, and ventrolateral area 6v. Only scattered cells were retrogradely labeled in other areas in the PFC. Caudal to the PFC, projections to the PAG also arise from the posterior cingulate cortex, the dorsal dysgranular, and granular parts of the temporal polar cortex, the ventral insula, and the dorsal bank of the superior temporal sulcus. Cells were also labeled in subcortical structures, including the central nucleus and ventrolateral part of the basal nucleus of the amygdala. The anterograde tracer experiments indicate that projections from distinct cortical areas terminate primarily in individual longitudinal PAG columns. The projections from medial prefrontal areas 10m, 25, and 32 end predominantly in the dorsolateral columns, bilaterally. Fibers from orbital areas 13a, Iai, 12o, and caudal 12l terminate primarily in the ventrolateral column, whereas fibers from dorsomedial areas 9 and 24b terminate mainly in the lateral column. The PFC areas that project to the PAG include most of the areas previously defined as the "medial prefrontal network." The areas that comprise this network represent a visceromotor system, distinct from the sensory related "orbital network."
Theta rhythm at the midline of the frontal area can be observed in normal subjects, during mental task performance, rest and sleep. Frontal midline theta rhythm (Fm theta) is a train of rhythmic waves at the frequency of 6- Hz and can be induced by various mental tasks. Fm theta is induced not only during mental tasks but also during nocturnal sleep in which it was most frequent during rapid eye movement (REM) and second most frequent during stage 1 of non-REM (NREM) sleep, and the relationship of Fm theta to dream images during sleep was found. It is concluded, therefore, that the appearance of Fm theta is related to mental activity even during sleep. Fm theta shows individual differences and is related to certain personality traits. High Fm theta groups showed the lowest anxiety score in the Manifest Anxiety Scale (MAS), the highest score in the extrovertive scale of the Maudsley Personality Inventory (MPI) and the lowest score in the neurotic scale of MPI. Low Fm theta groups showed the opposite correlation. Significant negative correlation was found between the amount of Fm theta and platelet monoamine oxidase (MAO) activity. Summarizing the above-mentioned results, it may be concluded that the appearance of Fm 0 is related to mental activity, personality traits and platelet MAO activity. Furthermore, the correlation of such markers as platelet MAO activity and Fm theta with personality traits as measured by various psychological tests may prove to be of great importance in the exploration of the biological bases of personality.
The pyramidal control of the heart rate (HR) and the arterial pressure (AP) was investigated in the cat. Experiments were conducted in order to determine relative contribution of vagal and sympathetic components to this control. In eighteen anesthetized and curarized cats, electrical stimulations were applied to the pyramidal tract (PT), followed by pharmacological blockade of the sympathetic cardiac control or by bivagotomy. HR and mean arterial pressure (MAP) were recorded in response to pyramidal stimulations before and after bulbar transections sparing only the PT, beta 1-blockade by atenolol administration and/or bilateral vagotomy. Results showed that the stimulation of the PT elicits significant cardiac accelerations and MAP increases in all animals. Furthermore, bulbar transections allowed to conclude that pyramidal influences acted at bulbar level and not on spinal cardiovascular neurons. After beta 1-blockade by atenolol, HR increases were reduced by about 70% and those of MAP by about 30%; after bilateral vagotomy, cardioaccelerations were reduced by about 30% but no significant reductions of MAP were observed; finally, beta 1-blockade combined with vagal section suppressed cardioaccelerations and significantly reduced the MAP increases. These results suggest the existence of a direct cortical control, via the pyramidal tract, to cardiovascular centers of the medulla, probably mediated by pyramidal collaterals. This control appears to be organized following a reciprocal autonomic pattern where the suppression of the vagal inhibition is associated with a concomitant sympathetic excitation. The present work also provides data in favour of a central command coupling somatic programs and cardiac adjustments during motor acts.
Frontal midline theta rhythm (Fm theta) is a distinct theta activity of EEG in the frontal midline area that appears during concentrated performance of mental tasks in normal subjects and reflects focused attentional processing. To tomographically visualize the source current density distributions of Fm theta, we recorded Fm theta by using a 64-channel whole-head MEG system from four healthy subjects, and applied a new analysis method, synthetic aperture magnetometry (SAM), an adaptive beam forming method. Fm theta was observed in the MEG signals over the bilateral frontal regions. SAM analysis showed bilateral medial prefrontal cortices, including anterior cingulate cortex, as the source of Fm theta. This result suggests that focused attention is mainly related to medial prefrontal cortex.
Visceral function is essential for survival. Discreet regions of the human brain controlling visceral function have been postulated from animal studies (Cechetto and Saper [1987] J. Comp. Neurol. 262:27-45) and suspected from lethal cardiac arrythmias (Cechetto [1994] Integr. Physiol. Behv. Sci. 29:362-373). However, these visceral sites remain uncharted in the normal human brain. We used 4-Tesla functional magnetic resonance imaging (fMRI) to identify changes in activity in discrete regions of the human brain previously identified in animal studies to be involved in visceral control. Five male subjects underwent heart rate (HR) and/or blood pressure (BP) altering tests: maximal inspiration (MX), Valsalva's maneuver (VM), and isometric handgrip (HG). Increased neuronal activity was observed during MX, VM, and HG, localized in the insular cortex, in the posterior regions of the thalamus, and in the medial prefrontal cortex. To differentiate special visceral (taste) regions from general visceral (HR, BP) regions in these areas, response to gustatory stimulation was also examined; subjects were administered saline (SAL) and sucrose (SUC) solutions as gustatory stimuli. Gustatory stimulation increased activity in the ventral insular cortex at a more inferior level than the cardiopulmonary stimuli. The observed neural activation is the first demonstration of human brain activity in response to visceral stimulation as measured by fMRI.
Several studies have shown that cortical damage, especially to the right hemisphere and to frontal lobes, may attenuate skin conductance responses selectively to psychologically significant stimuli. We tested this hypothesis in 32 patients with frontal lesions, verified by computer assisted tomography and magnetic resonance imaging, and 45 healthy controls. Patients and controls were given a protocol which included a rest period, a series of innocuous tones, and a reaction time task. Patients were given a second protocol in which they viewed slides with positive and negative emotional content and neutral slides. Results showed attenuated electrodermal activity (EDA) during task instructions and smaller skin conductance responses to reaction-time stimuli in patients compared to controls but few differences under passive conditions or in orienting responses to simple tones. Patients with lateral prefrontal and paraventricular lesions were especially low in EDA in the reaction time task, and those with right and bilateral lesions in the cingulate gyrus and/or frontal operculum had attenuated EDA in both protocols. We conclude that the effects of certain frontal lesions are on the psychological response to significance which is indexed by EDA rather than directly on EDA per se.
States of peripheral autonomic arousal accompany emotional behaviour, physical exercise and cognitive effort, and their central representation may influence decision making and the regulation of social and emotional behaviours. However, the cerebral functional neuroanatomy representing and mediating peripheral autonomic responses in humans is poorly understood.
Six healthy volunteer subjects underwent H 2 ¹⁵ O positron emission tomography (PET) scanning while performing isometric exercise and mental arithmetic stressor tasks, and during corresponding control tasks. Mean arterial blood pressure (MAP) and heart rate (HR) were monitored during scanning.
Data were analysed using statistical parametric mapping (SPM99). Conjunction analyses were used to determine significant changes in regional cerebral blood flow (rCBF) during states of cardiovascular arousal common to both exercise and mental stressor tasks.
Exercise and mental stressor tasks, relative to their control tasks, were associated with significantly ( P < 0.001 ) increased MAP and HR. Significant common activations (increased rCBF) were observed in cerebellar vermis, brainstem and right anterior cingulate. In both exercise and mental stress tasks, increased rCBF in cerebellar vermis, right anterior cingulate and right insula covaried with MAP; rCBF in pons, cerebellum and right insula covaried with HR. Cardiovascular arousal in both categorical and covariance analyses was associated with decreased rCBF in prefrontal and medial temporal regions.
Neural responses in discrete brain regions accompany peripheral cardiovascular arousal. We provide evidence for the involvement of areas previously implicated in cognitive and emotional behaviours in the representation of peripheral autonomic states, consistent with a functional organization that produces integrated cardiovascular response patterns in the service of volitional and emotional behaviours.
1. Positron emission tomography (PET) was used to identify the neuroanatomical correlates underlying 'central command' during imagination of exercise under hypnosis, in order to uncouple central command from peripheral feedback. 2. Three cognitive conditions were used: condition I, imagination of freewheeling downhill on a bicycle (no change in heart rate, HR, or ventilation, V(I)): condition II, imagination of exercise, cycling uphill (increased HR by 12 % and V(I) by 30 % of the actual exercise response): condition III, volitionally driven hyperventilation to match that achieved in condition II (no change in HR). 3. Subtraction methodology created contrast A (II minus I) highlighting cerebral areas involved in the imagination of exercise and contrast B (III minus I) highlighting areas activated in the direct volitional control of breathing (n = 4 for both; 8 scans per subject). End-tidal P(CO(2)) (P(ET,CO(2))) was held constant throughout PET scanning. 4. In contrast A, significant activations were seen in the right dorso-lateral prefrontal cortex, supplementary motor areas (SMA), the right premotor area (PMA), superolateral sensorimotor areas, thalamus, and bilaterally in the cerebellum. In contrast B, significant activations were present in the SMA and in lateral sensorimotor cortical areas. The SMA/PMA, dorso-lateral prefrontal cortex and the cerebellum are concerned with volitional/motor control, including that of the respiratory muscles. 5. The neuroanatomical areas activated suggest that a significant component of the respiratory response to 'exercise', in the absence of both movement feedback and an increase in CO(2) production, can be generated by what appears to be a behavioural response.
The purpose was to compare patterns of brain activation during imagined handgrip exercise and identify cerebral cortical structures participating in "central" cardiovascular regulation. Subjects screened for hypnotizability, five with higher (HH) and four with lower hypnotizability (LH) scores, were tested under two conditions involving 3 min of 1) static handgrip exercise (HG) at 30% of maximal voluntary contraction (MVC) and 2) imagined HG (I-HG) at 30% MVC. Force (kg), forearm integrated electromyography, rating of perceived exertion, heart rate (HR), mean blood pressure (MBP), and differences in regional cerebral blood flow distributions were compared using an ANOVA. During HG, both groups showed similar increases in HR (+13 +/- 5 beats/min) and MBP (+17 +/- 3 mmHg) after 3 min. However, during I-HG, only the HH group showed increases in HR (+10 +/- 2 beats/min; P < 0.05) and MBP (+12 +/- 2 mmHg; P < 0.05). There were no significant increases or differences in force or integrated electromyographic activity between groups during I-HG. The rating of perceived exertion was significantly increased for the HH group during I-HG, but not for the LH group. In comparison of regional cerebral blood flow, the LH showed significantly lower activity in the anterior cingulate (-6 +/- 2%) and insular cortexes (-9 +/- 4%) during I-HG. These findings suggest that cardiovascular responses elicited during imagined exercise involve central activation of insular and anterior cingulate cortexes, independent of muscle afferent feedback; these structures appear to have key roles in the central modulation of cardiovascular responses.
1. Sympathetic vasomotor nerves play a major role in determining the level of arterial blood pressure and the distribution of cardiac output. The present review will discuss briefly the central regulatory mechanisms that control the sympathetic outflow to the cardiovascular system in the short and long term.
2. In the short term, the sympathetic vasomotor outflow is regulated by: (i) homeostatic feedback mechanisms, such as the baroreceptor or chemoreceptor reflexes; or (ii) feed-forward mechanisms that evoke cardiovascular changes as part of more complex behavioural responses.
3. The essential central pathways that subserve the baroreceptor reflex and, to a lesser extent, other cardiovascular reflexes, have been identified by studies in both anaesthetized and conscious animals. A critical component of these pathways is a group of neurons in the rostral ventrolateral medulla that project directly to the spinal sympathetic outflow and that receive inputs from both peripheral receptors and higher centres in the brain.
4. Much less is known about the central pathways subserving feed-forward or ‘central command’ responses, such as the cardiovascular changes that occur during exercise or that are evoked by a threatening or alerting stimulus. However, recent evidence indicates that the dorsomedial hypothalamic nucleus is a critical component of the pathways mediating the cardiovascular response to an acute alerting stimulus.
5. Long-term sustained changes in sympathetic vasomotor activity occur under both physiological conditions (e.g. a change in salt intake) and pathophysiological conditions (e.g. heart failure). There is evidence that the paraventricular nucleus in the hypothalamus is a critical component of the pathways mediating these changes.
6. Understanding the central mechanisms involved in the long-term regulation of sympathetic activity and blood pressure is a major challenge for the future. As a working hypothesis, a model is presented of the postulated central mechanisms that result in sustained changes in sympathetic vasomotor activity that are evoked by different types of chronic stimulation.
The anterior cingulate cortex (ACC) has diverse functions and several functional subdivisions. This study implemented a counting Stroop task that presented incongruent (INC) and congruent (CON) stimuli at two speeds to probe dorsal (dACC) and ventral (vACC) using functional magnetic resonance imaging (fMRI). Eighteen healthy subjects completed the task twice: once outside the scanner while heart rate variability (HRV) was recorded and once during fMRI. In both sessions, subjects completed two runs. Stimuli were presented every 2.0 s in one run and every 1.5 s in the other. fMRI data analysis revealed two important findings. First, by computing differential activation between INC and CON stimuli, a cluster of activation related to response inhibition was observed in the left dACC. Additionally, by calculating the interaction of speed with stimulus congruency, a cluster of activation was observed in the left vACC. This activation correlated significantly with high-frequency HRV (P < 0.02 for CON and P < 0.003 for INC) and represents the parasympathetic modulatory role of the vACC. This study supports the notion of functional subdivisions within the ACC and links the processes of cognitive interference and parasympathetic modulation with activation in specific subregions of the ACC, a structure that is critical for the interface between cognition and emotion.