Anterior Anterior Cingulate Cortex Research Articles

A pharmaco-fMRI study on pain networks induced by electrical stimulation after sumatriptan injection

Sumatriptan, a drug widely used to alleviate migraine headaches, has several somatosensory adverse effects, including tactile allodynia. To understand whether sumatriptan affects sensory and affective circuitries simultaneously, we investigated the responses of 12 healthy volunteers to electrical stimuli after infusion with either sumatriptan or saline. Using a double-blind crossover study design, we used functional magnetic resonance imaging (fMRI) to measure brain activation in different areas during electrical stimulation. The visual analog scale (VAS) and short-form McGill pain questionnaire (SF-MPQ) were used to rate stimulation-evoked sensations and affections after drug administration. VAS rating, SF-MPQ, and block fMRI were all performed in each subject during sumatriptan and saline injection. Echo-planar imaging sequences were used to determine the whole-brain blood oxygenation level-dependent signal of the entire brain. Our results showed that sumatriptan predominantly activated regions in the medial pain system and smaller regions in the lateral pain system. These regions included the secondary somatosensory cortex (SII), anterior insular cortex, orbitofrontal cortex, medial thalamus, cerebellar supravermis, dentate nucleus, and the majority of the anterior cingulate cortex (ACC). In contrast, activation following saline administration was observed primarily in the lateral pain system, including the primary sensory cortex, lateral SII, posterior insular cortex, anterior ACC, and lateral thalamus. Importantly, we found that VAS ratings and MPQ scores were increased after sumatriptan infusion, but not after saline administration. Our fMRI, VAS, and SF-MPQ findings suggest that sumatriptan plays a significant role in the affective dimension of pain and a minor role related to sensory discrimination.

Glutamate normalization with ECT treatment response in major depression

Though psychotherapy, medications and brain stimulation are used to treat major depressive disorder (MDD), treatment response depends on several individualized clinical factors and frequently requires multiple treatment trials. To guide more effective personalized interventions, there is thus a need to identify biological markers to elucidate the mechanisms of response to predict treatment outcomes in MDD. Prior evidence suggests neurochemical disturbances in mood regulating networks, including the anterior cingulate cortex (ACC) and connected prefrontal and subcortical centers, contribute to MDD and play a role in treatment response1–4. To identify treatment-related changes in neurochemical markers implicated in MDD2, 4, 5, we applied single-voxel Proton Magnetic Resonance Spectroscopy (1HMRS) for cross sectional and longitudinal analysis of ACC glutamate (Glu), choline (Cho) and N-acetyl aspartate (NAA) in 10 patients with DSM-IVR diagnoses of MDD (mean age: 44.0 years, 7.93 SD; 6 females) followed prospectively during Index treatment and 10 demographically similar controls (mean age: 39.03 years, 9.55 SD; 6 females). Electroconvulsive therapy (ECT) was used as the therapeutic modality since it is a highly effective procedure for treating severe MDD that elicits rapid response in eligible individuals6. Patients were assessed at three time points: baseline, and after the 2nd and 6th ECT sessions, corresponding to ~48 hrs and 2 weeks post treatment initiation (see Supplementary Information (SI) for clinical details). The Hamilton (HAMD) and Montgomery-Asberg (MADRS) Depression Rating Scales recorded therapeutic response. Controls were assessed twice, ~2-weeks apart, to determine disease effects, normative values and to estimate the variance of serial scanning. All subjects, without neurological disorders, alcohol/substance abuse or dementia, provided UCLA Institutional Review Board-approved informed consent. High-resolution T1-weighted MPRAGE structural (FOV: 256; voxel size: 1 mm3; TR/TE: 2200/5.16 ms; flip angle: 12°) and single-voxel Point Resolved Spectroscopy (PRESS) acquisitions (TR/TE: 2000/30 ms; spectral width 2000 Hz; 1024 points) with (128 averages) and without water suppression (8 averages) were collected on a Siemens 3T Allegra system. Automatic and manual 3D shimming was applied to reduce B0 inhomogeneity for voxels (20×18×12 mm3) placed in midline anterior ACC gray matter [Fig 1A; see SI]. LCModel computed the levels of Glu, Cho and NAA relative to the unsuppressed water signal. Derived metabolites levels were corrected for voxel CSF content using corresponding tissue classified T1-weighted images7. Figure 1 A) Voxel placement and 1HMRS spectra in a single subject, B) Mean CSF-adjusted glutamate (left), NAA (middle) and choline (right) levels at each time point in patients and controls indicating significant disease effects (purple), group by time interactions ... Metabolites (with variances 0.50). For baseline comparisons, including age and gender as covariates, main effects of diagnosis were observed for Glu only, F(1,19)=8.61, p<.01 (lower in patients). General Linear Mixed Models (GLMMs) including metabolites from each time point and a subject variable to control for within-subject correlations, also showed a significant diagnosis by time interaction for Glu, F(1, 21.98)=4.94, p<.037. Glu levels increased significantly over time in patients approximating normal levels, F(2, 16.56)=4.05, p<.037, but remained stable in controls (p=.47). In patients, subsequent pairwise comparisons showed significant Glu elevations between baseline and the 6th ECT, p<.018. In the absence of overall effects of time, pairwise comparisons in patients also showed significant decreases in NAA, p<.048, and increases in Cho, p<.047 between baseline and the 6th ECT [Fig 1B]. HAMD and MADRS scores improved significantly with treatment, F(2, 16.67)=29.48 and F(2, 13.12)=19.79, both p<.0001. Variations in Glu correlated with MADRS scores across time, F(1, 15.78)=4.49, p<.05. Baseline Cho levels correlated significantly with overall change in HAMD ratings, r=.85, p<.0001; baseline Glu levels also showed a trend for predicting HAMD change, r=.59, p<.08 [Fig 1C]. MDD-related reductions in ACC glutamate normalize with ECT treatment and associate with clinically determined therapeutic response. Results are in line with prior reports indicating glutamate deficits in MDD2, 4 and extend earlier observations of increased glutamate/glutamine (Glx) in the left ACC in patients treated with ECT8, shown here to also mirror clinical response. NAA and Choline, though not discriminating diagnostic groups at baseline, also showed treatment effects in patients. Together, these neurochemical changes suggest treatment-induced neuroplasticity in the structure, density and integrity of mature neurons9 and/or may reflect changes relating to adult neurogenesis in connected hippocampal and subventricular regions10. Results also support that neurochemical signatures in the ACC may predict future therapeutic response through mechanisms potentially overlapping with other forms of treatment. Studies including additional treatment modalities, larger samples, and longer follow-ups with relapse rates may confirm these observations.

A functional magnetic resonance imaging study of human brain in pain-related areas induced by electrical stimulation with different intensities

Pain-related studies have mainly been performed through traditional methods, which lack the rigorous analysis of anatomical locations. Functional magnetic resonance imaging (fMRI) is a noninvasive method detecting neural activity, and has the ability to precisely locate related activations in vivo. Moreover, few studies have used painful stimulation of changed intensity to investigate relevant functioning nuclei in the human brain. This study mainly focused on the pain-related activations induced by electrical stimulation with different intensities using fMRI. Furthermore, the electrophysiological characteristics of different pain-susceptible-neurons were analyzed to construct the pain modulatory network, which was corresponding to painful stimulus of changed intensity. Twelve volunteers underwent functional scanning receiving different electrical stimulation. The data were collected and analyzed to generate the corresponding functional activation maps and response time curves related to pain. The common activations were mainly located in several specific regions, including the secondary somatosensory cortex (SII), insula, anterior cingulate cortex (ACC), thalamus, and other cerebral regions. Moreover, innocuous electrical stimulation primarily activated the lateral portions of SII and thalamus, as well as the posterior insula, anterior ACC, whereas noxious electrical stimulation primarily activated the medial portions of SII and thalamus, as well as the anterior insula, the posterior ACC, with larger extensions and greater intensities. Several specified cerebral regions displayed different response patterns during electrical stimulation by means of fMRI, which implied that the corresponding pain-susceptible-neurons might process specific aspects of pain. Elucidation of functions on pain-related regions will help to understand the delicate pain modulation of human brain.

The role of cingulate cortex in the detection of errors with and without awareness: a high‐density electrical mapping study

Error-processing research has demonstrated that the brain uses a specialized neural network to detect errors during task performance but the brain regions necessary for conscious awareness of an error are poorly understood. In the present study we show that two well-known error-related event-related potential (ERP) components, the error-related negativity (ERN) and error positivity (Pe) have a differential relationship with awareness during performance of a manual response inhibition task optimized to examine error awareness. While the ERN was unaffected by the participants' conscious experience of errors, the Pe was only seen when participants were aware of committing an error. Source localization of these components indicated that the ERN was generated by a caudal region of the anterior cingulate cortex (ACC) while the Pe was associated with contributions from a more anterior ACC region and the posterior cingulate-precuneus. Tonic EEG measures of cortical arousal were correlated with individual rates of error awareness and showed a specific relationship with the amplitude of the Pe. The latter finding is consistent with evidence that the Pe represents a P3-like facilitation of information processing modulated by subcortical arousal systems. Our data suggest that the ACC might participate in both preconscious and conscious error detection and that cortical arousal provides a necessary setting condition for error awareness. These findings may be particularly important in the context of clinical studies in which a proper understanding of self-monitoring deficits requires an explicit measurement of error awareness.

Noninvasive brain imaging: Brain correlates of the voluntary mental evocation of pain

Pain is consistently associated with the activation of a network of cerebral structures including S1, S2, insula (INS), and anterior cingulate cortex (ACC). This study examines the role of these structures in the mental representation of pain during voluntary mental imagery. BOLD signal acquired in 7 healthy volunteers was contrasted in four conditions: pain stimulation (contact heat at 46.5-49.0°C); warm stimulation (38.0°C); mental imagery of pain; and mental imagery of warmth. The contact probe was applied on the left leg for 9s, every 18s, in all conditions. In the imagery conditions, the temperature remained neutral (32.0°C) and subjects were instructed to imagine a WARM sensation or a highly unpleasant heat PAIN experience when the thermode touched the skin. Directed searches were conducted specifically on the four contralateral target areas using group analyses (t>2.55, p-corrected<.05). Contrasts between pain and warm stimulation conditions confirmed pain-related activation (t-value) in the posterior ACC (4.41), the anterior (3.93) and posterior (6.71) INS, the parietal operculum (2.64), and the leg area of S1 (2.59). Imagery of pain compared to warm significantly activated the ACC (3.28) and the parietal operculum (3.93) while INS activation was only marginally significant (peak-t=2.47) and no peak was found in S1 (t<2.00). A conjunction analysis of the pain vs. warm contrast in the stimulation and imagery conditions further confirmed the common activation of the posterior ACC (3.04), the parietal operculum (3.04), and a marginally significant effect in the posterior INS (2.54). Separate conjunction analyses revealed additional activations common to the stimulation and imagery conditions in the anterior INS in both the pain (3.20) and warm (2.65) conditions and in the anterior ACC in the warm condition (3.61). These results are consistent with the involvement of pain-related cortical areas in the mental evocation and imagery of pain experiences.

Dissociable Neural Responses Related to Pain Intensity, Stimulus Intensity, and Stimulus Awareness within the Anterior Cingulate Cortex: A Parametric Single-Trial Laser Functional Magnetic Resonance Imaging Study

Neuroimaging studies have demonstrated activations in the anterior cingulate cortex (ACC) related to the affective component of pain, but not to stimulus intensity. However, it is possible that the low spatial resolution of positron emission tomography, as used in the majority of these studies, obscured areas coding stimulus intensity. We revisited this issue, using a parametric single-trial functional magnetic resonance imaging design, and investigated pain, stimulus intensity, and stimulus awareness (i.e., pain unrelated) responses within the ACC in nine healthy volunteers. Four different stimulus intensities ranging from warm to painful (300-600 mJ) were applied with a thulium yttrium-aluminum granite infrared laser in a randomized order and rated by the subjects on a five point scale (P0-P4). Pain-related regions in the ventral posterior ACC showed a response that did not distinguish between innocuous trials (P0 and P1) but showed a positive linear relationship with the blood oxygenation level-dependent contrast signal for painful trials (P2-P4). Regions in the dorsal anterior ACC along the cingulate sulcus differentiated between P0 (not perceived) and P1 but exhibited no additional signal increase with P2; these regions are related to stimulus awareness and probably to cognitive processing. Most importantly, we identified a region in the dorsal posterior ACC showing a response that discriminated between nonpainful trials (P0 and P1); therefore, this region was simply related to basic sensory processing and not to pain intensity. Stimulus-related activations were all located adjacent to the cingulate motor area, highlighting the strategic link of stimulus processing and response generation in the posterior ACC.

An fMRI study of the anterior cingulate cortex and surrounding medial wall activations evoked by noxious cutaneous heat and cold stimuli

The anterior cingulate cortex (ACC) and adjacent regions in the medial wall have been implicated in sensory, motor and cognitive processes, including pain. Our previous functional magnetic resonance imaging (fMRI) studies have demonstrated pain-related activation of the posterior portion of the ACC during transcutaneous electrical nerve stimulation (TENS) and variable patterns of cortical activation with innocuous and noxious thermal stimuli in individual subjects. The present study represents the companion paper to our recent study of pain- and thermal-related cortical activations with the aim to use fMRI to delineate the activations in the ACC and surrounding regions of the medial wall during application of innocuous and noxious thermal stimuli as well as during performance of a motor task in individual subjects. Ten normal subjects were imaged on a conventional 1.5 T GE ‘echospeed’ system. Functional images were obtained from sagittal sections through each hemisphere centered at approximately 3–5 and 7–9 mm from midline. Each subject was imaged during innocuous (cool, warm) and noxious thermal (cold, hot) stimulation of the thenar eminence, and execution of a motor (sequential finger-thumb opposition) task. Task-related activations were mostly confined to contralateral and medial ipsilateral images. Although the present results demonstrate intersubject variability in the task-related activations, some general modality-specific patterns were apparent: (i) innocuous thermal-related activations were located mainly in the anterior ACC; (ii) noxious thermal-related activations were primarily located in the anterior ACC, the ventral portion of the posterior ACC, and the supplementary motor area (SMA); (iii) motor-related activations were primarily located in the SMA and dorsal portion of the posterior ACC. These results indicate that specific spatial patterns of activation exist within the ACC and surrounding regions of the medial wall for innocuous and noxious thermal stimuli, and that noxious thermal- and motor-related activations appear to be segregated within the ACC. Therefore, we propose a segregation of the ACC into an anterior non-specific attention/arousal system and a posterior pain system.

Activation of the anterior cingulate cortex by thalamic stimulation in patients with chronic pain: a positron emission tomography study

Object Deep brain stimulation (DBS) of the sensory thalamus has been used to treat chronic, intractable pain. The goal of this study was to investigate the thalamocortical pathways activated during thalamic DBS. Methods The authors compared positron emission tomography (PET) images obtained before, during, and after DBS in five patients with chronic pain. Two of the five patients reported significant DBS-induced pain relief during PET scanning, and the remaining three patients did not report any analgesic effect of DBS during scanning. The most robust effect associated with DBS was activation of the anterior cingulate cortex (ACC). An anterior ACC activation was sustained throughout the 40 minutes of DBS, whereas a more posteriorly located ACC activation occurred at a delay after onset of DBS, although these activations were not dependent on the degree of pain relief reported during DBS. However, implications specific to the analgesic effect of DBS require further study of a larger, more homogeneous patient population. Additional effects of thalamic DBS were detected in motor-related regions (the globus pallidus, cortical area 4, and the cerebellum) and visual and association cortical areas. Conclusions The authors demonstrate that the ACC is activated during thalamic DBS in patients with chronic pain.

Activation of the anterior cingulate cortex by thalamic stimulation in patients with chronic pain: a positron emission tomography study.

Deep brain stimulation (DBS) of the sensory thalamus has been used to treat chronic, intractable pain. The goal of this study was to investigate the thalamocortical pathways activated during thalamic DBS. The authors compared positron emission tomography (PET) images obtained before, during, and after DBS in five patients with chronic pain. Two of the five patients reported significant DBS-induced pain relief during PET scanning, and the remaining three patients did not report any analgesic effect of DBS during scanning. The most robust effect associated with DBS was activation of the anterior cingulate cortex (ACC). An anterior ACC activation was sustained throughout the 40 minutes of DBS, whereas a more posteriorly located ACC activation occurred at a delay after onset of DBS, although these activations were not dependent on the degree of pain relief reported during DBS. However, implications specific to the analgesic effect of DBS require further study of a larger, more homogeneous patient population. Additional effects of thalamic DBS were detected in motor-related regions (the globus pallidus, cortical area 4, and the cerebellum) and visual and association cortical areas. The authors demonstrate that the ACC is activated during thalamic DBS in patients with chronic pain.