Anterior cingulate cortex (ACC) is known to be involved in functions such as emotion, pain, and cognitive control. While studies in humans and nonhuman mammals have advanced our understanding of ACC function, the subjective correlates of ACC activity have remained largely unexplored. In the current study, we show that electrical charge delivery in the anterior midcingulate cortex (aMCC) elicits autonomic changes and the expectation of an imminent challenge coupled with a determined attitude to overcome it. Seed-based, resting-state connectivity analysis revealed that the site of stimulation in both patients was at the core of a large-scale distributed network linking aMCC to the frontoinsular and frontopolar as well as some subcortical regions. This report provides compelling, first-person accounts of electrical stimulation of this brain network and suggests its possible involvement in psychopathological conditions that are characterized by a reduced capacity to endure psychological or physical distress.

In the current multimodal study, we provide detailed, first-person accounts of neuromodulation in the anterior midcingulate cortex (aMCC) and its associated functional network using a combination of electrical brain stimulation (EBS) and preoperative resting-state functional magnetic resonance imaging (fMRI) in two epilepsy patients implanted with intracranial electrodes. In both patients, we demonstrate a remarkably stereotyped set of autonomic, cognitive, and emotional changes and establish a common functional connectivity map linking the aMCC stimulation site to a distributed network of regions, often referred to as the “emotional salience” or “cingulo-opercular” network ().

While lesion studies in humans have shown that the ACC is important for decision making and emotional processing, the anatomical imprecision of this approach can be problematic. It is often unclear the extent to which the cognitive and behavioral deficits in these patients are due to the compromise of the ACC itself rather than the adjacent cortical gray and white matter tissue frequently included in the lesion. In addition, subjective correlates of ACC activity have been methodologically difficult to assess given its hidden position deep within the mesial surface of the brain.

Two lines of evidence suggest that the anterior cingulate cortex (ACC) and a set of connected regions might be the key network in this context. First, studies in humans and nonhuman mammals suggest that the ACC (including its midcingulate region) is essential for initiating changes in behavior, making associations between reward and action, determining the action necessary to obtain a goal, and synthesizing information about reinforcers ranging from pain and threatening conspecifics to aversive cues and negative feedback (). Second, the ACC is anatomically well situated for such functions. For instance, anatomical tracing studies in nonhuman primates, as well as tractography and functional connectivity studies in humans, have suggested strong anatomical and functional connectivity between the ACC and brain structures known to be important for pain, pleasure, emotion, and decision making (for original references see).

The greatest of life’s challenges leave us mired in “a sea of troubles,” battered by the “slings and arrows of outrageous fortune” (). It is at such moments that an individual’s will to persevere is put to the test. While some are able to marshal the necessary physical and psychological resources in the face of challenges, others have a pathologically lowered motivation and mental strength for enduring physical or psychological pain. Understanding the structure and physiology of the brain networks mediating attributes, such as the resolve to overcome upcoming challenges, will create new diagnostic and therapeutic frontiers for disorders such as depression and chronic pain that are characterized, in part, by reduced motivation, endurance, and perseverance.

Results

Two patients with refractory epilepsy were implanted with intracranial depth electrodes to localize the source of seizure activity. We localized the anatomical position of intracranial electrodes in each subject’s native neuroanatomical space. As part of their routine clinical diagnosis, a volley of electrical charge was delivered in a select number of electrode contacts. These electrodes were clinically selected to probe the target region’s function and its potential involvement in the patients’ seizures. EEG and clinical signs in both patients suggested medial temporal lobe epilepsy. To rule out the involvement of other limbic areas in the patients’ seizures, a mild electrical current was delivered in extratemporal sites within the orbitofrontal, cingulate, and retrosplenial regions, and the patients were instructed to report if the electrical stimulation caused their typical seizure auras.

Each stimulation trial was defined as the time when the patient thought his brain was being stimulated. These trials were defined as “real” if electrical charge was delivered and “sham” if the patient thought he was being stimulated but no electrical charge was delivered. During some of the sham trials, we specifically tested the placebo effect by counting “1, 2, 3” before clicking the stimulator button while the electrical current was set at 0 mA.

While electrical charge delivered in the medial temporal lobe structures caused electrographical seizures and typical clinical auras, EBS in nontemporal target sites was void of any EEG after-discharges or seizures and the patients’ perceptual changes were distinct from their typical clinical auras.

Figure 1 Anatomical Location of the Intracranial Electrodes and Electroencephalographic Activity Show full caption In P1 (A) and P2 (B) electrical stimulation was between adjacent contacts (i.e., bipolar stimulation). As noted in the magnetic resonance images (MRIs) and the electroencephalographic (EEG) traces, contacts 1 and 2 in P1 and contact 1 in P2 were clearly in the gray matter. We attribute the results of the EBS to the engagement of the aMCC gray matter and its white matter connections with other brain regions. Note the decrement of EEG activity between sites 2–3 compared to the activity recorded between sites 1 and 2. The MNI coordinates of the EBS targets were as follows: P1 (electrode 1 = 2.00, 26.00, 26.00; electrode 2 = 8.00, 26.00, 26.00) and P2 (electrode 1 = 10.00, 18.00, 26.00; electrode 2 = 16.00, 20.00, 26.00). Note that the right side of the image corresponds to the right side of the brain. One second (1 s) EEG timescale is shown. Sites of stimulation in the subgenual and retrosplenial regions are shown as controls sites 1 or 2 (C1 and C2, blue filled circles). Besides these cingulate control regions, sites immediately adjacent to the aMCC were also stimulated as control sites (see Table 1 ). Stimulation of these control sites did not elicit similar cognitive and emotional effects as the stimulation of the aMCC sites. Table 1 Details of Electrical Stimulation Procedure and Subjective Reports P1 a a Only results from the stimulation of the electrodes in the aMCC (electrodes 1 & 2) and 5 mm adjacent to the aMCC (electrodes 2 & 3) are shown here. Stimulation of the other control sites (shown in Figure 1 ) did not cause any similar effects. Current (mA) Prompting Question Patient Response Stimulation Duration (s) EBS Target Electrodes 1 & 2 (aMCC) 2 “Any difference?” “No.” 1.8 4 “No change?” “No, probably the next one I would start feeling it, it’s starting to get kind of disillusional. It’s starting to get to the point where I’m starting to have a hard time making a decision about what answer I want to say, or how to pursue it or what. It’s not clear.” 2.2 6 “Let me know what you feel.” “Yeah, my upper respiratory … started, kind of … my chest and respiratory system started getting shaky, like it was wanting to … go push itself out the door.” 2.4 6 “Any change in your emotion and mood?” “Not in my emotion, but my mood, I started getting this feeling like … I was driving into a storm. That’s the kind of feeling I got. Like, almost like you’re headed towards a storm that’s on the other side, maybe a couple of miles away, and you’ve got to get across the hill and all of a sudden you’re sitting there going how am I going to get over that, through that? And that’s the way my brain started functioning.” 2.4 8 “Weaker or stronger? Longer or shorter?” “That’s just about the same way as last time. My chest never sits there pounding like it’s, you know, like you’re a football player getting ready to go out and make his first touchdown for the season or something; it’s not that type of thing. It’s more like this thing of trying to figure out your way out of, how you’re going to get through something. It’s not a matter of how you’re going to production-wise do something … Let’s say … if you knew you were driving your car and it was … one of the tires was half flat and you’re only halfway there and you have no other way to turn around and go back, you have to keep going forward … That type of a, you know, feeling you have. You’re like, you’re like (pats chest) am I gonna, am I gonna to get through this? Am I gonna get through this?” 3.2 8 “Was it negative or positive?” “I’d say it is a question, not a … not a worry like a negative like I’m not … ‘cause there’re not too many things I don’t … it was more of a positive thing like … push harder, push harder, push harder to try and get through this and that’s when my heart started … my, my … I don’t know if you were reading my pulse or anything, or heart rate. Was it starting to go up at that time or …?” 3.2 8 “Was it stronger of the same as the time before?” “The same.” 3.2 SHAM “Nothing, absolutely nothing” 0 SHAM “My ears... Well this ear [right] starting to get a lot of pressure and sensitivity built up in it. Thinks it’s the one that got banged up real good when they were starting to put screws in it.” 0 Electrodes 2 & 3 (adjacent to aMCC) 2 “Anything?” “Nothing” 2.4 4 “No” 2.6 6 “No” 2 8 “No” 2.6 P2 a a Only results from the stimulation of the electrodes in the aMCC (electrodes 1 & 2) and 5 mm adjacent to the aMCC (electrodes 2 & 3) are shown here. Stimulation of the other control sites (shown in Figure 1 ) did not cause any similar effects. Current (mA) Prompting Question Patient Response Stimulation Duration (s) EBS Target Electrodes 1 & 2 (aMCC) SHAM “Any change?” “No.” 0 SHAM “One more time.” “No.” 0 1 “How about now?” “No.” 2.1 2 “What about now?” “Yeah, that felt weird. Umm … I felt like a clicking here and then like a twitch starting in my shoulder.” 2.3 2 “A twitch in your shoulder?” “Yeah … and then my ear at the same time.” 2.3 3 “Now?” “No. Maybe … little bit of irritable. No physical, just emotional. I just, I get impatient sometimes. I know it’s just an attitude.” 2.3 3 “Did I make you impatient?” “I think it’s—it’s the overall. I don’t believe you did anything to me.” 2.3 3 “I’m going to do a couple of times with electricity and without, and we’ll see if you can guess. I’m going to do it four times … two of them with, two of them without. See if that emotional change happens. Do you want to close your eyes?” “Open will be fine.” 2.3 5 “(No question or probe)” (P2 spontaneously reports) “A little hot flash. ” 2.9 5 “Where was it?” “Just … in my chest and a little in my face.” 2.9 5 “Emotional change?” “No, not really.” 2.9 SHAM “How about now? Hot flash?” “No. No.” 0 SHAM “How about now?” “No. Nothing.” 0 5 “Now?” “No … just a little bit as the last one, same thing. Just, just like a hot flash and I started to get a little irritable.” 2.5 5 “What does irritability mean to you?” “Impatient. Yeah … you get short. Short-fused, you know, irritable. Yeah …” 2.5 5 “Alright. Let’s do it this way now: Once with, once without. You were pretty good at guessing by the way.” “I’m trying not to guess, like you said.” 2.5 5 “No, I know. But you did a good job.” 2.5 SHAM “Now?” “No.” 0 5 “Now?” “Yes. Same thing, I get this hot flash. (Motions to neck) Starts in my neck and you know … then I try to fight it to calm down.” 2.2 5 “Is that the hot flash that makes you irritated or is it your emotions?” “Yeah … it’s the emotion of I know something is going happen that I can’t control. Then I get irritated and then from there it’s all …” 2.2 5 “Do you think you became anxious or worried or super excited?” “Worried. Worried that something bad is going to happen.” 2.2 5 “Something bad is going to happen?” “You know … physically. Not that I’m going to do something bad but something, physically, I’m not going to be able to control.” 2.2 5 “Sure. But how was your stamina? Doomed to fail or you knew you were going to make it?” “No, I knew I had to fight to make it.” 2.2 5 “Tell us more.” “If I don’t fight I give up. I can’t give up. If I give up, then … then, you know …” 2.2 P2 Current (mA) Prompting Question Patient Response Stimulation Duration (s) EBS Target 5 “I’m going to do it once now. You can pretty much guess when I’m stimulating, because when I don’t stimulate you don’t feel anything. I’m going to stimulate and I want you to pay attention to whether you feel that you are going to fail or that you should try harder. One is optimistic. There is trouble but you know you are going to make it, and the other is pessimistic, the world is black and you are doomed. Pay attention to that attitude part.” 2.2 4 “Now?” “Yeah … I don’t feel like there’s nothing I can do about it. I feel like … ‘cause I have to fight it, you know? I have to make it through.” 3.0 4 “Can you give us some examples of how this could happen in your daily life? Let’s say you are driving …” (Laughs) “I don’t get to drive.” 3.0 4 “I know, but let’s say you were driving when you were 30 … what should happen on the road that would give you this feeling?” “You mean what would happen when I would start to feel like that before? Something like that would only be triggered by a major accident, you know, cause anything small in life you have to be able to handle. ‘Cause there are so many millions of small things that happen to you daily that, you have to handle them, you have to deal with them. It’s the major things that if you give up on, you’re in trouble. You can’t give up.” 3.0 4 “Can you tell us more about your feeling of not giving up?” “I feel like if I give up, then I’ve let everybody else down.” 3.0 4 “But, right now, do you think I made you stronger or weaker?” “I felt the flash and as we talked through it … it made me stronger. 3.0 Electrodes 2 & 3 (adjacent to aMCC) SHAM “Tell me if the same thing or a different thing happens? Any change?” “No.” 0 SHAM “Now?” “No.” 0 SHAM “Now?” “No.” 0 SHAM “Are you okay?” “Yeah, just trying to relax, yeah.” 0 SHAM “Now?” “No.” 0 4 “Now?” “Yeah, a little bit. I was, no not really hardly … same thing, anticipation … I really didn’t feel anything.” 2.9 4 “Anticipation of what?” “About what’s going to get stimulated? You know, what’s going to happen? How’s it going to feel?” 2.9 4 “Now I’m going to do the same thing. Don’t anticipate any change, don’t guess that I’m going to make any change. Pay attention to your emotions. Describe if anything changed.” “No.” 2.6 In both patients, electrical stimulation in the anterior midcingulate cortex (aMCC) ( Figure 1 ) caused a strikingly similar and consistent set of perceptual and behavioral changes of a physical and psychological nature ( Table 1 ). These changes were absent during sham trials and when electrical current was delivered below a certain threshold (i.e., subthreshold: 6 mA in P1 and 4 mA in P2). Both patients reported autonomic symptoms including “shakiness” or “hot flashes” in the upper chest and neck region. Heart rate seemed to increase in both cases. Trends of heart rate changes in the three conditions of sham, subthreshold EBS, and real EBS trials were (in mean beats per minute ± standard deviation) 77 ± 6, 86 ± 9, and 92 ± 7 in P1 and 81 ± 8, 90 ± 5, and 94 ± 7 in P2. Moreover, both patients recounted a sense of “challenge” or “worry” (also known as foreboding) but remained motivated and aware that they would overcome the challenge. Patient 1 used an interesting analogy to explain his feeling. He reported that he felt as if he were driving a car into a storm. In his words: “Like you’re headed towards a storm that’s on the other side, maybe a couple of miles away, and you’ve got to get across the hill and all of a sudden you’re sitting there going how am I going to get over that?” With repeated stimulation, he reported, “Let’s say … if you knew you were driving your car and it was … one of the tires was half flat and you’re only halfway there and you have no other way to turn around and go back, you have to keep going forward.” When cued whether the feeling was negative or positive, he reported, “It was more of a positive thing like … push harder, push harder, push harder to try and get through this…” ( Movie S1 , available online). Patient 2 recounted feeling worried and anxious about something negative that was going to happen, but simultaneously knowing that he had to fight to make it through and not give up. Both patients described the same physical or psychological phenomena during each of the six repetitions of real trials. By contrast, no perceptual changes were reported during any repetitions of the sham trials in which all parameters of the EBS procedure were the same except the electrical current, which was set to 0 mA. Stimulation of subgenual or retrosplenial cingulate regions or the adjacent electrodes in the white matter did not elicit any perceptual or behavioral responses.

Parvizi, 2009 Parvizi J. Corticocentric myopia: old bias in new cognitive sciences. Knowing that each cortical site has a specific set of anatomical connections linking it to a broader network of cortical as well as subcortical regions (), the electrical current applied to the aMCC site should not only affect the local activity of the aMCC neuronal populations but also modulate activity in the network of regions connected to it. Reasoning from this perspective, we hypothesized that the complex perceptual and behavioral changes provoked by aMCC stimulation were attributable to functional changes in a large-scale distributed network, which we sought to identify with a resting-state fMRI analysis.