The dorsal anterior cingulate cortex (dACC) has previously been implicated in processes that influence action initiation. In humans however, there has been little direct evidence connecting dACC to the temporal onset of actions. We studied reactive behavior in patients undergoing therapeutic bilateral cingulotomy to determine the immediate effects of dACC ablation on action initiation. In a simple reaction task, three patients were instructed to respond to a specific visual cue with the movement of a joystick. Within minutes of dACC ablation, the frequency of false starts increased, where movements occurred prior to presentation of the visual cue. In a decision making task with three separate patients, the ablation effect on action initiation persisted even when action selection was intact. These findings suggest that human dACC influences action initiation, apart from its role in action selection.

Funding: LS is supported by the American Heart Association Scientist Development Grant (11SDG7550015), the DARPA Reliable Neural-Interface Technology (RE-NET) Program, and the UCLA Radiology Exploratory Development Grant. WFA is supported by a Tosteson award from the Massachusetts Biomedical Research Corporation. TJS is supported by the Howard Hughes Medical Institute. EE is supported by grants from the National Science Foundation (IOB 0645886), the National Institutes of Health (NEI R01EY017658, NIDA R01DA026297, NIMH MH086400), the Howard Hughes Medical Institute, and the Klingenstein Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2013 Srinivasan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Introduction

Human dorsal anterior cingulate cortex (dACC) includes the cingulate gyrus and cingulate sulcus from the levels of the genu of the corpus callosum anteriorly to the anterior commissure posteriorly. The human dACC has been implicated in various aspects of action selection, including reward-dependent decision making [1], conflict monitoring [2], [3] and representation of error likelihood [4], [5]. A smaller body of work has suggested that human dACC could influence action initiation apart from its role in action selection [4], [6]–[8]. A fundamental question is whether action selection and action initiation are separable functions of dACC.

Because action initiation and action selection are co-dependent in many tasks, separating these two roles in human dACC has been difficult. This is because initiation is modulated by components of action selection including reward expectancy [9], error likelihood [4], [5], and decision conflict [2], [3]. Resulting correlations between dACC activity and action selection are intertwined with action initiation. Other experiments on dACC have explored simple reaction time tasks where the action is pre-selected, while initiation was randomly cued [4], [6]–[8]. These studies correlated metabolic and electrophysiological activity in dACC with action initiation in the absence of action selection. This raised the possibility that dACC could causally influence action initiation, apart from its effects on action selection.

Early anatomical work on dACC in monkeys established direct connections from neurons in the cingulate sulcus to primary motor cortex and spinal cord, and preliminary efforts were made through fMRI to identify homologous regions in human. In the seminal monkey work, a group of cingulate motor areas (CMA) were defined through cytoarchitectural examination and electrical stimulation studies on the basis of connections to primary motor cortex and the spinal cord [10]–[13]. By definition, the CMA comprise grey matter lining the monkey cingulate sulcus (dorsal and ventral banks) extending anteriorly to the level of the genu of the corpus callosum and posteriorly to roughly the level of the posterior commissure. In the original definition, the CMA are a subset of the dACC, where the CMA exclude the cingulate gyrus [10]. The CMA are anatomically subdivided by the vertical anterior commissure line (VAC). Anterior to the VAC is the rostral CMA (rCMA). Posterior to the VAC are the dorsal CMA (dCMA) and ventral CMA (vCMA) which are located on the dorsal and ventral banks of grey matter that comprise the cingulate sulcus.

The homology between monkey and human cingulate motor areas is widely employed, but this relationship is largely based on resemblance between PET and fMRI activation patterns in human and divisions of the medial frontal cortex in monkey [12], [13]. As noted by the originators of this homology, the sulci and gyri of the human medial frontal cortex are highly variable, so that rigid landmarks that represent cingulate motor areas based on these surface features are not asserted with certainty [13]. Related work by another group provides helpful anatomical labeling on human MRI images [14]. In this framework, the grey matter along the cingulate sulcus is described as the cingulate zones (CZ), depicted in Figure 1. Whether the CZ additionally include the cingulate gyrus is ambiguous. Anterior to the VAC line is the rostral CZ (RCZ). Posterior to the VAC line is the caudal CZ (CCZ). The human RCZ may be comparable to monkey rCMA and vCMA. The human CCZ may be comparable to monkey dCMA. In retrospective analyses of activation patterns during various motor and decision-making tasks in humans via positron emission tomography (PET) [12] and fMRI [13], Strick and colleagues developed a hypothesis that CCZ is involved in simple motor tasks, while RCZ is more involved in complex motor tasks, including conflict monitoring anteriorly (RCZa) and response selection posteriorly (RCZp).

PPT PowerPoint slide

PowerPoint slide PNG larger image

larger image TIFF original image Download: Figure 1. Cingulotomy relative to motor areas of the medial wall as described by Strick and colleagues [14]. Cingulotomy relative to motor areas of the medial wall as described by Strick and colleagues [12] Parasagittal postoperative T1 weighted MPRAGE sequence demonstrates three neighboring foci of radiofrequency (RF) ablation with surrounding edema in the dorsal anterior cingulate cortex (dACC). Three additional stereotactically guided RF ablation foci are located in the contralateral dACC. The patient imaged in this high resolution sequence was more recent to S1–S6. Imaging was performed in the immediate postoperative period, within hours to days following ablation. https://doi.org/10.1371/journal.pone.0055247.g001

In non-human primate, dACC has been linked to reward-dependent decision making [15]–[18] and the CMA subdivision of dACC has been studied with relation to motor control, although its specific role in motor control is not yet completely clear. To elaborate on this point, we briefly survey the existing non-human primate literature on the CMA and motor control. Intracortical microstimulation of the CMA demonstrated measurable muscle response [11]. These areas exhibit pre-movement and peri-movement neural activity with varying degrees of directionality tuning [19]–[22]. Spiking activity in rCMA is correlated with motor learning [23]. Although these non-human primate studies implicate dACC in some element of motor control, they do not provide substantial additional specificity. In related work, recordings from the dorsal bank of the monkey anterior cingulate sulcus found no correlation between reaction time, movement time, and spiking rates during a decision-making task that required eye and arm movements [17]. In general, these electrophysiology studies are also limited by a correlation-causality confound.

Some work in rat dorsomedial prefrontal cortex (dmPFC) has attempted to provide causal statements about movement initiation, although the homology between dmPFC and human dACC is further removed and controversial [24]. In this work, reversible inactivation of dmPFC with muscimol caused increased premature movement (false starts) in a reaction time task [25]. Electrophysiological recording in primary motor cortex (MI) combined with dmPFC inactivation also demonstrated a delay-period-specific interaction between dmPFC and primary motor cortex [25]. Although these experiments causally relate dmPFC to motor control, they do not concurrently examine action initiation and action selection. Moreover, these results do not extend immediately to the structure and function of human dACC.

Recently, several groups have used human cingulotomy, undertaken for purely therapeutic indications, as an opportunity to study the function of the human dACC [1], [26]–[31]. Cingulotomy involves the bilateral ablation of dACC (Figure 1A). This treatment is performed for intractable obsessive-compulsive disorder (OCD), depression and chronic pain [32]. Only a handful of cingulotomies are performed each year; the number of patients included in this paper represent a significant fraction of those patients [32]. Previously, we studied patients undergoing this procedure to establish a causal link between human dACC and the processes that control action selection [1]. We also previously showed that in decision making, dACC causally modulates reaction times in relation to expected cognitive demand [33]. In this study, we examined the performance of patients undergoing cingulotomy on either a simple reaction time task with a pre-selected action or a reward-dependent decision-making task that required action selection and action initiation. We quantified performance in action initiation and action selection based on rates of false starts and percentages of incorrect decisions respectively. Measurements were taken within minutes before and after bilateral dACC ablation in the intraoperative setting.