The role of anterior midcingulate cortex in cognitive motor control: Evidence from functional connectivity analyses

“Resting-state fMRI images were acquired in 100 healthy volunteers (50 females; age range 22–71 years, mean 45.3 6 14.1), all of which were right handed according to the Edinburgh handedness inventory [Oldfield, 1971].”

“The mean image was then spatially normalized to the MNI single subject template [Holmes et al., 1998] using the “unified segmentation” approach [Ashburner and Friston, 2005].”

“It has long been conjectured that regions functionally connected in a resting-state also co-activate in functional neuroimaging studies and vice versa [Biswal et al., 1995; Fox and Raichle, 2007].”

“…of different methods should be less susceptible to drawbacks inherent in each individual method (MACM, resting-state analysis), the conjunction analyses should moreover represent a conservative approach to FC [Eickhoff et al., 2011; Jakobs et al., 2012; Reetz et al., 2012; Smith et al., 2009].”

“…parameters; (iii) mean grey and white matter as well as CSF signal intensity; (iv) coherent r 2744 r signal changes across the whole brain as reflected by the first five components of a PCA decomposition of the whole-brain time-series (CompCor denoising [Behzadi et al., 2007; Chai et al., 2012]).”

“Interestingly, the anterior part of the latter region (aMCC) is one of the most frequently activated brain structures in functional neuroimaging [Yarkoni et al., 2011].”

“, 1998] and conflict monitoring [Botvinick et al., 2004].”

“However, it is commonly the case that strong functional connections also exist between brain regions with no direct structural connection [Honey et al., 2009].”

“Among these, one influential set of theories claim that the aMCC crucially contributes to cognitive control by conflict detection [Carter et al., 1998] and conflict monitoring [Botvinick et al.”

“In general, good convergence was found between structural (probabilistic tracing) and functional (resting-state and MACM) connection pattern [Eickhoff et al., 2010; Greicius et al., 2009] and FC seems positively correlated with structural connectivity strength [Damoiseaux and Greicius, 2009].”

“Meta-analytic connectivity modeling (MACM) is a relatively new approach to the analysis of functional connectivity [Friston et al., 1993] based on correlations of neural activity in different brain areas over studies, i.e., coactivation.”

“It is involved in numerous different contexts from self-initiated finger tapping [Deiber et al., 1999] to reward-based decision making [Bush et al., 2002] as well as processing of pain and negative affect [Shackman et al., 2011].”

“…one focus of activation within the seed volume was then modeled using the revised version of the activation likelihood estimation (ALE) algorithm [Eickhoff et al., 2009]. r 2743 r The ALE approach is based on modeling the coordinates reported in the identified experiments as centers of 3D…”

“In order to delineate brain regions showing FC with the aMCC region in task-dependent (MACM) as well as in task-free states (resting-state), a conjunction analysis over both connectivity analyses was performed using the conservative minimum statistic [Nichols et al., 2005].”

“This approach is based on findings from a comprehensive simulation approach to FC [Smith et al., 2011] which recently showed that functional specific seed VOIs provide better results for modeling functional networks than atlas based VOIs or single points.”

“In contrast to the more prevailing time-series approach to FC [Van Dijk et al., 2010], the unit of observation in MACM is thus not a specific point in an acquired time-series but a particular neuroimaging experiment.”

“1 [Vogt, 2005; Vogt et al., 2004]).”

“It may thus be hypothesized that the aMCC is crucial for the implementation of intentional motor control by translating abstract cognition and intentions to actions and connecting cognitive and motor systems [Paus, 2001].”

“…region was also found by Shackman et al. [2011] in a quantitative meta-analyses to feature overlapping activity for the three domains: cognitive control, pain, and negative affect (Talairach coordinates: x 5 0, y 5 12, z 5 42; MNI-transformation [Lancaster et al., 2007]: x 5 1, y 5 17, z 5 41).”

“To distinguish “true” convergence from random convergence, ALE scores are compared with an empirical null distribution reflecting a random spatial association between experiments (random effects analysis [Eickhoff et al., 2012]).”

“monkeys, Dum and Strick [1991] found direct projections”

“The mean image was then spatially normalized to the MNI single subject template [Holmes et al., 1998] using the “unified segmentation” approach [Ashburner and Friston, 2005].”

“Furthermore, contrasting cognitive tasks to “action” tasks, the aMCC co-activated more consistently the highly integrative areas DLPFC [Koechlin and Summerfield, 2007], IFJ [Brass et al., 2005], and the aIns [Kurth et al., 2010].”

“Furthermore, contrasting cognitive tasks to “action” tasks, the aMCC co-activated more consistently the highly integrative areas DLPFC [Koechlin and Summerfield, 2007], IFJ [Brass et al.”

“…parameters; (iii) mean grey and white matter as well as CSF signal intensity; (iv) coherent r 2744 r signal changes across the whole brain as reflected by the first five components of a PCA decomposition of the whole-brain time-series (CompCor denoising [Behzadi et al., 2007; Chai et al., 2012]).”

“In this study, contrasting neural activity related to self-initiated movements with activity related to (closely matched) reactive movements yielded the neural correlate of intentional action as the contrast eliminates purely movement related neural activity [Haggard, 2008].”

“For each experiment, the probability distributions of all reported foci are combined into a modeled activation (MA) map [Turkeltaub et al., 2012].”

“It is involved in numerous different contexts from self-initiated finger tapping [Deiber et al., 1999] to reward-based decision making [Bush et al., 2002] as well as processing of pain and negative affect [Shackman et al., 2011].”

“8 [Eickhoff et al., 2007]), which is based on various cytoarchitectonic studies providing maximum probability maps of several brain areas [cf.”

“Repeating this process 1,000 times yielded an empirical null distribution of ALEscore differences between the two conditions (“cognition” vs. “action”) [Rottschy et al., 2012].”

“In general, good convergence was found between structural (probabilistic tracing) and functional (resting-state and MACM) connection pattern [Eickhoff et al., 2010; Greicius et al., 2009] and FC seems positively correlated with structural connectivity strength [Damoiseaux and Greicius, 2009].”

“For example, invasive tract tracing in rhesus monkeys demonstrated that the amygdala is ana- tomically connected only to the ACC and the aMCC [Vogt and Pandya, 1987] whereas the posterior MCC (pMCC) and the PCC are connected to the inferior parietal cortex.”

“Finally, the specific FC pattern observed in the current study may be a specific functional feature of r 2750 r the human aMCC, which despite the mentioned restrictions largely resembles the structural connectivity found with diffusion imaging [Beckmann et al., 2009].”

“…variance that could be explained by the following nuisance variables was removed from each voxel’s time series [cf. Jakobs et al., 2012; Weissenbacher et al., 2009; zu Eulenburg et al., 2012] applying a GLM approach: (i) the six motion parameters derived from the image realignment;…”

“The current results are well in line with previous investigations of resting-state FC, which used anatomically defined seeds throughout the ACC/MCC [Kelly et al., 2009; Margulies et al., 2007; Yu et al., 2011], rather than a functionally derived and, hence, functionally specific seed region used here.”

“, 2008, 2009], premotor cortex [Geyer et al., 1996], primary motor [Geyer et al.”

“8 [Eickhoff et al., 2007]), which is based on various cytoarchitectonic studies providing maximum probability maps of several brain areas [cf. Zilles and Amunts, 2010].”

“The current results are well in line with previous investigations of resting-state FC, which used anatomically defined seeds throughout the ACC/MCC [Kelly et al., 2009; Margulies et al., 2007; Yu et al., 2011], rather than a functionally derived and, hence, functionally specific seed region used…”

“…links the aMCC with prefrontal, premotor and parietal areas as well as the basal ganglia forming a core network for the internal generation of movements [Cunnington et al., 2002; Debaere et al., 2003; Deiber et al., 1999; Jankowski et al., 2009; Lau et al., 2004; van Eimeren et al., 2006].”

“To identify studies reporting neural activation within the aMCC region, the BrainMap database was employed (www.brainmap.org [Fox and Lancaster, 2002; Laird et al., 2005]), which did not contain any results of the study the seed VOI was taken from.”

“…of different methods should be less susceptible to drawbacks inherent in each individual method (MACM, resting-state analysis), the conjunction analyses should moreover represent a conservative approach to FC [Eickhoff et al., 2011; Jakobs et al., 2012; Reetz et al., 2012; Smith et al., 2009].”

“…[1991] found direct projections to the spinal cord originating from the pMCC. Cytoarchi- tectonic characteristics of the MCC were largely replicated for the human brain [Vogt et al., 2003; Vogt and Vogt, 2003] highlighting the similarity of this region with medial premotor regions (pre-SMA, SMA).”

“The comparison between these MACMs revealed higher convergence of coactivation for “cognition” in contrast to “action” mainly in higher-order and multimodal association areas like DLPFC, IFJ and aIns.”

“…be explained by the following nuisance variables was removed from each voxel’s time series [cf. Jakobs et al., 2012; Weissenbacher et al., 2009; zu Eulenburg et al., 2012] applying a GLM approach: (i) the six motion parameters derived from the image realignment; (ii) the first derivative of the…”

“It is involved in numerous different contexts from self-initiated finger tapping [Deiber et al., 1999] to reward-based decision making [Bush et al.”

“, 2013], inferior parietal cortex [Caspers et al., 2008], superior parietal cortex and intraparietal sulcus [Caspers et al.”

“To identify studies reporting neural activation within the aMCC region, the BrainMap database was employed (www.brainmap.org [Fox and Lancaster, 2002; Laird et al., 2005]), which did not contain any results of the study the seed VOI was taken from.”

“…et al., 1996], primary motor [Geyer et al., 1996] and sensory cortex [Geyer et al., 2000], fusiform gyrus [Caspers et al., 2013], inferior parietal cortex [Caspers et al., 2008], superior parietal cortex and intraparietal sulcus [Caspers et al., 2008; Choi et al., 2006; Scheperjans et al., 2008].”

“…and receptor architectonics may be found in the following publications reporting on Broca’s region [Amunts et al., 1999], inferior frontal junction [Amunts et al., 2010], anterior and midcingulate cortex [PalomeroGallagher et al., 2008, 2009], premotor cortex [Geyer et al., 1996], primary motor…”

“The first approach made use of the BrainMap database [Laird et al., 2009] to determine convergent task based (stimulus-evoked) neural coactivation with the aMCC VOI across a large variety neuroimaging experiments [cf. Eickhoff et al., 2010].”

“With respect to the current study, the constitutive distinction between ACC and MCC was validated by extensive cytoarchitectural [Palomero- Gallagher et al., 2008] and multireceptor mapping [Palo- mero-Gallagher et al., 2009] in humans.”

“…has most commonly been used to investigate the functional connectivity of anatomically defined seed regions [Cauda et al., 2011; Eickhoff et al., 2010; Robinson et al., 2010], brain regions defined by functional properties as in the current study, may likewise be assessed [Jakobs et al., 2012].”

“…cortex [PalomeroGallagher et al., 2008, 2009], premotor cortex [Geyer et al., 1996], primary motor [Geyer et al., 1996] and sensory cortex [Geyer et al., 2000], fusiform gyrus [Caspers et al., 2013], inferior parietal cortex [Caspers et al., 2008], superior parietal cortex and…”

“…links the aMCC with prefrontal, premotor and parietal areas as well as the basal ganglia forming a core network for the internal generation of movements [Cunnington et al., 2002; Debaere et al., 2003; Deiber et al., 1999; Jankowski et al., 2009; Lau et al., 2004; van Eimeren et al., 2006].”

“…et al., 1996], primary motor [Geyer et al., 1996] and sensory cortex [Geyer et al., 2000], fusiform gyrus [Caspers et al., 2013], inferior parietal cortex [Caspers et al., 2008], superior parietal cortex and intraparietal sulcus [Caspers et al., 2008; Choi et al., 2006; Scheperjans et al., 2008].”

“…links the aMCC with prefrontal, premotor and parietal areas as well as the basal ganglia forming a core network for the internal generation of movements [Cunnington et al., 2002; Debaere et al., 2003; Deiber et al., 1999; Jankowski et al., 2009; Lau et al., 2004; van Eimeren et al., 2006].”

“The current results are well in line with previous investigations of resting-state FC, which used anatomically defined seeds throughout the ACC/MCC [Kelly et al., 2009; Margulies et al., 2007; Yu et al., 2011], rather than a functionally derived and, hence, functionally specific seed region used here.”

“That is, while MACM has most commonly been used to investigate the functional connectivity of anatomically defined seed regions [Cauda et al., 2011; Eickhoff et al., 2010; Robinson et al., 2010], brain regions defined by functional properties as in the current study, may likewise be assessed [Jakobs et al.”

“05; [Hoffstaedter et al., 2013]) and the overall FC map of the aMCC seed.”

“, 2000], fusiform gyrus [Caspers et al., 2013], inferior parietal cortex [Caspers et al.”

“In the cur- rent study, we addressed this question by investigating the functional connectivity (FC) of a functionally defined part of the aMCC associated with intentional movement generation [Hoffstaedter et al., 2013] applying two complementary approaches [cf. Eickhoff and Grefkes, 2011].”

“…to reduce spurious correlations, variance that could be explained by the following nuisance variables was removed from each voxel’s time series [cf. Jakobs et al., 2012; Weissenbacher et al., 2009; zu Eulenburg et al., 2012] applying a GLM approach: (i) the six motion parameters derived from the…”

“…links the aMCC with prefrontal, premotor and parietal areas as well as the basal ganglia forming a core network for the internal generation of movements [Cunnington et al., 2002; Debaere et al., 2003; Deiber et al., 1999; Jankowski et al., 2009; Lau et al., 2004; van Eimeren et al., 2006].”

“…of different methods should be less susceptible to drawbacks inherent in each individual method (MACM, resting-state analysis), the conjunction analyses should moreover represent a conservative approach to FC [Eickhoff et al., 2011; Jakobs et al., 2012; Reetz et al., 2012; Smith et al., 2009].”

“…links the aMCC with prefrontal, premotor and parietal areas as well as the basal ganglia forming a core network for the internal generation of movements [Cunnington et al., 2002; Debaere et al., 2003; Deiber et al., 1999; Jankowski et al., 2009; Lau et al., 2004; van Eimeren et al., 2006].”

“…[1991] found direct projections to the spinal cord originating from the pMCC. Cytoarchi- tectonic characteristics of the MCC were largely replicated for the human brain [Vogt et al., 2003; Vogt and Vogt, 2003] highlighting the similarity of this region with medial premotor regions (pre-SMA, SMA).”

“Notably, higher MCG activity was observed when subjects were required to perform a dual task, e.g., deciding which hand will perform the action and when to give the response (Hoffstaedter et al. 2013, 2014).”

“, 2009), high similarity of resting state networks with task-related activations (Hoffstaedter et al., 2014; Smith et al., 2009), and correspondence with structural pathways (Greicius et al.”

“The midcingulate cortex, particularly its anterior part, is implicated in motor control and movement generation (Hoffstaedter et al., 2014).”

“These regions work in the context of broader EF networks with nodes in the dorsolateral prefrontal cortex (dlPFC), dorsal anterior cingulate cortex (dACC), and superior parietal lobule (SPL) which contribute to working memory (30), motor control (31,32), and attention (33), respectively (see (25) for review) (Figure 1…”

“Initially assumed to reflect the activity of a neural error-monitoring system sensitive to internal conflict (see Botvinick & Cohen, 2014; Holroyd & Coles, 2002), the ERN (and its neural generators in the dACC) is now conceptualized as part of a broader neural salience network that is necessary for making performance…”

“These results are in line with previous studies proposing cognitive-motor control as the core functional computation of this region (Botvinick et al., 2004; Guo et al., 2013; Hoffstaedter et al., 2014; Shackman et al., 2011; Shenhav et al., 2014; Singer et al., 2004).”

“, strength and dexterity) and cerebral regions involved in attention control, particularly cingulate, inferior frontal, and temporoparietal cortices (17, 18), that become more apparent with aging or brain injury (19–22).”

“The aMCC has a key role for cognitive aspects of movement generation, that is, intentional motor control (Hoffstaedter et al., 2014).”

“This is further supported by negative connectivity found between the amygdala and the posterior MCC as a region of intentional motor control (36) (see Fig.”

“…mask does not specifically identify the region we label as the dACC, we identified those portions of the structure that have been most closely associated with motor control (Paus, 2001), and in separate studies have been referred to as the ‘‘midcingulate’’ cortex (Hoffstaedter et al., 2014, 2015).”

“Both aMCC and dAI are key structures in an inhibitory control system that constrains cognition and behavior and may also downregulate physiological arousal (Aron et al., 2004; Nee et al., 2007; Touroutoglou et al., 2012; EnriquezGeppert et al., 2013; Hoffstaedter et al., 2014).”

“More precisely, our aim was to cross-validate task-independent functional connectivity using an independent dataset, following previous reports that this combination allows the robust definition of consensus (across task and rest) functional connectivity patterns (Amft et al. 2014; Reetz et al. 2012; Jakobs et al. 201…”

“Finally, human neuroimaging studies suggest a key role for the anterior midcingulate cortex in the voluntary initiation of movements [37] and integration of environmental cues during learning, potentially providing top-down control signals to other regions [38].”

“, 2011), which is in line with the involvement of the MCC (together with LPFC and premotor areas) in intentional initiation of behavior (Hoffstaedter et al., 2014).”

“, 2017) which are dorsomedial frontal areas involved in intentional motor control including decisions regarding which action to perform and when to perform it (Picard and Strick, 2001; Hoffstaedter et al., 2014; Zapparoli et al., 2017).”

“2014) as well as intentional motor control (Hoffstaedter et al. 2014).”

“Additionally, it is suggested that task-evoked activity is not independent from resting-state spontaneous functional connectivity (Hoffstaedter et al., 2014; Smith et al., 2009); however, the relationship between them is not straightforward (He, 2013; Lynch et al.”

“Thereof, the aMCC seems to represent a crucial region for cognitive motor control (Paus 2001; Hoffstaedter et al. 2013a), while the pre-SMA is associated with rather specific movement selection (van Eimeren et al. 2006) and inhibition (Swick et al. 2011).”

“Seed-based resting state functional connectivity Images were acquired using a Siemens Tim Trio 3 T scanner using blood oxygen level–dependent (BOLD) contrast (260 whole-brain echo-planar imaging (EPI) volumes per subject, gradient-echo EPI pulse sequence, repetition time (TR) = 2.5 s, echo time…”

“The contrast analysis was performed to test the “true” difference between two MACMs against the contrast null-distribution with the resulting Pvalues thresholded at P 0.95 and an extended cluster threshold size of 50 [cf. Hoffstaedter et al., 2014].”

“In addition to that, artificial and counfounding signals were further removed by a PCA denoising (Behzadi et al., 2007; Hoffstaedter et al., 2014; Soltysik et al., 2015; Bright et al., 2017; Varikuti et al., 2017).”

“Similarly, SMA is associated with linking conditional rules to actions (Nachev et al., 2008), and is important to self-initiated actions (Deecke and Kornhuber, 1978; Hoffstaedter et al., 2013b).”

“Abbreviations: ALE, activation likelihood estimation; MACM, meta-analytic connectivity modelling; CBP, coactivation-based parcellation; RS-fMRI, resting-state fMRI connectivity.”

“…causal connection is strengthened by the FC of the insula seed with key structures for cognitive and motor control such as inferior frontal gyrus, supplementary motor area, midcingulate cortex, thalamus, basal ganglia, and cerebellum (cf. Table I) [Cieslik et al., 2013; Hoffstaedter et al., 2014].”

“Evidence indicates that resting-state and task-specific functional connectivity patterns of a network overlap strongly (Dosenbach et al. 2007; Hoffstaedter et al. 2014), implicating that the task-free intrinsic connectivity of a network may shed light on the basic neural organization of behavior (Seeley et al.”

“The MCC might monitor the contextual situation and urge to take action, representing negative emotions associated with the transgression (Hoffstaedter et al., 2014; Lieberman and Eisenberger, 2015).”

“Premotor areas have the anatomical substrate to influence motor processing and motor output via connections with the anterior midcingulate cortex (Dum et al. 2009; Perini et al. 2013; Hoffstaedter et al. 2014; Misra and Coombes 2015) and the primary motor cortex (Picard and Strick 1996, 2001, 2003).”

“Neuroimaging studies suggest that the dACC plays a critical role in the cognitive aspect of movement generation, that is, intentional motor control (Hoffstaedter, Grefkes, Zilles, & Eickhoff, 2013; Hoffstaedter et al., 2014).”

“However, the mid-anterior cingulate cortex has recently been identified as an important region in the cognitive control of movement (Hoffstaedter, Grefkes, Zilles, & Eickhoff, 2013, 2014).”

“Cognitive score (SCAT5) (baseline) 38 (34, 41) 40 (37, 42) 37 (35, 42) 39 (28, 41)”

“Numerous studies indicate that aMCC is engaged by cognitively demanding tasks involving executive function, motor function, memory, attention, language, and mathematics (Cole and Schneider, 2007; Duncan, 2010, 2013; Duncan and Owen, 2000; Power and Petersen, 2013; Hoffstaedter et al., 2014).”

“The significant brain regions, which include inferior frontal, anterior midcingulate and rostral thalamic ROIs, are consistently implicated in motor control (Hoffstaedter et al., 2014; Lissek et al., 2007; Peyron et al., 2007).”

“The midcingulate cortex is hypothesized to be involved in cognitive control and intentional motor control and selection.(45) Larabi et al found that with regard to cognitive insight, patients with poorer self-reflective abilities had lower activation of brain systems managing control and execution of emotion regulatio…”

“Furthermore, the anterior midcingulate cortex has been shown to be crucially involved in a functional network implementing the realization of intentional motor control (Hoffstaedter et al., 2013).”

“Involvement of cingulate gyrus is related to conflict processing (Haupt et al., 2009; Christensen et al., 2011), action selection (Akam et al., 2021) and translation of intentions into motor actions (Hoffstaedter et al., 2014; Holroyd and Verguts, 2021).”

“The midcingulate cortex (MCC) has been suggested to be involved in cognitive control and intentional motor control and selection (Ho ff staedter et al., 2014), while the pre-and postcentral gyri have been associated with movement but also with motor imagery and task execution (Stippich et al., 2002).”

“The ACC, an integral part of the prefrontal cortex, is involved in regulating cognitive behavioral control over environmental demands, internal generation of movements or intentional motor control as well as emotional processing (Sheth et al., 2012; Hoffstaedter et al., 2014).”

“The ACC supports not only motor responses but also the suppression of inappropriate movements during motor control (Paus et al. 1993; Hoffstaedter et al. 2014).”

“2014), cognition (Hoffstaedter et al. 2014), emotion regulation (Kohn et al.”

“Our results showed that residual cortical plasticity mainly occurred in the damaged motor regions and in the anterior cingulate cortex (known to be part of the motor control network (Hoffstaedter et al., 2014)) in two patients with chronic stroke.”

“Previous studies demonstrated that the dACC connectivity network is significantly associated with motor function and cognitive function, both during tasks and resting states.(28,29,31) Bidirectional interactions exist between the dACC and the SMA.”

“Decreased FC was observed between the pgACC and the anterior mid cingulate cortex (aMCC), a region implicated in cognitive aspects of motor control [72], and the experience of negative affect and pain [73].”

“The recent efforts address the functional role that resting state network interactions might play, and this emergent evidence suggests that the resting state often assumes highly specific “active” roles and/or resting networks are associated with task-active networks in specific domains (Dosenbach et al., 2007; Hoffst…”

“The midcingulate cortex is involved in cognitive and motor control, conflict monitoring and response conflict (Enriquez-Geppert et al., 2013; Hoffstaedter et al., 2014; Shackman et al., 2011).”

“13 responses) [21, 22], whereas more lateral areas such as the BA6 and the Broca’s area (BA44) have been considered involved in movement organization.”

“In the current FDG-PET study, we found that the appearance of PM was associated with dysfunction of the CMAr in free writing and with dysfunction of the SOG in copying.”

“The pre-SMA is not only known as a key structure for planning complex voluntary movements, including word production, but also plays a crucial role in inhibitory control [37,38].”

“The mid-cingulate area had been previously shown to be functionally connected with the superior parietal lobule (Hoffstaedter et al. , 2014) and, although data in the literature suggest that this brain region is mainly involved in cognitive processes, more recent views have also shown its…”

“When participants were required to perform a dual task, such as the Stroop task, stronger middle cingulate cortex activation could be observed (Hoffstaedter et al., 2013, 2014; Palomero-Gallagher et al., 2019).”

“The N2 is larger on incongruent relative to congruent trials (see Folstein & Van Petten, 2008), reflecting the ACC’s signaling of conflict in the moment, believed to direct motor responses in a goal-consistent manner (Hoffstaedter et al., 2014).”