A network approach to response inhibition: dissociating functional connectivity of neural components involved in action restraint and action cancellation

The ability to inhibit action tendencies is vital for adaptive human behaviour. Various paradigms are supposed to assess action inhibition and are often used interchangeably. However, these paradigms are based on different conceptualizations (action restraint vs. action cancellation) and the question arises as to what extent different conceptualizations of inhibitory processing are mirrored in a distinct neural activation pattern. We used functional magnetic resonance imaging to investigate the neural correlates of action restraint vs. action cancellation. Analyses of local activity changes as well as network connectivity measures revealed a strong overlap of activation within a common action inhibition network including inferior frontal, pre‐supplementary motor and thalamic brain areas as well as the anterior cingulate cortex. Furthermore, our findings pointed to additional neural networks that are distinct for action restraint (i.e. right superior frontal gyrus, left middle frontal gyrus, and bilateral anterior cingulate cortex) and action cancellation (i.e. right middle frontal gyrus, posterior cingulate cortex, and parietal regions). Our connectivity analyses showed that different inhibitory modalities largely relied on a task‐independent global inhibition network within the brain. Furthermore, they suggested that the conceptually distinct inhibitory aspects of action restraint vs. action cancellation also activated additional specific brain regions in a task‐dependent manner. This has implications for the choice of tasks in an empirical setting, but is also relevant for various clinical contexts in which inhibition deficits are considered a diagnostic feature.     

When response inhibition is followed by response reengagement: An event‐related fMRI study

In the course of daily living, changing environmental demands often make our actions, once initiated, unnecessary or even inappropriate. Under such circumstances, the ability to inhibit the obsolete action and to update behavior can be of vital importance. Previous lesion and neuroimaging studies have shown that the right prefrontal cortex and the basal ganglia seem to play an important role in the inhibition of already initiated motor responses. The present study was designed to investigate whether the neural activity of inhibitory motor control was altered if the inhibition process was succeeded by an additional process, namely the reengagement into an alternative action. Therefore, cerebral blood oxygenation during performance of a stop‐change paradigm was registered in 15 male participants using event‐related functional magnetic resonance imaging. Data analysis showed, that during successful and failed stopping and changing (response inhibition and subsequent response reengagement) of initiated motor responses a very similar network was activated including primarily the right inferior frontal cortex (IFC). Besides, stopping‐related activation in right IFC was significantly greater for fast inhibitors than for slow ones. Results of the present study thus further underline the important role of right IFC in response inhibition and suggest that the inhibition process functions similarly regardless whether changing task demands require the complete suppression of an already initiated motor response or its suppression and a subsequent response reengagement into an alternative action. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

The role of stop‐signal probability and expectation in proactive inhibition

The subjective belief of what will happen plays an important role across many cognitive domains, including response inhibition. However, tasks that study inhibition do not distinguish between the processing of objective contextual cues indicating stop‐signal probability and the subjective expectation that a stop‐signal will or will not occur. Here we investigated the effects of stop‐signal probability and the expectation of a stop‐signal on proactive inhibition. Twenty participants performed a modified stop‐signal anticipation task while being scanned with functional magnetic resonance imaging. At the beginning of each trial, the stop‐signal probability was indicated by a cue (0% or > 0%), and participants had to indicate whether they expected a stop‐signal to occur (yes/no/don't know). Participants slowed down responding on trials with a > 0% stop‐signal probability, but this proactive response slowing was even greater when they expected a stop‐signal to occur. Analyses were performed in brain regions previously associated with proactive inhibition. Activation in the striatum, supplementary motor area and left dorsal premotor cortex during the cue period was increased when participants expected a stop‐signal to occur. In contrast, activation in the right inferior frontal gyrus and right inferior parietal cortex activity during the stimulus‐response period was related to the processing of contextual cues signalling objective stop‐signal probability, regardless of expectation. These data show that proactive inhibition depends on both the processing of objective contextual task information and the subjective expectation of stop‐signals.     

Distinguishing stimulus and response codes in theta oscillations in prefrontal areas during inhibitory control of automated responses

Response inhibition mechanisms are mediated via cortical and subcortical networks. At the cortical level, the superior frontal gyrus, including the supplementary motor area (SMA) and inferior frontal areas, is important. There is an ongoing debate about the functional roles of these structures during response inhibition as it is unclear whether these structures process different codes or contents of information during response inhibition. In the current study, we examined this question with a focus on theta frequency oscillations during response inhibition processes. We used a standard Go/Nogo task in a sample of human participants and combined different EEG signal decomposition methods with EEG beamforming approaches. The results suggest that stimulus coding during inhibitory control is attained by oscillations in the upper theta frequency band (～7 Hz). In contrast, response selection codes during inhibitory control appear to be attained by the lower theta frequency band (～4 Hz). Importantly, these different codes seem to be processed in distinct functional neuroanatomical structures. Although the SMA may process stimulus codes and response selection codes, the inferior frontal cortex may selectively process response selection codes during inhibitory control. Taken together, the results suggest that different entities within the functional neuroanatomical network associated with response inhibition mechanisms process different kinds of codes during inhibitory control. These codes seem to be reflected by different oscillations within the theta frequency band. Hum Brain Mapp 38:5681–5690, 2017. © 2017 Wiley‐Liss, Inc.     

Functional parcellation of the inferior frontal and midcingulate cortices in a flanker‐stop‐change paradigm

Conflict monitoring and motor inhibition are engaged in the performance of complex tasks. The midcingulate cortex (MCC) has been suggested to detect conflicts, whereas the right inferior frontal cortex (IFC) seems to be of relevance for the inhibition process. The current experiment investigates the neural underpinnings of their interplay via a modified flanker paradigm. Conflict was manipulated by the congruency of flanking stimuli relative to a target (congruent vs. incongruent) and motor inhibition by a within‐trial response change of the initiated response (keep response vs. stop‐change). We used event‐related functional magnetic resonance imaging, decomposition with high model order ICA, and single trial analysis to derive a functional parcellation of the whole‐brain data. Results demonstrate the segmentation of the MCC into anterior and posterior subregions, and of the IFC into the pars opercularis, pars triangularis, and pars orbitalis. The pars opercularis and pars triangularis of the right IFC constituted the foundation of inhibition‐related networks. With high conflict on incongruent trials, activity in the posterior MCC network, as well as in one right IFC network was observed. Stop‐change trials modulated both the MCC as well as networks covering extended parts of the IFC. Whereas conflict processing and inhibition most often are studied separately, this study provides a synopsis of functionally coupled brain regions acting in concert to enable an optimal performance in situations involving interference and inhibition. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

The cognitive neuroscience of response inhibition: relevance for genetic research in attention-deficit/hyperactivity disorder.

Psychological functions that are behaviorally and neurally well specified may serve as endophenotypes for attention-deficit/hyperactivity disorder (ADHD) research. Such endophenotypes, which lie between genes and symptoms, may relate more directly to relevant genetic variability than does the clinical ADHD syndrome itself. Here we review evidence in favor of response inhibition as an endophenotype for ADHD research. We show that response inhibition--operationalized by Go/NoGo or Stop-signal tasks--requires the prefrontal cortex (PFC), in particular the right inferior frontal cortex (IFC); that patients with ADHD have significant response inhibition deficits and show altered functional activation and gray matter volumes in right IFC; and that a number of studies indicate that response inhibition performance is heritable. Additionally, we review evidence concerning the role of the basal ganglia in response inhibition, as well as the role of neuromodulatory systems. All things considered, a combined right IFC structure/function/response inhibition phenotype is a particularly good candidate for future heritability and association studies. Moreover, a dissection of response inhibition into more basic components such as rule maintenance, vigilance, and target detection may provide yet better targets for association with genes for neuromodulation and brain development.     

Dissociation of response inhibition and performance monitoring in the stop signal task using event-related fMRI

We examined the neural substrate of motor response inhibition and performance monitoring in the stop signal task (SST) using event-related functional magnetic resonance imaging (fMRI). The SST involves a go task and the occasional requirement to stop the go response. We posit that both the go and the stop phases of the SST involve components of inhibition and performance monitoring. The goal of this study was to determine whether inhibition and performance monitoring during go and stop phases of the task activated different networks. We isolated go-phase activities underlying response withholding, monitoring, and sensorimotor processing and contrasted these with successful inhibition to identify the substrate of response inhibition. Error detection activity was isolated using trials in which a stop signal appeared but the response was executed. These trials were modeled as a hand-specific go trial followed by error processing. Cognitive go-phase processes included response withholding and monitoring and activated right prefrontal and midline networks. Response withdrawal additionally activated right inferior frontal gyrus and basal ganglia (caudate). Error detection invoked by failed inhibition activated dorsal anterior cingulate cortex (dACC) and right middle frontal Brodmann's area 9. Our results confirm that there are distinct aspects of inhibition and performance monitoring functions which come into play at various phases within a given trial of the SST, and that these are separable using fMRI.     

Prefrontal and midline interactions mediating behavioural control

Top-down control processes are thought to interact with bottom-up stimulus-driven task demands to facilitate the smooth execution of behaviour. Frontal and midline brain areas in humans are believed to subserve these control processes but their distinct roles and the interactions between them remain to be fully elucidated. In this functional magnetic resonance imaging (fMRI) study, we utilized a GO/NO-GO task with cued and uncued inhibitory events to investigate the effect of cue-induced levels of top-down control on NO-GO trial response conflict. We found that, on a within-subjects, trial-for-trial basis, high levels of top-down control, as indexed by left dorsolateral prefrontal activation prior to the NO-GO, resulted in lower levels of activation on the NO-GO trial in the pre-supplementary motor area. These results suggest that prefrontal and midline regions work together to implement cognitive control and reveal that intra-subject variability is reflected in these lateral and midline interactions.     

Comparison of learning-related neuronal activity in the dorsal premotor cortex and striatum

Previous studies have reported learning-related changes in neuronal activity during conditional visuomotor learning, also known as arbitrary sensorimotor mapping, conditional visual discrimination, and symbolic or endogenous mapping. Qualitatively similar observations have been reported for the dorsal premotor cortex, the supplementary eye field, the prefrontal cortex, the hippocampus, the striatum and the globus pallidus. The fact that cells in both the dorsal premotor cortex (PMd) and the basal ganglia show changes in activity during associative learning enables a test of the hypothesis that cortex and basal ganglia function in distributed architectures known as cortical-basal ganglionic modules or 'loops'. We reasoned that if these loops represent functional entities, as proposed, then learning-related changes in activity should occur simultaneously in both the cortical and striatal nodes of a loop. The present results confirmed this prediction; as monkeys learned conditional visuomotor associations, neurons in the premotor cortex and associated parts of the putamen changed their rates at approximately the same time. For the largest number of neurons, the evolution in neural activity occurred in close correspondence to the monkeys' learning curves. As a population, however, learning-related changes in activity continued after the monkeys reached an asymptote in performance.     

Primary and secondary neural networks of auditory prepulse inhibition: a functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle response

Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMG-recorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating.     

Organizing principles of cortical integration in the rat neostriatum: Corticostriate map of the body surface is an ordered lattice of curved laminae and radial points

The neuroanatomic organizing principles underlying integrative functions in the striatum are only partially understood. Within the three major subdivisions of the striatum—sensorimotor, associative, and limbic—longitudinal zones of axonal plexuses from the cerebral cortex end in bands and clusters that innervate cell groups. To identify organizing principles of the corticostriate bands and clusters, we localized somatosensory cortical cells receptive to light touch on the hindlimb, forelimb, or vibrissae by extracellular recording, and we labeled their projections by iontophoretic application of dextran anterograde tracers. The results show that cortical cells in columnar groups project to the striatum in the form of successive strips, or laminae, that parallel the curve of the external capsule. The vibrissae somatosensory cortex projects to the most lateral lamina. Just medial to the vibrissae projection, the major axonal arborizations arising from hindlimb and forelimb somatosensory cortex are organized within a common lamina, where they interdigitate and overlap as well as remain separate. In addition, the hindlimb and forelimb cortex send small projections to the vibrissae lamina, and vice versa, forming broken, radially oriented lines of points across the laminar strips. The major somatosensory projections are in the dorsolateral, calbindin-poor sensorimotor striatum, whereas the radially oriented projection points extend into the medial, calbindin-rich associative striatum. Extending previous studies of corticostriate projections, this report shows a grid translation of columnar somatosensory cortical inputs into striatum and a detailed map for the rat sensorimotor zone. The lattice-like grid is a novel functional/neuroanatomic organization that is ideal for distributing, combining, and integrating information for sensorimotor and cognitive processing. J. Comp. Neurol. 392:468–488, 1998. © 1998 Wiley-Liss, Inc.     

Differential control of cortical activity by the basal forebrain in rats: a role for both cholinergic and inhibitory influences

Using microdialysis and high-performance liquid chromatography, we measured acetylcholine (ACh) release simultaneously from two cortical sites in anesthetized rats. One site was always in the somatosensory cortex, and the other was in either the visual or the motor cortex. After baseline measurements were obtained, selected sites in the basal forebrain (BF) were stimulated to increase ACh release. Some BF sites provoked more release in one microdialysis probe than in the other, suggesting some degree of corticotropic organization of the cholinergic projections from the BF. BF sites optimal for release from the visual cortex were separated from optimal sites for release from the somatosensory cortex by greater distances than were the best sites for release from the somatosensory and the motor cortex. Stimulation of a single BF site often provoked similar release from the latter two cortical areas. Electrical stimulation of the BF also modified cortical neuronal activity. Activation of some BF sites provoked an intense discharge of many neurons in the vicinity of the cortical recording electrode, and the same stimulus site in the BF provoked release of large amounts of ACh in the cortex. Stimulation of other BF sites produced strong inhibition of ongoing cortical activity and no increase in cortical ACh release. When other sites were stimulated, they had no effect or they generated stereotyped bursting patterns in the cortex without any observable effect on ACh release. BF sites that generated inhibition of cortical neural activity were generally located near the sites that activated the cortex and provoked release of ACh. These data suggest an elaborate control of the sensory cortex by a mechanism involving both gamma-aminobutyric acid-containing and cholinergic neurons of the BF. J. Comp. Neurol. 381:53-67, 1997. © 1997 Wiley-Liss, Inc.     

The interaction of perceived control and Gambler's fallacy in risky decision making: An fMRI study

Limited recent evidence implicates the anterior/posterior cingulate (ACC/PCC) and lateral prefrontal networks as the neural substrates of risky decision‐making biases such as illusions of control (IoC) and gambler's fallacy (GF). However, investigation is lacking on the dynamic interactive effect of those biases during decision making. Employing a card‐guessing game that independently manipulates trial‐by‐trial perceived control and gamble outcome among 29 healthy female participants, we observed both IoC‐ and GF‐type behaviors, as well as an interactive effect of previous control and previous outcome, with GF‐type behaviors only following computer‐selected, but not self‐selected, outcomes. Imaging results implicated the ACC and left dorsolateral prefrontal cortex (DLPFC) in agency processing, and the cerebellum and right DLPFC in previous outcome processing, in accordance with past literature. Critically, the right inferior parietal lobule (IPL) exhibited significant betting‐related activities to the interaction of previous control and previous outcome, showing more positive signals to previous computer‐selected winning versus losing outcomes but the reverse pattern following self‐selected outcomes, as well as responding to the interactive effect of control and outcome during feedback. Associations were also found between participants' behavioral sensitivity to the interactive effect of previous control and previous outcome, and right IPL signals, as well as its functional connectivity with neural networks implicated in agency and previous outcome processing. We propose that the right IPL provides the neural substrate for the interaction of perceived control and GF, through coordinating activities in the anterior and posterior cingulate cortices and working conjunctively with lateral PFC and other parietal networks. Hum Brain Mapp 37:1218–1234, 2016. © 2016 Wiley Periodicals, Inc .     

Response inhibition results in the emotional devaluation of faces: neural correlates as revealed by fMRI

Although it is well established that prior experience with faces determines their subsequent social-emotional evaluation, recent work shows that top-down inhibitory mechanisms, including response inhibition, can lead to social devaluation after even a single, brief exposure. These rapidly induced effects indicate interplay among perceptual, attentional, response-selection and social-emotional networks; yet, the brain mechanisms underlying this are not well understood. This study used functional magnetic resonance imaging (fMRI) to investigate the neural mechanism mediating the relationship between inhibitory control and emotional devaluation. Participants performed two tasks: (i) a Go/No-Go task in response to faces and (ii) a trustworthiness rating task involving the previously seen faces. No-Go faces were rated as significantly less trustworthy than Go faces. By examining brain activations during Task 1, behavioral measures and brain activations obtained in Task 2 could be predicted. Specifically, activity in brain areas during Task 1 associated with (i) executive control and response suppression (i.e. lateral prefrontal cortex) and (ii) affective responses and value representation (i.e. orbitofrontal cortex), systematically covaried with behavioral ratings and amygdala activity obtained during Task 2. The present findings offer insights into the neural mechanisms linking inhibitory processes to affective responses.     

The role of anterior midcingulate cortex in cognitive motor control

The rostral cingulate cortex has been associated with a multitude of cognitive control functions. Recent neuroimaging data suggest that the anterior midcingulate cortex (aMCC) has a key role for cognitive aspects of movement generation, i.e., intentional motor control. We here tested the functional connectivity of this area using two complementary approaches: (1) resting‐state connectivity of the aMCC based on fMRI scans obtained in 100 subjects, and (2) functional connectivity in the context of explicit task conditions using meta‐analytic connectivity modeling (MACM) over 656 imaging experiment. Both approaches revealed a convergent functional network architecture of the aMCC with prefrontal, premotor and parietal cortices as well as anterior insula, area 44/45, cerebellum and dorsal striatum. To specifically test the role of the aMCC's task‐based functional connectivity in cognitive motor control, separate MACM analyses were conducted over “cognitive” and “action” related experimental paradigms. Both analyses confirmed the same task‐based connectivity pattern of the aMCC. While the “cognition” domain showed higher convergence of activity in supramodal association areas in prefrontal cortex and anterior insula, “action” related experiments yielded higher convergence in somatosensory and premotor areas. Secondly, to probe the functional specificity of the aMCC's convergent functional connectivity, it was compared with a neural network of intentional movement initiation. This exemplary comparison confirmed the involvement of the state independent FC network of the aMCC in the intentional generation of movements. In summary, the different experiments of the present study suggest that the aMCC constitute a key region in the network realizing intentional motor control. Hum Brain Mapp 35:2741–2753, 2014. © 2013 Wiley Periodicals, Inc .     

The neural basis of the abnormal self‐referential processing and its impact on cognitive control in depressed patients

Persistent pondering over negative self‐related thoughts is a central feature of depressive psychopathology. In this study, we sought to investigate the neural correlates of abnormal negative self‐referential processing (SRP) in patients with Major Depressive Disorder and its impact on subsequent cognitive control‐related neuronal activation. We hypothesized aberrant activation dynamics during the period of negative and neutral SRP in the rostral anterior cingulate cortex (rACC) and in the amygdala in patients with major depressive disorder. Additionally, we assumed abnormal activation in the fronto‐cingulate network during Stroop task execution. 19 depressed patients and 20 healthy controls participated in the study. Using an event‐related functional magnetic resonance imaging (fMRI) design, negative, positive and neutral self‐referential statements were displayed for 6.5 s and followed by incongruent or congruent Stroop conditions. The data were analyzed with SPM8. In contrast to controls, patients exhibited no significant valence‐dependent rACC activation differences during SRP. A novel finding was the significant activation of the amygdala and the reward‐processing network during presentation of neutral self‐referential stimuli relative to baseline and to affective stimuli in patients. The fMRI analysis of the Stroop task revealed a reduced BOLD activation in the right fronto‐parietal network of patients in the incongruent condition after negative SRP only. Thus, the inflexible activation in the rACC may correspond to the inability of depressed patients to shift their attention away from negative self‐related stimuli. The accompanying negative affect and task‐irrelevant emotional processing may compete for neuronal resources with cognitive control processes and lead thereby to deficient cognitive performance associated with decreased fronto‐parietal activation. Hum Brain Mapp 36:2781–2794, 2015. © 2015 Wiley Periodicals, Inc.     

Intentional inhibition: How the “veto‐area” exerts control

One important aspect of self‐control is refraining voluntarily from already planned behavior, by a final intervention before commitment to action. Despite its crucial role in human existence, and clear social implications, this aspect of self‐control has proved hard to study experimentally. One recent study used a perceptual timing paradigm to identify specific activations in the dorsal fronto‐median cortex (dFMC) associated with voluntary inhibition of action (Brass and Haggard 2007 : J Neurosci 27:9141–9145). Here, we extend this work in two important new directions. First, we developed a more naturalistic task that gives participants a strong reason to inhibit or to execute actions, and therefore involves self‐control in the sense of voluntary inhibition of prepotent impulsive responses. Second, we investigated the relation between dFMC and other cognitive‐motor areas using effective connectivity analysis. We show that dFMC is activated when inhibiting prepared responses to external events. Moreover, its effective connectivity suggests that it allows intentional inhibition of action through top‐down inhibition of premotor areas. This view of dFMC is consistent with a new view of self‐control as a key stage in a cognitive‐motor interface. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Individual differences in neural responses to social rejection: the joint effect of self-esteem and attentional control

Individuals with low self-esteem have been found to react more negatively to signs of interpersonal rejection than those with high self-esteem. However, previous research has found that individual differences in attentional control can attenuate negative reactions to social rejection among vulnerable, low self-esteem individuals. The current fMRI study sought to elucidate the neurobiological substrate of this buffering effect. We hypothesized and found that while looking at scenes of social rejection (vs negative scenes) low self-esteem high attentional control individuals engaged the rostral anterior cingulate cortex (rACC), an area of the brain associated with emotional control, more than their low self-esteem low attentional control peers. Furthermore, we found that low self-esteem high attentional control individuals evaluated social rejection as less arousing and less rejecting in a separate behavioral task. Importantly, activation in the rACC fully mediated the relationship between the interaction of self-esteem and attentional control and emotional evaluations, suggesting that the rACC activation underlies the buffering effects of attentional control. Results are discussed in terms of individual differences in emotional vulnerability and protection and by highlighting the role of rACC in emotion regulation.     

Neural activations at the junction of the inferior frontal sulcus and the inferior precentral sulcus: interindividual variability, reliability, and association with sulcal morphology

The sulcal morphology of the human frontal lobe is highly variable. Although the structural images usually acquired in functional magnetic resonance imaging studies provide information about this interindividual variability, this information is only rarely used to relate structure and function. Here, we investigated the spatial relationship between posterior frontolateral activations in a task-switching paradigm and the junction of the inferior frontal sulcus and the inferior precentral sulcus (inferior frontal junction, IFJ) on an individual-subject basis. Results show that, although variable in terms of stereotaxic coordinates, the posterior frontolateral activations observed in task-switching are consistently and reliably located at the IFJ in the brains of individual participants. The IFJ shares such consistent localization with other nonprimary areas as motion-sensitive area V5/MT and the frontal eye field. Building on tension-based models of morphogenesis, this structure-function correspondence might indicate that the cytoarchitectonic area underlying activations of the IFJ develops at early stages of cortical folding.