Anna Smith

Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection

Inhibitory control and error detection are among the highest evolved human self-monitoring functions. Attempts in functional neuroimaging to effectively isolate inhibitory motor control from other cognitive functions have met with limited success. Different brain regions in inferior, mesial, and dorsolateral prefrontal cortices and parietal and temporal lobes have been related to inhibitory control in go/no-go and stop tasks. The widespread activation reflects the fact that the designs used so far have comeasured additional noninhibitory cognitive functions such as selective attention, response competition, decision making, target detection, and inhibition failure. Here we use rapid, mixed trial, event-related functional magnetic resonance imaging to correlate brain activation with an extremely difficult situation of inhibitory control in a challenging stop task that controls for noninhibitory functions. The difficulty of the stop task, requiring withholding of a triggered motor response, was assured by an algorithm that adjusted the task individually so that each subject only succeeded on half of all stop trials, failing on the other half. This design allowed to elegantly separate brain activation related to successful motor response inhibition and to inhibition failure or error detection. Brain activation correlating with successful inhibitory control in 20 healthy volunteers could be isolated in right inferior prefrontal cortex. Failure to inhibit was associated with activation in mesial frontopolar and bilateral inferior parietal cortices, presumably reflecting an attention network for error detection.

Progressive increase of frontostriatal brain activation from childhood to adulthood during event-related tasks of cognitive control

Higher cognitive inhibitory and attention functions have been shown to develop throughout adolescence, presumably concurrent with anatomical brain maturational changes. The relatively scarce developmental functional imaging literature on cognitive control, however, has been inconsistent with respect to the neurofunctional substrates of this cognitive development, finding either increased or decreased executive prefrontal function in the progression from childhood to adulthood. Such inconsistencies may be due to small subject numbers or confounds from age‐related performance differences in block design functional MRI (fMRI). In this study, rapid, randomized, mixed‐trial event‐related fMRI was used to investigate developmental differences of the neural networks mediating a range of motor and cognitive inhibition functions in a sizeable number of adolescents and adults. Functional brain activation was compared between adolescents and adults during three different executive tasks measuring selective motor response inhibition (Go/no‐go task), cognitive interference inhibition (Simon task), and attentional set shifting (Switch task). Adults compared with children showed increased brain activation in task‐specific frontostriatal networks, including right orbital and mesial prefrontal cortex and caudate during the Go/no‐go task, right mesial and inferior prefrontal cortex, parietal lobe, and putamen during the Switch task and left dorsolateral and inferior frontotemporoparietal regions and putamen during the Simon task. Whole‐brain regression analyses with age across all subjects showed progressive age‐related changes in similar and extended clusters of task‐specific frontostriatal, frontotemporal, and frontoparietal networks. The findings suggest progressive maturation of task‐specific frontostriatal and frontocortical networks for cognitive control functions in the transition from childhood to mid‐adulthood. Hum Brain Mapp, 2006.

Linear age-correlated functional development of right inferior fronto-striato-cerebellar networks during response inhibition and anterior cingulate during error-related processes

Inhibitory and performance‐monitoring functions have been shown to develop throughout adolescence. The developmental functional magnetic resonance imaging (fMRI) literature on inhibitory control, however, has been relatively inconsistent with respect to functional development of prefrontal cortex in the progression from childhood to adulthood. Age‐related performance differences between adults and children have been shown to be a confound and may explain inconsistencies in findings. The development of error‐related processes has not been studied so far using fMRI. The aim of this study was to investigate the neural substrates of the development of inhibitory control and error‐related functions by use of an individually adjusted task design that forced subjects to fail on 50% of trials, and therefore controlled for differences in task difficulty and performance between different age groups. Event‐related fMRI was used to compare brain activation between 21 adults and 26 children/adolescents during successful motor inhibition and inhibition failure. Adults compared with children/adolescents showed increased brain activation in right inferior prefrontal cortex during successful inhibition and in anterior cingulate during inhibition failure. A whole‐brain age‐regression analysis between 10 and 42 years showed progressive age‐related changes in activation in these two brain regions, with additional changes in thalamus, striatum, and cerebellum. Age‐correlated brain regions correlated with each other and with inhibitory performance, suggesting they form developing fronto‐striato‐thalamic and fronto‐cerebellar neural pathways for inhibitory control. This study shows developmental specialization of the integrated function of right inferior prefrontal cortex, basal ganglia, thalamus, and cerebellum for inhibitory control and of anterior cingulate gyrus for error‐related processes. Hum Brain Mapp 2007.

A review of fronto-striatal and fronto-cortical brain abnormalities in children and adults with Attention Deficit Hyperactivity Disorder (ADHD) and new evidence for dysfunction in adults with ADHD during motivation and attention.

Attention Deficit Hyperactivity Disorder (ADHD) has long been associated with abnormalities in frontal brain regions. In this paper we review the current structural and functional imaging evidence for abnormalities in children and adults with ADHD in fronto-striatal, fronto-parieto-temporal, fronto-cerebellar and fronto-limbic regions and networks. While the imaging studies in children with ADHD are more numerous and consistent, an increasing number of studies suggests that these structural and functional abnormalities in fronto-cortical and fronto-subcortical networks persist into adulthood, despite a relative symptomatic improvement in the adult form of the disorder. We furthermore present new data that support the notion of a persistence of neurofunctional deficits in adults with ADHD during attention and motivation functions. We show that a group of medication-naïve young adults with ADHD behaviours who were followed up 20 years from a childhood ADHD diagnosis show dysfunctions in lateral fronto-striato-parietal regions relative to controls during sustained attention, as well as in ventromedial orbitofrontal regions during reward, suggesting dysfunctions in cognitive-attentional as well as motivational neural networks. The lateral fronto-striatal deficit findings, furthermore, were strikingly similar to those we have previously observed in children with ADHD during the same task, reinforcing the notion of persistence of fronto-striatal dysfunctions in adult ADHD. The ventromedial orbitofrontal deficits, however, were associated with comorbid conduct disorder (CD), highlighting the potential confound of comorbid antisocial conditions on paralimbic brain deficits in ADHD. Our review supported by the new data therefore suggest that both adult and childhood ADHD are associated with brain abnormalities in fronto-cortical and fronto-subcortical systems that mediate the control of cognition and motivation. The brain deficits in ADHD therefore appear to be multi-systemic and to persist throughout the lifespan.

Neural Correlates of Executive Function in Autistic Spectrum Disorders

BACKGROUND Some clinical characteristics of high-functioning individuals with autistic spectrum disorder (ASD) such as repetitive stereotyped behaviors, perseveration, and obsessionality have been related to executive function (EF) deficits, more specifically to deficits in inhibitory control and set shifting and mediating frontostriatal neural pathways. However, to date, no functional imaging study on ASD has investigated inhibition and cognitive flexibility and no one has related EF brain activation to brain structure. METHODS We compared brain activation (using functional magnetic resonance imaging) in 10 normal intelligence adults with ASD and 12 healthy control subjects during three different EF tasks: 1) motor-inhibition (GO/NO-GO); 2) cognitive interference-inhibition (spatial STROOP); and 3) set shifting (SWITCH). Using voxel-based morphometry, we investigated if cortical areas which were functionally different in people with ASD were also anatomically abnormal. RESULTS Compared with control subjects, ASD individuals showed significantly increased brain activation in 1) left inferior and orbital frontal gyrus (motor-inhibition); 2) left insula (interference-inhibition); and 3) parietal lobes (set shifting). Moreover, in individuals with ASD, increased frontal gray matter density and increased functional activation shared the same anatomical location. CONCLUSIONS Our findings suggest an association between successful completion of EF tasks and increased brain activation in people with ASD, which partially may be explained by differences in brain anatomy.

Disorder-Specific Dissociation of Orbitofrontal Dysfunction in Boys With Pure Conduct Disorder During Reward and Ventrolateral Prefrontal Dysfunction in Boys With Pure ADHD During Sustained Attention

OBJECTIVE Among children, attention deficit hyperactivity disorder (ADHD) and conduct disorder are often comorbid and overlap clinically. Neuropsychological evidence suggests that children with conduct disorder demonstrate more prominent motivational problems and children with ADHD demonstrate more prominent attention deficits relative to healthy comparison subjects. The purpose of the present study was to investigate disorder-specific abnormalities in the neurobiological correlates of motivation and sustained attention in children and adolescents with pure conduct disorder and children and adolescents with pure ADHD. METHOD Participants were male pediatric patients, ages 9-16 years, with noncomorbid conduct disorder (N=14) and noncomorbid ADHD, combined hyperactive-inattentive subtype (N=18), as well as age- and IQ-matched healthy comparison subjects (N=16). Both patient groups were medication naive. Event-related functional magnetic resonance imaging (fMRI) was used to compare brain activation during a rewarded continuous performance task that measured sustained attention as well as the effects of reward on performance. RESULTS During the sustained attention condition, patients with noncomorbid ADHD showed significantly reduced activation in the bilateral ventrolateral prefrontal cortex and increased activation in the cerebellum relative to patients with noncomorbid conduct disorder and healthy comparison subjects. Patients with noncomorbid conduct disorder showed decreased activation in paralimbic regions of the insula, hippocampus, and anterior cingulate as well as the cerebellum relative to patients with noncomorbid ADHD and healthy comparison subjects. However, during the reward condition, patients with noncomorbid conduct disorder showed disorder-specific underactivation in the right orbitofrontal cortex, while patients with noncomorbid ADHD showed disorder-specific dysfunction in the posterior cingulate gyrus. CONCLUSIONS The findings revealed a process-related dissociation of prefrontal dysfunction in ADHD and conduct disorder patients. Attention-related dysfunction in the ventrolateral prefrontal cortex was seen in ADHD patients, and reward-related dysfunction in the orbitofrontal cortex was seen in conduct disorder patients. These findings, together with the pattern of paralimbic dysfunction demonstrated among children with conduct disorder during sustained attention, support theories of abnormalities in orbitofrontal-paralimbic motivation networks in individuals with conduct disorder and, in contrast, ventrolateral fronto-cerebellar attention network dysfunction in individuals with ADHD.

Evidence for a pure time perception deficit in children with ADHD

BACKGROUND Deficits have been found previously in children with ADHD on tasks of time reproduction, time production and motor timing, implicating a deficit in temporal processing abilities, which has been interpreted as either secondary or primary to core executive dysfunctions. The aim of this study was to explore further the abilities of hyperactive children in skills of time estimation, using a range of time perception tasks in different temporal domains. METHOD Time estimation was tested in a verbal estimation task of 10 seconds. Time reproduction was also acquired for two time intervals of 5 and 12 seconds. A temporal discrimination task aimed to determine the idiosyncratic threshold of minimum time interval (in milliseconds) necessary to distinguish two intervals differing by approximately 300 milliseconds. Twenty-two children diagnosed with ADHD were compared to 22 healthy children, matched for age, handedness and working memory skills. RESULTS Children with ADHD were significantly impaired in their time discrimination threshold: on average, time intervals had to be 50 ms longer for the hyperactive children in order to be discriminated when compared with controls. Children with ADHD also responded earlier on a 12-second reproduction task, which however only approached significance after controlling for IQ and short-term memory. No group differences were found for the 5-second time reproduction or verbal time estimation tasks. CONCLUSIONS The findings suggest that children with ADHD perform poorly on time reproduction tasks which load heavily on impulsiveness and attentional processes and they also suggest that these children may have a perceptual deficit of time discrimination, which may only be detectable in brief durations which differ by several hundred milliseconds. A temporal perception deficit in the range of milliseconds in ADHD may impact upon other functions such as perceptual language skills and motor timing.

Motor Timing Deficits in Community and Clinical Boys With Hyperactive Behavior: The Effect of Methylphenidate on Motor Timing

In a previous paper we showed that community children with hyperactive behavior were more inconsistent than controls in the temporal organization of their motor output. In this study we investigated: (1) various aspects of motor timing processes in 13 clinically diagnosed boys with attention deficit hyperactivity disorder (ADHD) who were compared to 11 community boys with hyperactive behavior and to a control group and (2) the effect of methylphenidate on the motor timing processes in the clinical group with ADHD in a double blind, cross-over, medication-placebo design, including 4 weeks of medication. The clinical group with ADHD, like the community group with hyperactivity, showed greater variability in sensorimotor synchronization and in sensorimotor anticipation relative to controls. The clinical group was also impaired in time perception, which was spared in the community group with hyperactivity. The persistent, but not the acute dose, of methylphenidate reduced the variability of sensorimotor synchronization and anticipation, but had no effect on time perception. This study shows that motor timing functions are impaired in both clinical and community children with hyperactivity. It is the first study to show the effectiveness of persistent administration of methylphenidate on deficits in motor timing in ADHD children and extends the use of methylphenidate from the domain of attentional and inhibitory functions to the domain of executive motor timing.

Performance of children with attention deficit hyperactivity disorder (ADHD) on a test battery of impulsiveness.

Children with ADHD were compared to healthy controls on a task battery of cognitive control, measuring motor inhibition (Go/No-Go and Stop tasks), cognitive inhibition (motor Stroop and Switch tasks), sustained attention and time discrimination. Children with ADHD showed an inconsistent and premature response style across all 6 tasks. In addition they showed task-specific impairments in measures of sustained attention, time discrimination, and motor inhibition, but spared cognitive inhibition. Measures of impairment correlated with behavioral hyperactivity and with each other, suggesting that they measure interrelated aspects of a multifaceted construct of cognitive impulsiveness. The task battery as a whole showed 76% correct discrimination of cases and controls.

Dissociated Functional Brain Abnormalities of Inhibition in Boys With Pure Conduct Disorder and in Boys With Pure Attention Deficit Hyperactivity Disorder

OBJECTIVE Inhibitory dysfunction may be a transdiagnostic etiopathophysiology of disruptive behavior disorders. Functional magnetic resonance imaging (fMRI) of inhibitory control has only been investigated in patients with attention deficit hyperactivity disorder (ADHD), including comorbidity with conduct disorder, showing frontal-striatal dysfunction. This study investigates differences and commonalities in functional neural networks mediating inhibitory control between medication-naive adolescents with pure conduct disorder and those with pure ADHD to identify biological markers that distinguish these clinically overlapping disorders. METHOD Event-related fMRI was used to compare brain activation of 13 boys with noncomorbid conduct disorder, 20 with noncomorbid ADHD, and 20 normal boys during an individually adjusted tracking stop task that measures the neural substrates of inhibition and stopping failure. RESULTS During successful inhibition, only patients with ADHD showed reduced activation in the left dorsolateral prefrontal cortex in relation to comparison subjects and patients with conduct disorder. During inhibition failures compared to go responses, both patient groups shared underactivation in the posterior cingulate gyrus in relation to comparison subjects. Patients with conduct disorder showed reduced activation in bilateral temporal-parietal regions compared to the other groups, which did not differ in this measure. CONCLUSIONS Patients with pure ADHD or pure conduct disorder show qualitative differences in their brain abnormality patterns during inhibitory control. Inhibition-mediating prefrontal regions appear to be specifically reduced in ADHD, whereas posterior temporal-parietal, performance monitoring networks are specifically dysfunctional in conduct disorder. The findings provide pioneering evidence that distinct neurobiological abnormalities may be underlying the overlapping behavioral phenotype of the two disruptive disorders.