Human dorsal anterior cingulate cortex neurons mediate ongoing behavioural adaptation.

The ability to optimize behavioural performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, is important in regulating cognitive control. Hypotheses about its function include guiding reward-based decision making, monitoring for conflict between competing responses and predicting task difficulty. Precise mechanisms of dACC function remain unknown, however, because of the limited number of human neurophysiological studies. Here we use functional imaging and human single-neuron recordings to show that the firing of individual dACC neurons encodes current and recent cognitive load. We demonstrate that the modulation of current dACC activity by previous activity produces a behavioural adaptation that accelerates reactions to cues of similar difficulty to previous ones, and retards reactions to cues of different difficulty. Furthermore, this conflict adaptation, or Gratton effect, is abolished after surgically targeted ablation of the dACC. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioural responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands it engenders accuracy by delaying responses.

Effect of dopamine transporter gene (SLC6A3) variation on dorsal anterior cingulate function in attention-deficit/hyperactivity disorder.

Although attention-deficit/hyperactivity disorder (ADHD) is associated both with brain alterations in attention and executive function (EF) circuitry and with genetic variations within the dopamine system (including the dopamine transporter gene [SLC6A3]), few studies have directly investigated how genetic variations are linked to brain alterations. We sought to examine how a polymorphism in the 3' untranslated region (UTR) of SLC6A3, associated with ADHD in meta-analysis, might contribute to variation in dorsal anterior cingulate cortex (dACC) function in subjects with ADHD. We collected fMRI scans of 42 individuals with ADHD, all of European descent and over the age of 17, while they performed the multi-source interference task (MSIT), a cognitive task shown to activate dACC. SLC6A3 3' UTR variable number tandem repeat (VNTR) polymorphisms were genotyped and brain activity was compared for groups based on allele status. ADHD individuals homozygous for the 10R allele showed significant hypoactivation in the left dACC compared to 9R-carriers. Exploratory analysis also showed trends toward hypoactivation in the 10R homozygotes in left cerebellar vermis and right lateral prefrontal cortex. Further breakdown of genotype groups showed similar activation in individuals heterozygous and homozygous for the 9R allele. Alterations in activation of attention and EF networks found previously to be involved in ADHD are likely influenced by SLC6A3 genotype. This genotype may contribute to heterogeneity of brain alterations found within ADHD samples.

Attention and executive systems abnormalities in adults with childhood ADHD: A DT-MRI study of connections.

Attention-deficit/hyperactivity disorder (ADHD) is hypothesized to be due, in part, to structural defects in brain networks influencing cognitive, affective, and motor behaviors. Although the current literature on fiber tracts is limited in ADHD, gray matter abnormalities suggest that white matter (WM) connections may be altered selectively in neural systems. A prior study (Ashtari et al. 2005), using diffusion tensor magnetic resonance imaging (DT-MRI), showed alterations within the frontal and cerebellar WM in children and adolescents with ADHD. In this study of adults with childhood ADHD, we hypothesized that fiber pathways subserving attention and executive functions (EFs) would be altered. To this end, the cingulum bundle (CB) and superior longitudinal fascicle II (SLF II) were investigated in vivo in 12 adults with childhood ADHD and 17 demographically comparable unaffected controls using DT-MRI. Relative to controls, the fractional anisotropy (FA) values were significantly smaller in both regions of interest in the right hemisphere, in contrast to a control region (the fornix), indicating an alteration of anatomical connections within the attention and EF cerebral systems in adults with childhood ADHD. The demonstration of FA abnormalities in the CB and SLF II in adults with childhood ADHD provides further support for persistent structural abnormalities into adulthood.

Neuroimaging of attention deficit hyperactivity disorder: can new imaging findings be integrated in clinical practice?

Recent advances in neuroimaging research have helped elucidate the neurobiology of attention deficit hyperactivity disorder (ADHD) and the mechanisms by which medications used to treat ADHD exert their effects. The complex nature and array of imaging techniques, however, present challenges for the busy clinician in assessing possible clinical uses of brain imaging. Even though currently there are no accepted uses for imaging in diagnosing ADHD (other than ruling out identifiable medical or neurologic conditions that may mimic ADHD), this review introduces the main imaging techniques used to study ADHD, identifies relevant complexities facing psychiatric researchers in implementing neuroimaging techniques for clinical purposes, and provides benchmarks to help determine when imaging modalities have advanced to a point that they are deemed clinically useful.

Human anterior cingulate neurons and the integration of monetary reward with motor responses.

The human dorsal anterior cingulate cortex (dACC) has been implicated in cognitive processes that have been proposed to play a role in integrating contextual information needed to select or modify appropriate motor responses. In humans, however, there has been little direct evidence tying the dACC to the integration of contextual information and behavioral response. We used single-neuron recordings from human subjects to evaluate the role of the dACC in reward-based decision making. Subjects undergoing planned surgical cingulotomy performed a task where they were instructed to make specific movements in response to changing monetary rewards. In many neurons, activity increased in response to a diminished reward, and was also predictive of the movement ultimately made. After dACC ablation, subjects made selectively more errors when they were required to change movement based on reward reduction. These findings suggest that the dACC in humans plays an important role in linking reward-related information with alternative actions.

A preliminary study of dopamine D4 receptor genotype and structural brain alterations in adults with ADHD.

An emerging literature has demonstrated an association between the dopamine D4 receptor (DRD4) gene and volumetric brain abnormalities in children with ADHD. However, these results have not been extended to adults and have not addressed the impact of comorbidity. Our objective was to examine the DRD4 7R gene and volumetric brain abnormalities in adults with ADHD while accounting for comorbidity with bipolar disorder (BPD). Subjects were male and female adult outpatient referrals stratified into two diagnostic groups: 24 with ADHD, 19 with ADHD and BPD, as well as 20 male and female adult community controls without ADHD or BPD. We measured volumes (cm(3)) of a priori selected brain regions (superior frontal, middle frontal, anterior cingulate, and cerebellum cortices) by structural magnetic resonance imaging. Among adults with ADHD, subjects with the 7-repeat allele of the DRD4 gene had a significantly smaller mean volume in the superior frontal cortex and cerebellum cortex compared to subjects without this allele. In contrast, no such effects were detected in the adults with ADHD + BPD or controls. Our findings suggest that volumetric abnormalities in the dorsolateral prefrontal cortex and cerebellum may represent an intermediate neuroanatomical phenotype between DRD4 genotype and the clinical expression of ADHD in adults, but only in ADHD subjects without comorbid BPD. These result support the heterogeneity of ADHD and provides insights as to its underlying pathophysiology.

Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging.

OBJECTIVES: Gray and white matter volume deficits have been reported in a number of studies of children with attention-deficit/hyperactivity disorder (ADHD); however, there is a paucity of structural magnetic resonance imaging (MRI) studies of adults with ADHD. This structural MRI study used an a priori region of interest approach. METHODS: Twenty-four adults with DSM-IV ADHD and 18 healthy controls comparable on age, socioeconomic status, sex, handedness, education, IQ, and achievement test performance had an MRI on a 1.5T Siemens scanner. Cortical and sub-cortical gray and white matter were segmented. Image parcellation divided the neocortex into 48 gyral-based units per hemisphere. Based on a priori hypotheses we focused on prefrontal, anterior cingulate cortex (ACC) and overall gray matter volumes. General linear analyses of the volumes of brain regions, adjusting for age, sex, and total cerebral volumes, were used to compare groups. RESULTS: Relative to controls, ADHD adults had significantly smaller overall cortical gray matter, prefrontal and ACC volumes. CONCLUSIONS: Adults with ADHD have volume differences in brain regions in areas involved in attention and executive control. These data, largely consistent with studies of children, support the idea that adults with ADHD have a valid disorder with persistent biological features.

Functional neuroimaging of attention-deficit/hyperactivity disorder: a review and suggested future directions.

Over the past few decades, functional neuroimaging techniques have begun to provide unprecedented windows on the neurobiology of attention-deficit/hyperactivity disorder (ADHD) and the neural effects of medications used to treat the disorder. Convergent data from neuroimaging, neuropsychological, genetics, and neurochemical studies have implicated dysfunction of fronto-striatal structures (lateral prefrontal cortex, dorsal anterior cingulate cortex, caudate, and putamen) as likely contributing to the pathophysiology of ADHD. This review 1) provides an overview of the main imaging techniques being used to study ADHD; 2) discusses their relative strengths and weaknesses, highlighting how they can complement one another; 3) shows how the functional imaging literature, which has built on the structural imaging data, is now being used to test focused hypotheses regarding the neurobiological substrate of ADHD; and 4) suggests guidelines for improving future functional imaging studies. Although at present there are no accepted uses for functional imaging in diagnosing ADHD, this article mentions possible future clinical uses of imaging in ADHD.

Architecture and neurocytology of monkey cingulate gyrus.

Human functional imaging and neurocytology have produced important revisions to the organization of the cingulate gyrus and demonstrate four structure/function regions: anterior, midcingulate (MCC), posterior (PCC), and retrosplenial. This study evaluates the brain of a rhesus and 11 cynomolgus monkeys with Nissl staining and immunohistochemistry for neuron-specific nuclear binding protein, intermediate neurofilament proteins, and parvalbumin. The MCC region was identified along with its two subdivisions (a24' and p24'). The transition between areas 24 and 23 does not involve a simple increase in the number of neurons in layer IV but includes an increase in neuron density in layer Va of p24', a dysgranular layer IV in area 23d, granular area 23, with a neuron-dense layer Va and area 31. Each area on the dorsal bank of the cingulate gyrus has an extension around the fundus of the cingulate sulcus (f 24c, f 24c', f 24d, f 23c), whereas most cortex on the dorsal bank is composed of frontal motor areas. The PCC is composed of a dysgranular area 23d, area 23c in the caudal cingulate sulcus, a dorsal cingulate gyral area 23a/b, and a ventral area 23a/b. Finally, a dysgranular transition zone includes both area 23d and retrosplenial area 30. The distribution of areas was plotted onto flat maps to show the extent of each and their relationships to the vertical plane at the anterior commissure, corpus callosum, and cingulate sulcus. This major revision of the architectural organization of monkey cingulate cortex provides a new context for connection studies and for devising models of neuron diseases.

Neural and behavioral substrates of mood and mood regulation.

A review of behavioral and neurobiological data on mood and mood regulation as they pertain to an understanding of mood disorders is presented. Four approaches are considered: 1) behavioral and cognitive; 2) neurobiological; 3) computational; and 4) developmental. Within each of these four sections, we summarize the current status of the field and present our vision for the future, including particular challenges and opportunities. We conclude with a series of specific recommendations for National Institute of Mental Health priorities. Recommendations are presented for the behavioral domain, the neural domain, the domain of behavioral-neural interaction, for training, and for dissemination. It is in the domain of behavioral-neural interaction, in particular, that new research is required that brings together traditions that have developed relatively independently. Training interdisciplinary clinical scientists who meaningfully draw upon both behavioral and neuroscientific literatures and methods is critically required for the realization of these goals.

Anterior cingulate cortex activation during cognitive interference in schizophrenia.

BACKGROUND: Previous studies have reported evidence of structural and functional abnormalities in the anterior cingulate cortex of patients with schizophrenia. METHOD: The authors studied 19 male patients with chronic schizophrenia and 15 healthy male comparison subjects with functional magnetic resonance imaging and the novel Multi-Source Interference Task, a task designed to elicit robust dorsal anterior cingulate cortex activation in individual subjects. Group averaged and individual (region-of-interest-based) brain activation patterns were compared during the performance of control and interference trials. RESULTS: Performance (reaction times and accuracy) did not differ between healthy subjects and patients with schizophrenia. Comparison of interference and neutral blocks revealed activation in the medial wall of the prefrontal cortex in 93% (N=14) of the healthy subjects and 84% (N=16) of the subjects with schizophrenia. Sixty-seven percent (N=10) of the healthy subjects but only 16% (N=3) of the subjects with schizophrenia displayed maximum medial wall activation within the dorsal anterior cingulate cortex. CONCLUSIONS: The Multi-Source Interference Task produced robust activation in the medial wall of the prefrontal cortex during cognitive interference. Analysis of individual activation patterns revealed medial wall abnormalities in schizophrenia patients.

Brain function and structure in adults with attention-deficit/hyperactivity disorder.

Cross-sectional data suggest that brain dysfunctions are a central component of attention-deficit/hyperactivity disorder (ADHD) in children, and a growing literature is suggesting the same for adults. This article reviews the current state of the literature pertaining to the structural and functional brain abnormalities that are found in adults with ADHD. Because the literature on ADHD in children is more extensive than that reported heretofore in ADHD in adults,the authors include brief summaries of the child literature to help inform that found in adults.

Atomoxetine increases fronto-parietal functional MRI activation in attention-deficit/hyperactivity disorder: a pilot study.

We hypothesized that atomoxetine (ATMX) would produce similar brain effects in attention-deficit/hyperactivity disorder (ADHD) as those of methylphenidate (MPH). Eleven ADHD adults performed the Multi-Source Interference Task (MSIT) during functional magnetic resonance imaging (fMRI) at baseline and after 6 weeks of ATMX treatment. ATMX was associated with increased fMRI activation of dorsolateral prefrontal cortex, parietal cortex and cerebellum but not dorsal anterior midcingulate cortex (daMCC). These results suggest that ATMX and MPH have similar but not identical brain effects.

Cingulate, frontal, and parietal cortical dysfunction in attention-deficit/hyperactivity disorder.

Functional and structural neuroimaging have identified abnormalities of the brain that are likely to contribute to the neuropathophysiology of attention-deficit/hyperactivity disorder (ADHD). In particular, hypofunction of the brain regions comprising the cingulo-frontal-parietal cognitive-attention network have been consistently observed across studies. These are major components of neural systems that are relevant to ADHD, including cognitive/attention networks, motor systems, and reward/feedback-based processing systems. Moreover, these areas interact with other brain circuits that have been implicated in ADHD, such as the "default mode" resting state network. The ADHD imaging data related to cingulo-frontal-parietal network dysfunction will be selectively highlighted here to help facilitate its integration with the other information presented in this special issue. Together, these reviews will help shed light on the neurobiology of ADHD.

Exaggerated activation of dorsal anterior cingulate cortex during cognitive interference: a monozygotic twin study of posttraumatic stress disorder.

OBJECTIVE: Neuroimaging studies have revealed functional abnormalities in the anterior cingulate cortex in posttraumatic stress disorder (PTSD). The goal of this study was to determine whether hyperresponsivity of the dorsal anterior cingulate in PTSD is an acquired characteristic or a familial risk factor. METHOD: Using a case-control twin design, the authors studied combat-exposed veterans with PTSD (N=12) and their identical combat-unexposed co-twins (N=12), as well as combat-exposed veterans without PTSD (N=14) and their identical combat-unexposed co-twins (N=14). Participants underwent functional MRI during completion of the Multi-Source Interference Task, which reliably activates the dorsal anterior cingulate. RESULTS: Combat-exposed veterans with PTSD and their unexposed co-twins had significantly greater activation in the dorsal anterior cingulate and tended to have larger response time difference scores, as compared to combat-exposed veterans without PTSD and their co-twins. Dorsal anterior cingulate activation in the exposed twins was positively correlated with their PTSD symptom severity. Dorsal anterior cingulate activation in the unexposed twins was positively correlated with their combat-exposed co-twins' PTSD symptom severity, but not with depression or alcohol use severity in the combat-exposed co-twins. CONCLUSIONS: Hyperresponsivity in the dorsal anterior cingulate appears to be a familial risk factor for the development of PTSD following psychological trauma.

Attention-deficit/hyperactivity disorder and attention networks.

Research attempting to elucidate the neuropathophysiology of attention-deficit/hyperactivity disorder (ADHD) has not only shed light on the disorder itself, it has simultaneously provided new insights into the mechanisms of normal cognition and attention. This review will highlight and integrate this bidirectional flow of information. Following a brief overview of ADHD clinical phenomenology, ADHD studies will be placed into a wider historical perspective by providing illustrative examples of how major models of attention have influenced the development of neurocircuitry models of ADHD. The review will then identify major components of neural systems potentially relevant to ADHD, including attention networks, reward/feedback-based processing systems, as well as a 'default mode' resting state network. Further, it will suggest ways in which these systems may interact and be influenced by neuromodulatory factors. Recent ADHD imaging data will be selectively provided to both illustrate the field's current level of knowledge and to show how such data can inform our understanding of normal brain functions. The review will conclude by suggesting possible avenues for future research.

Anterior cingulate volumetric alterations in treatment-naïve adults with ADHD: a pilot study.

OBJECTIVE: We sought to examine preliminary results of brain alterations in anterior cingulate cortex (ACC) in treatment-naïve adults with ADHD. The ACC is a central brain node for the integration of cognitive control and allocation of attention, affect and drive. Thus its anatomical alteration may give rise to impulsivity, hyperactivity and inattention, which are cardinal behavioral manifestations of ADHD. METHOD: Segmentation and parcellation of the ACC was performed on controls (n = 22), treated (n = 13) and treatment-naïve adults with ADHD (n = 13). RESULTS: There was a 21% volume reduction in the left ACC of the treatment-naïve group relative to the control group. Also, there was a 23% volume reduction in the right ACC of the treated group relative to the control group. CONCLUSION: These results raise the possibility that in ADHD there are volumetric deficits persistent into adulthood, that are independent of medical treatment.