Dorsal Anterior Cingulate Research Articles

Brain Mechanisms Underlying Urge Incontinence and its Response to Pelvic Floor Muscle Training

Urge urinary incontinence is a major problem, especially in the elderly, and to our knowledge the underlying mechanisms of disease and therapy are unknown. We used biofeedback assisted pelvic floor muscle training and functional brain imaging (functional magnetic resonance imaging) to investigate cerebral mechanisms, aiming to improve the understanding of brain-bladder control and therapy. Before receiving biofeedback assisted pelvic floor muscle training functionally intact, older community dwelling women with urge urinary incontinence as well as normal controls underwent comprehensive clinical and bladder diary evaluation, urodynamic testing and brain functional magnetic resonance imaging. Evaluation was repeated after pelvic floor muscle training in those with urge urinary incontinence. Functional magnetic resonance imaging was done to determine the brain reaction to rapid bladder filling with urgency. Of 65 subjects with urge urinary incontinence 28 responded to biofeedback assisted pelvic floor muscle training with 50% or greater improvement of urge urinary incontinence frequency on diary. However, responders and nonresponders displayed 2 patterns of brain reaction. In pattern 1 in responders before pelvic floor muscle training the dorsal anterior cingulate cortex and the adjacent supplementary motor area were activated as well as the insula. After the training dorsal anterior cingulate cortex/supplementary motor area activation diminished and there was a trend toward medial prefrontal cortex deactivation. In pattern 2 in nonresponders before pelvic floor muscle training the medial prefrontal cortex was deactivated, which changed little after the training. In older women with urge urinary incontinence there appears to be 2 patterns of brain reaction to bladder filling and they seem to predict the response and nonresponse to biofeedback assisted pelvic floor muscle training. Moreover, decreased cingulate activation appears to be a consequence of the improvement in urge urinary incontinence induced by training while prefrontal deactivation may be a mechanism contributing to the success of training. In nonresponders the latter mechanism is unavailable, which may explain why another form of therapy is required.

Dysfunctional Activation and Brain Network Profiles in Youth with Obsessive-Compulsive Disorder: A Focus on the Dorsal Anterior Cingulate during Working Memory.

Brain network dysfunction is emerging as a central biomarker of interest in psychiatry, in large part, because psychiatric conditions are increasingly seen as disconnection syndromes. Understanding dysfunctional brain network profiles in task-active states provides important information on network engagement in an experimental context. This in turn may be predictive of many of the cognitive and behavioral deficits associated with complex behavioral phenotypes. Here we investigated brain network profiles in youth with obsessive-compulsive disorder (OCD), contrasting them with a group of age-comparable controls. Network interactions were assessed during simple working memory: in particular, we focused on the modulation by the dorsal anterior cingulate cortex (dACC) of cortical, striatal, and thalamic regions. The focus on the dACC was motivated by its hypothesized role in the pathophysiology of OCD. However, its task-active network signatures have not been investigated before. Network interactions were modeled using psychophysiological interaction, a simple directional model of seed to target brain interactions. Our results indicate that OCD is characterized by significantly increased dACC modulation of cortical, striatal, and thalamic targets during working memory, and that this aberrant increase in OCD patients is maintained regardless of working memory demand. The results constitute compelling evidence of dysfunctional brain network interactions in OCD and suggest that these interactions may be related to a combination of network inefficiencies and dACC hyper-activity that has been associated with the phenotype.

Neurostructural abnormalities in pediatric anxiety disorders

Functional neuroimaging studies have consistently demonstrated abnormalities in fear and threat processing systems in youth with anxiety disorders; however, the structural neuroanatomy of these systems in children and adolescents remains largely unknown. Using voxel-based morphometry (VBM), gray matter volumes were compared between 38 medication-free patients with anxiety disorders (generalized anxiety disorder; social phobia; separation anxiety disorder, mean age: 14.4±3 years) and 27 comparison subjects (mean age: 14.8±4 years). Compared to healthy subjects, youth with anxiety disorders had larger gray matter volumes in the dorsal anterior cingulate and had decreased gray matter volumes in the inferior frontal gyrus (ventrolateral prefrontal cortex), postcentral gyrus, and cuneus/precuneus. These data suggest the presence of structural differences in regions previously implicated in the processing and regulation of fear in pediatric patients with anxiety disorders.

Reproducibility of phase rotation stimulated echo acquisition mode at 3T in schizophrenia: Emphasis on glutamine.

To determine the reproducibility and reliability of glutamine (Gln), measured with a very short echo time phase rotation stimulated echo acquisition mode (VTE-PR STEAM) sequence at 3T, in subjects with schizophrenia. Seven subjects with schizophrenia were scanned twice with VTE-PR STEAM in a Siemens 3T TIM Trio scanner with a 32-channel head coil. Spectroscopic data were collected from two voxels in gray matter, one in the dorsal anterior cingulate and the other in the medial occipital cortex. Reproducibility was assessed using coefficients of variation (CVs) and reliability with standard error of measurement and intraclass correlations (ICCs). Phantoms containing increasing concentrations of Gln in a physiologic solution of other neurometabolites with overlapping resonances were scanned to assess the validity of spectral Gln measurement. Very good reliability and reproducibility for Gln in both regions of interest were supported by CVs of ≤10.0% and ICCs of ≥0.6, respectively. Phantom studies documented a robust correspondence between known Gln concentrations and VTE-PR STEAM measurements of this metabolite (R(2) = 0.988). The VTE-PR STEAM approach at 3T permits the longitudinal assessment of Gln and other (1) H MR spectroscopy neurometabolites in a clinically plausible setting.

Can Genetic Testing Provide Information to Develop Customized Nutrigenomic Solutions for Reward Deficiency Syndrome?

We are entering the era of genomic medicine and neuroimaging as it relates to addiction a subset of Reward Deficiency Syndrome (RDS) [1-3]. In 2005 our laboratory received the first USA patent on Nutrigenomics and RDS treatment. This was awarded on the basis of our earlier work showing anti-addiction activity of a nutraceutical consisting of amino-acid precursors and enkephalinase inhibition properties and our discovery of the first polymorphic gene (Dopamine D2 Receptor Gene [DRD2] to associate with sever alcoholism [4-7]. Prior to the later genetic finding we developed the concept of Brain Reward Cascade which continues to act as blue-print for stratification of addiction risk through neurogentics [8]. In 1996 our laboratory also coined the term “Reward Deficiency Syndrome (RDS” to define a common genetic rubric for both substance and non-substance related addictive behaviors [9,10]. Following many reiterations we utilized polymorphic targets of a number of reward genes (serotonergic, Opioidergic, GABAergic and Dopaminergic) to customize KB220 [Neuroaaptogen- aminoacid therapy (NAAT)] by specific algorithms. Identifying 1,000 obese subjects in the Netherlands a subsequent small subset was administered various KB220 formulae customized according to respective DNA polymorphisms individualized that translated to significant decreases in both Body Mass Index (BMI) and weight in pounds [11]. This was followed up in the USA with similar significant effects [12,13]. Following these experiments we have been successfully developing a panel of genes known as “Genetic Addiction Risk Score [14,15] (GARSDX).™ In unpublished work, we found that when we selected 10 genes with appropriate variants, a statistically significant association between the ASI- Media Version -alcohol and drug severity scores and GARSDx provided the first validated genetic panel for RDS. This observation was found in 273 patients attending seven diverse treatment centers. This now validated panel could be utilized to provide a personalized approach by coupling gene polymorphisms with potential nutrigenomic solutions. Independently, a variant of NAAT –KB220Z in abstinent heroin addicts, increased resting state functional connectivity. Specifically we observed enhanced rs functional connectivity in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum [16].In other unpublished rat work using a novel segmented rat atlas, we show that KB220Z significantly activates, above placebo, seed regions of interest including the left nucleus accumbens, cingulate gyrus, anterior thalamic nuclei, hippocampus, pre-limbic and infra-limbic loci. This response induced by KB220Z demonstrates significant functional connectivity, increased brain volume recruitment and enhanced dopaminergic functionality across the brain reward circuitry. This robust yet selective response implies clinical relevance. These results and other quantitative electroencephalogy (qEEG) experiments results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction [17]. We are now paused to propose a Reward Deficiency System Solution that promotes early identification and stratification of risk alleles by utilizing GARSDx allowing for customized nutrigenomic targeting of these risk alleles by altering NAAT ingredients as an algorithmic function of carrying these polymorphic DNA –SNPS potentially yielding the first ever nutrigenomic solution for addiction and pain[18]. The concept of dopaminergic activation in the long term is supported by the recent work of Willuhn et al. showing that a deficiency of phasic dopamine causes escalation of cocaine intake in animals. This suggests dopamine agonistic therapy rather than dopamine antagonistic therapy in the long-term treatment with patients presenting with RDS [19]. Certainly, we encourage others to also develop similar addiction algorithms based on reward gene polymorphisms and as therapeutic targets to improve clinical outcomes and long term remission for all RDS addictive behaviors.

Neuronal Prediction of Opponent’s Behavior during Cooperative Social Interchange in Primates

A cornerstone of successful social interchange is the ability to anticipate each other's intentions or actions. While generating these internal predictions is essential for constructive social behavior, their single neuronal basis and causal underpinnings are unknown. Here, we discover specific neurons in the primate dorsal anterior cingulate that selectively predict an opponent's yet unknown decision to invest in their common good or defect and distinct neurons that encode the monkey's own current decision based on prior outcomes. Mixed population predictions of the other was remarkably near optimal compared to behavioral decoders. Moreover, disrupting cingulate activity selectively biased mutually beneficial interactions between the monkeys but, surprisingly, had no influence on their decisions when no net-positive outcome was possible. These findings identify a group of other-predictive neurons in the primate anterior cingulate essential for enacting cooperative interactions and may pave a way toward the targeted treatment of social behavioral disorders.

Neuronal Activity in Primate Dorsal Anterior Cingulate Cortex Signals Task Conflict and Predicts Adjustments in Pupil-Linked Arousal

Whether driving a car, shopping for food, or paying attention in a classroom of boisterous teenagers, it's often hard to maintain focus on goals in the face of distraction. Brain imaging studies in humans implicate the dorsal anterior cingulate cortex (dACC) in regulating the conflict between goals and distractors. Here we show that single dACC neurons signal conflict between task goals and distractors in the rhesus macaque, particularly for biologically relevant social stimuli. For some neurons, task conflict signals predicted subsequent changes in pupil size-a peripheral index of arousal linked to noradrenergic tone-associated with reduced distractor interference. dACC neurons also responded to errors, and these signals predicted adjustments in pupil size. These findings provide the first neurophysiological endorsement of the hypothesis that dACC regulates conflict, in part, via modulation of pupil-linked processes such as arousal.

Chapter 7 - Functional imaging of structures involved in neural control of the lower urinary tract

Recent functional brain imaging studies, building on earlier observations, suggest a working model of brain control of the lower urinary tract. It comprises a few cerebral neural circuits that, during the storage phase, act on the midbrain periaqueductal gray to inhibit the long-loop, spinobulbospinal voiding reflex, thus promoting continence. Circuit 1, centered on the medial prefrontal cortex, appears to be concerned with conscious control of both continence and voiding. Circuit 2, centered on the dorsal anterior cingulate (midcingulate) and supplementary motor area, is concerned with emotional aspects of bladder control: desire to void or urgency with concomitant urethral sphincter activation to delay leakage. A subcortical circuit 3 has been less well studied. Circuit 1 is bilateral with a right-sided preference. Scattered studies of the connectivity of the control network suggest that white-matter damage may contribute to urinary incontinence. A few studies confirm that isolated cerebral lesions, if in the medial prefrontal cortex or its connecting pathways, may lead to incontinence. Lower urinary tract dysfunction in other neurologic diseases (normal-pressure hydrocephalus, Parkinson's disease, and multiple systems atrophy) appears consistent with the working model, and even spinal or peripheral lesions have central effects. However, this model omits the contributions of brain regions already observed in some imaging studies and therefore is certainly oversimplified.

The Neural Basis of Temporal Order Processing in Past and Future Thought

Although growing evidence has shown that remembering the past and imagining the future recruit a common core network of frontal-parietal-temporal regions, the extent to which these regions contribute to the temporal dimension of autobiographical thought remains unclear. In this fMRI study, we focused on the event-sequencing aspect of time and examined whether ordering past and future events involve common neural substrates. Participants had to determine which of two past (or future) events occurred (or would occur) before the other, and these order judgments were compared with a task requiring to think about the content of the same past or future events. For both past and future events, we found that the left posterior hippocampus was more activated when establishing the order of events, whereas the anterior hippocampus was more activated when representing their content. Aside from the hippocampus, most of the brain regions that were activated when thinking about temporal order (notably the intraparietal sulcus, dorsolateral pFC, dorsal anterior cingulate, and visual cortex) lied outside the core network and may reflect the involvement of controlled processes and visuospatial imagery to locate events in time. Collectively, these findings suggest (a) that the same processing operations are engaged for ordering past events and planned future events in time, (b) that anterior and posterior portions of the hippocampus are involved in processing different aspects of autobiographical thought, and (c) that temporal order is not necessarily an intrinsic property of memory or future thought but instead requires additional, controlled processes.

Coupling Neurogenetics (GARS™) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS): Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms.

Earlier work from our laboratory, showing anti-addiction activity of a nutraceutical consisting of amino-acid precursors and enkephalinase inhibition properties and our discovery of the first polymorphic gene (Dopamine D2 Receptor Gene [DRD2]) to associate with severe alcoholism serves as a blue-print for the development of “Personalized Medicine” in addiction. Prior to the later genetic finding, we developed the concept of Brain Reward Cascade, which continues to act as an important component for stratification of addiction risk through neurogenetics. In 1996 our laboratory also coined the term “Reward Deficiency Syndrome (RDS)” to define a common genetic rubric for both substance and non-substance related addictive behaviors. Following many reiterations we utilized polymorphic targets of a number of reward genes (serotonergic, Opioidergic, GABAergic and Dopaminergic) to customize KB220 [Neuroadaptogen- amino-acid therapy (NAAT)] by specific algorithms. Identifying 1,000 obese subjects in the Netherlands a subsequent small subset was administered various KB220Z formulae customized according to respective DNA polymorphisms individualized that translated to significant decreases in both Body Mass Index (BMI) and weight in pounds. Following these experiments, we have been successfully developing a panel of genes known as “Genetic Addiction Risk Score” (GARSpDX)™. Selection of 10 genes with appropriate variants, a statistically significant association between the ASI-Media Version-alcohol and drug severity scores and GARSpDx was found A variant of KB220Z in abstinent heroin addicts increased resting state functional connectivity in a putative network including: dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. In addition, we show that KB220Z significantly activates, above placebo, seed regions of interest including the left nucleus accumbens, cingulate gyrus, anterior thalamic nuclei, hippocampus, pre-limbic and infra-limbic loci. KB220Z demonstrates significant functional connectivity, increased brain volume recruitment and enhanced dopaminergic functionality across the brain reward circuitry. We propose a Reward Deficiency System Solution that promotes early identification and stratification of risk alleles by utilizing GARSDx, allowing for customized nutrigenomic targeting of these risk alleles by altering KB220Z ingredients as an algorithmic function of carrying these polymorphic DNA–SNPS, potentially yielding the first ever nutrigenomic solution for addiction and pain.

Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome.

The ability to divide one's attention deteriorates in patients with childhood chronic fatigue syndrome (CCFS). We conducted a study using a dual verbal task to assess allocation of attentional resources to two simultaneous activities (picking out vowels and reading for story comprehension) and functional magnetic resonance imaging. Patients exhibited a much larger area of activation, recruiting additional frontal areas. The right middle frontal gyrus (MFG), which is included in the dorsolateral prefrontal cortex, of CCFS patients was specifically activated in both the single and dual tasks; this activation level was positively correlated with motivation scores for the tasks and accuracy of story comprehension. In addition, in patients, the dorsal anterior cingulate gyrus (dACC) and left MFG were activated only in the dual task, and activation levels of the dACC and left MFG were positively associated with the motivation and fatigue scores, respectively. Patients with CCFS exhibited a wider area of activated frontal regions related to attentional resources in order to increase their poorer task performance with massive mental effort. This is likely to be less efficient and costly in terms of energy requirements. It seems to be related to the pathophysiology of patients with CCFS and to cause a vicious cycle of further increases in fatigue.

Sensory Deprivation during Early Postnatal Period Alters the Density of Interneurons in the Mouse Prefrontal Cortex.

Early loss of one sensory system can cause improved function of other sensory systems. However, both the time course and neuronal mechanism of cross-modal plasticity remain elusive. Recent study using functional MRI in humans suggests a role of the prefrontal cortex (PFC) in cross-modal plasticity. Since this phenomenon is assumed to be associated with altered GABAergic inhibition in the PFC, we have tested the hypothesis that early postnatal sensory deprivation causes the changes of inhibitory neuronal circuit in different regions of the PFC of the mice. We determined the effects of sensory deprivation from birth to postnatal day 28 (P28) or P58 on the density of parvalbumin (PV), calbindin (CB), and calretinin (CR) neurons in the prelimbic, infralimbic, and dorsal anterior cingulate cortices. The density of PV and CB neurons was significantly increased in layer 5/6 (L5/6). Moreover, the density of CR neurons was higher in L2/3 in sensory deprived mice compared to intact mice. These changes were more prominent at P56 than at P28. These results suggest that long-term sensory deprivation causes the changes of intracortical inhibitory networks in the PFC and the changes of inhibitory networks in the PFC may contribute to cross-modal plasticity.

On Weight and Waiting: Delay Discounting in Anorexia Nervosa Pretreatment and Posttreatment

BackgroundIndividuals with anorexia nervosa (AN) override the drive to eat, forgoing immediate rewards in favor of longer-term goals. We examined delay discounting and its neural correlates in AN before and after treatment to test a potential mechanism of illness persistence. MethodsInpatients with AN (n = 59) and healthy control subjects (HC, n = 39) performed a delay discounting task at two time points. A subset (n = 30 AN, n = 22 HC) participated in functional magnetic resonance imaging scanning during the task. The task consisted of a range of monetary choices with variable delay times, yielding individual discount rates—the rate by which money loses value over time. ResultsBefore treatment, the AN group showed a preference for delayed over earlier rewards (i.e., less steep discount rates) compared with HC; after weight restoration, AN did not differ from HC. Underweight AN showed slower response times for earlier versus delayed choices; this reversed with treatment. Underweight AN showed abnormal neural activity in striatum and dorsal anterior cingulate; normalization of behavior was associated with increased activation in reward regions (striatum and dorsal anterior cingulate) and decision-making regions (dorsolateral prefrontal cortex and parietal cortex). ConclusionsThe undernourished state of AN may amplify the tendency to forgo immediate rewards in favor of longer-term goals. The results suggest that behavior that looks phenotypically like excessive self-control does not correspond with enhanced prefrontal recruitment. Rather, the results point to alterations in cingulostriatal circuitry that offer new insights on the potential role of abnormalities in decision-making neural systems in the perpetuation of AN.

RsfMRI effects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts

Recently, Willuhn et al. reported that cocaine use and even non-substance-related addictive behavior increases as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors and was also associated with lower activation of cues in occipital cortex and cerebellum, in a recent PET study by Volkow’s et al. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of 10 heroin addicts undergoing protracted abstinence (average 16.9 months). In a randomized placebo-controlled crossover study of KB220Z, five subjects completed a triple-blinded experiment in which the subject, the person administering the treatment, and the person evaluating the response to treatment were blinded to the treatment that any particular subject was receiving. In addition, nine subjects were genotyped utilizing the GARSDX™ test. We preliminarily report that KB220Z induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following 1-hour acute administration. Furthermore, KB220Z also reduced resting-state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all 10 abstinent heroin-dependent subjects, we observed that three brain regions of interest were significantly activated from resting state by KB220Z compared to placebo (p < 0.05). Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. These results and other quantitative electroencephalogy (qEEG) study results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results, and confirmation with additional research and ongoing rodent and human studies of KB220Z is required.

Dissociated neural representations induced by complex and simple odorant molecules

An important challenge in olfaction research is to understand how percepts relate to the molecular structure of stimuli. Previous psychophysical studies showed that, whereas structurally simple odorant molecules evoked a more uniform qualitative perception as revealed by the use of a small number of labels to describe their olfactory quality, more complex odorants evoked a larger variety of olfactory qualities, reflecting a more heterogeneous qualitative perception. The present study examined how this influence of odorant molecular complexity on perception is reflected in the human brain. To this end, participants were stimulated with structurally simple and complex odorant molecules and their brain responses were assessed by functional magnetic resonance imaging (fMRI). Low- and high-complexity odorants were judged to have the same intensity, pleasantness and familiarity (p>0.05 in all cases), whereas complex odorants induced more quality labels than simple odorants (p<0.02) as expected. Imaging analysis of complex vs. simple odorants revealed significant activation in dorsal anterior cingulate gyrus, but not in primary olfactory areas. Taken together, these findings suggest dissociated neural representations of uniform and heterogeneous olfactory perception, highlighting for the first time the impact of odorant complexity on activity of the cingulate gyrus.

Frontal networks associated with command following after hemorrhagic stroke.

Level of consciousness is frequently assessed by command-following ability in the clinical setting. However, it is unclear what brain circuits are needed to follow commands. We sought to determine what networks differentiate command following from noncommand following patients after hemorrhagic stroke. Structural MRI, resting-state functional MRI, and electroencephalography were performed on 25 awake and unresponsive patients with acute intracerebral and subarachnoid hemorrhage. Structural injury was assessed via volumetric T1-weighted MRI analysis. Functional connectivity differences were analyzed against a template of standard resting-state networks. The default mode network (DMN) and the task-positive network were investigated using seed-based functional connectivity. Networks were interrogated by pairwise coherence of electroencephalograph leads in regions of interest defined by functional MRI. Functional imaging of unresponsive patients identified significant differences in 6 of 16 standard resting-state networks. Significant voxels were found in premotor cortex, dorsal anterior cingulate gyrus, and supplementary motor area. Direct interrogation of the DMN and task-positive network revealed loss of connectivity between the DMN and the orbitofrontal cortex and new connections between the task-positive network and DMN. Coherence between electrodes corresponding to right executive network and visual networks was also decreased in unresponsive patients. Resting-state functional MRI and electroencephalography coherence data support a model in which multiple, chiefly frontal networks are required for command following. Loss of DMN anticorrelation with task-positive network may reflect a loss of inhibitory control of the DMN by motor-executive regions. Frontal networks should thus be a target for future investigations into the mechanism of responsiveness in the intensive care unit environment.

Capturing the dynamics of response variability in the brain in ADHD.

ADHD is characterized by increased intra-individual variability in response times during the performance of cognitive tasks. However, little is known about developmental changes in intra-individual variability, and how these changes relate to cognitive performance. Twenty subjects with ADHD aged 7–24 years and 20 age-matched, typically developing controls participated in an fMRI-scan while they performed a go-no-go task. We fit an ex-Gaussian distribution on the response distribution to objectively separate extremely slow responses, related to lapses of attention, from variability on fast responses. We assessed developmental changes in these intra-individual variability measures, and investigated their relation to no-go performance. Results show that the ex-Gaussian measures were better predictors of no-go performance than traditional measures of reaction time. Furthermore, we found between-group differences in the change in ex-Gaussian parameters with age, and their relation to task performance: subjects with ADHD showed age-related decreases in their variability on fast responses (sigma), but not in lapses of attention (tau), whereas control subjects showed a decrease in both measures of variability. For control subjects, but not subjects with ADHD, this age-related reduction in variability was predictive of task performance. This group difference was reflected in neural activation: for typically developing subjects, the age-related decrease in intra-individual variability on fast responses (sigma) predicted activity in the dorsal anterior cingulate gyrus (dACG), whereas for subjects with ADHD, activity in this region was related to improved no-go performance with age, but not to intra-individual variability. These data show that using more sophisticated measures of intra-individual variability allows the capturing of the dynamics of task performance and associated neural changes not permitted by more traditional measures.

An integrative neurocircuit perspective on psychogenic nonepileptic seizures and functional movement disorders: neural functional unawareness.

Functional neurological disorder (conversion disorder) is a neurobehavioral condition frequently encountered by neurologists. Psychogenic nonepileptic seizure (PNES) and functional movement disorder (FMD) patients present to epileptologists and movement disorder specialists respectively, yet neurologists lack a neurobiological perspective through which to understand these enigmatic groups. Observational research studies suggest that PNES and FMD may represent variants of similar (or the same) conditions given that both groups exhibit a female predominance, have increased prevalence of mood-anxiety disorders, frequently endorse prior abuse, and share phenotypic characteristics. In this perspective article, neuroimaging studies in PNES and FMD are reviewed, and discussed using studies of emotional dysregulation, dissociation and psychological trauma in the context of motor control. Convergent neuroimaging findings implicate alterations in brain circuits mediating emotional expression, regulation and awareness (anterior cingulate and ventromedial prefrontal cortices, insula, amygdala, vermis), cognitive control and motor inhibition (dorsal anterior cingulate, dorsolateral prefrontal, inferior frontal cortices), self-referential processing and perceptual awareness (posterior parietal cortex, temporoparietal junction), and motor planning and coordination (supplementary motor area, cerebellum). Striatal-thalamic components of prefrontal-parietal networks may also play a role in pathophysiology. Aberrant medial prefrontal and amygdalar neuroplastic changes mediated by chronic stress may facilitate the development of functional neurological symptoms in a subset of patients. Improved biological understanding of PNES and FMD will likely reduce stigma and aid the identification of neuroimaging biomarkers guiding treatment development, selection, and prognosis. Additional research should investigate neurocircuit abnormalities within and across functional neurological disorder subtypes, as well as compare PNES and FMD with mood-anxiety-dissociative disorders.

Learning to minimize efforts versus maximizing rewards: computational principles and neural correlates.

The mechanisms of reward maximization have been extensively studied at both the computational and neural levels. By contrast, little is known about how the brain learns to choose the options that minimize action cost. In principle, the brain could have evolved a general mechanism that applies the same learning rule to the different dimensions of choice options. To test this hypothesis, we scanned healthy human volunteers while they performed a probabilistic instrumental learning task that varied in both the physical effort and the monetary outcome associated with choice options. Behavioral data showed that the same computational rule, using prediction errors to update expectations, could account for both reward maximization and effort minimization. However, these learning-related variables were encoded in partially dissociable brain areas. In line with previous findings, the ventromedial prefrontal cortex was found to positively represent expected and actual rewards, regardless of effort. A separate network, encompassing the anterior insula, the dorsal anterior cingulate, and the posterior parietal cortex, correlated positively with expected and actual efforts. These findings suggest that the same computational rule is applied by distinct brain systems, depending on the choice dimension-cost or benefit-that has to be learned.

Separate neural representations for physical pain and social rejection.

Current theories suggest that physical pain and social rejection share common neural mechanisms, largely by virtue of overlapping functional magnetic resonance imaging (fMRI) activity. Here we challenge this notion by identifying distinct multivariate fMRI patterns unique to pain and rejection. Sixty participants experience painful heat and warmth and view photos of ex-partners and friends on separate trials. FMRI pattern classifiers discriminate pain and rejection from their respective control conditions in out-of-sample individuals with 92% and 80% accuracy. The rejection classifier performs at chance on pain, and vice versa. Pain- and rejection-related representations are uncorrelated within regions thought to encode pain affect (for example, dorsal anterior cingulate) and show distinct functional connectivity with other regions in a separate resting-state data set (N = 91). These findings demonstrate that separate representations underlie pain and rejection despite common fMRI activity at the gross anatomical level. Rather than co-opting pain circuitry, rejection involves distinct affective representations in humans.