Effects of age and gender on neural networks of motor response inhibition: from adolescence to mid-adulthood.

Functional inhibitory neural networks mature progressively with age. However, nothing is known about the impact of gender on their development. This study employed functional magnetic resonance imaging (fMRI) to investigate the effects of age, sex, and sex by age interactions on the brain activation of 63 healthy males and females, between 13 and 38 years, performing a Stop task. Increasing age was associated with progressively increased activation in typical response inhibition areas of right inferior and dorsolateral prefrontal and temporo-parietal regions. Females showed significantly enhanced activation in left inferior and superior frontal and striatal regions relative to males, while males showed increased activation relative to females in right inferior and superior parietal areas. Importantly, left frontal and striatal areas that showed increased activation in females, also showed significantly increased functional maturation in females relative to males, while the right inferior parietal activation that was increased in males showed significantly increased functional maturation relative to females. The findings demonstrate for the first time that sex-dimorphic activation patterns of enhanced left fronto-striatal activation in females and enhanced right parietal activation in males during motor inhibition appear to be the result of underlying gender differences in the functional maturation of these brain regions.

Developmental effects of reward on sustained attention networks.

Adolescence is typified by significant maturation in higher-level attention functions coupled with less developed control over motivation, and enhanced sensitivity to novelty and reward. This study used event-related functional magnetic resonance imaging (fMRI) in seventy male and female participants aged between 10 and 43 years to identify age-related linear changes in cognitive sustained attention systems and the impact of reward on these systems, using a sustained attention task with and without a rewarded condition. For the non-rewarded sustained attention contrast, increasing age was associated with activation increases in typical regions of sustained attention including right inferior frontal, superior temporo-parietal and cerebellar cortices. Age-related activation decreases were observed within more posterior regions including posterior cingulate, insula and posterior cerebellar cortices, presumably mediating visual-spatial saliency detection. The effect of reward on sustained attention networks was associated with increased activation with age in regions associated with both executive attention control and reward processing, including dorsolateral, inferior and ventromedial prefrontal cortices (PFC), striatum, and temporo-parietal regions, suggestive of greater integration and executive control of motivation and cognition with maturity. Activation in paralimbic posterior cingulate and inferior temporal brain regions of visual-spatial saliency processing was progressively reduced in activation with increasing development. Thus, with increasing development between adolescence and adulthood, reward appears to enhance maturing cognitive sustained attention and executive reward-processing networks, whilst reducing paralimbic regions of saliency detection. These findings may be the neural underpinnings for the progressive maturation of motivational control over risk taking behaviours between adolescence and adulthood.

Fronto-striatal underactivation during interference inhibition and attention allocation in grown up children with attention deficit/hyperactivity disorder and persistent symptoms.

Attention deficit hyperactivity disorder (ADHD) in medication-naïve children has been associated with reduced activation in inferior/medial prefrontal, striatal and parieto-temporal cortices during inhibitory control and attention allocation. Functional magnetic resonance imaging (fMRI) studies in adult ADHD, however, have been inconsistent and confounded by medication-history and the need for a retrospective diagnosis of childhood ADHD. We used fMRI combined with a Simon task that measured interference inhibition and controlled for and co-measured attention allocation to compare brain function in 11 medication-naïve adults with persistent inattentive/hyperactive behaviours, followed up from childhood ADHD, and 15 age-matched controls. Despite comparable task performance, patients showed reduced activation compared to controls in left orbital/medial frontal cortex and striatum during interference inhibition and in left lateral inferior/dorsolateral prefrontal cortex during attention allocation. Whole-brain regression analyses within patients showed a negative correlation between symptom severity and fronto-striatal, temporo-parietal and cerebellar brain activation. The findings demonstrate that the typical fronto-striatal dysfunction observed in children with ADHD during interference inhibition and attention allocation is also observed in adults grown up from childhood ADHD with persistent symptoms. Furthermore, they show that functional deficits in adult ADHD are not related to chronic stimulant medication given that this sample was medication-naive.

Effects of age and sex on developmental neural networks of visual-spatial attention allocation.

Compared to our understanding of the functional maturation of brain networks underlying complex cognitive abilities, hardly anything is known of the neurofunctional development of simpler cognitive abilities such as visuo-spatial attention allocation. Furthermore, nothing is known on the effect of gender on the functional development of attention allocation. This study employed event related functional magnetic resonance imaging to investigate effects of age, sex, and sex by age interactions on the brain activation of 63 males and females, between 13 to 38years, during a visual-spatial oddball task. Behaviourally, with increasing age, speed was traded for accuracy, indicative of a less impulsive performance style in older subjects. Increasing age was associated with progressively increased activation in typical areas of selective attention of lateral fronto-striatal and temporo-parietal brain regions. Sex difference analysis showed enhanced activation in right-hemispheric inferior frontal and superior temporal regions in females, and in left-hemispheric inferior temporo-parietal regions in males. Importantly, the age by sex interaction findings showed that these sex-dimorphic patterns of brain activation may be the result of underlying sex differences in the functional maturation of these brain regions, as females had sex-specific progressive age-correlations in the same right inferior fronto-striato-temporal areas, while male-specific age-correlations were in left medial temporal and parietal areas. The findings demonstrate progressive functional maturation of fronto-striato-parieto-temporal networks of the relatively simple function of attention allocation between early adolescence and mid-adulthood. They furthermore show that sex-dimorphic patterns of enhanced reliance on right inferior frontal, striatal and superior temporal regions in females and of left temporo-parietal regions in males during attention allocation may be the result of underlying sex differences in the functional maturation of these brain regions.

Disorder-specific inferior prefrontal hypofunction in boys with pure attention-deficit/hyperactivity disorder compared to boys with pure conduct disorder during cognitive flexibility.

BACKGROUND: Problems with cognitive flexibility have been observed in patients with attention deficit hyperactivity disorder (ADHD) and in patients with conduct disorder (CD), characterized by the violation of societal rules and the rights of others. Functional magnetic resonance imaging (fMRI) of cognitive switching, however, has only been investigated in patients with ADHD, including comorbidity with CD, finding frontostriatal and temporoparietal underactivation. This study investigates disorder-specific functional abnormalities during cognitive flexibility between medication-naïve children and adolescents with noncomorbid CD and those with noncomorbid ADHD compared to healthy controls. METHODS: Event-related fMRI was used to compare brain activation of 14 boys with noncomorbid, childhood-onset CD, 14 boys with noncomorbid ADHD, and 20 healthy comparison boys during a visual-spatial Switch task. RESULTS: Behaviorally, children with ADHD compared to children with CD had significantly slower reaction times to switch compared to repeat trials. The fMRI comparison showed that the patients with ADHD compared to both controls and patients with CD showed underactivation in right and left inferior prefrontal cortex. No disorder-specific brain underactivation was observed in patients with CD. Only when compared with controls alone, the disruptive behavior group showed reduced activation in bilateral temporoparietal and occipital brain regions. CONCLUSIONS: The findings extend previous evidence for disorder-specific underactivation in patients with ADHD compared to patients with CD in inferior prefrontal cortex during tasks of inhibitory control to the domain of cognitive flexibility. Inferior prefrontal underactivation thus appears to be a disorder-specific neurofunctional biomarker for ADHD when compared with patients with CD.

Sex-dependent age modulation of frontostriatal and temporo-parietal activation during cognitive control.

Developmental functional imaging studies of cognitive control show progressive age-related increase in task-relevant fronto-striatal activation in male development from childhood to adulthood. Little is known, however, about how gender affects this functional development. In this study, we used event related functional magnetic resonance imaging to examine effects of sex, age, and their interaction on brain activation during attentional switching and interference inhibition, in 63 male and female adolescents and adults, aged 13 to 38. Linear age correlations were observed across all subjects in task-specific frontal, striatal and temporo-parietal activation. Gender analysis revealed increased activation in females relative to males in fronto-striatal areas during the Switch task, and laterality effects in the Simon task, with females showing increased left inferior prefrontal and temporal activation, and males showing increased right inferior prefrontal and parietal activation. Increased prefrontal activation clusters in females and increased parietal activation clusters in males furthermore overlapped with clusters that were age-correlated across the whole group, potentially reflecting more mature prefrontal brain activation patterns for females, and more mature parietal activation patterns for males. Gender by age interactions further supported this dissociation, revealing exclusive female-specific age correlations in inferior and medial prefrontal brain regions during both tasks, and exclusive male-specific age correlations in superior parietal (Switch task) and temporal regions (Simon task). These findings show increased recruitment of age-correlated prefrontal activation in females, and of age-correlated parietal activation in males, during tasks of cognitive control. Gender differences in frontal and parietal recruitment may thus be related to gender differences in the neurofunctional maturation of these brain regions.

Shared and disorder-specific prefrontal abnormalities in boys with pure attention-deficit/hyperactivity disorder compared to boys with pure CD during interference inhibition and attention allocation.

BACKGROUND: Inhibitory and attention deficits have been suggested to be shared problems of disruptive behaviour disorders. Patients with attention deficit hyperactivity disorder (ADHD) and patients with conduct disorder (CD) show deficits in tasks of attention allocation and interference inhibition. However, functional magnetic resonance imaging (fMRI) of inhibitory and attention control has only been investigated in patients with ADHD, including comorbidity with CD, finding fronto-striatal and temporo-parietal dysfunction. This study investigates differences and commonalities in functional neural networks mediating interference inhibition and attention allocation between medication-naïve children and adolescents with pure CD and those with pure ADHD. METHODS: Event-related fMRI was used to compare brain activation of 13 boys with non-comorbid CD, 20 boys with non-comorbid ADHD and 20 healthy comparison boys during a Simon task that measures interference inhibition and controls for attention allocation, thus tapping into interference inhibition and selective attention networks. RESULTS: During interference inhibition, both patient groups shared reduced activation compared to controls in right superior temporal lobe and in predominantly right precuneus. During the oddball condition, both patient groups showed reduced activation compared to healthy control children in right medial prefrontal lobe. However, only ADHD patients showed a disorder-specific under-activation compared to the other two groups in an extensive activation cluster in left inferior prefrontal cortex. CONCLUSIONS: This study shows shared dysfunction in both patients groups in right hemispheric temporal and parietal brain regions during interference inhibition and in right dorsolateral prefrontal cortex during attention allocation. Ventrolateral prefrontal dysfunction, however, was specific to ADHD and not observed in patients with CD in the context of attention allocation. The findings suggest that the typically reduced functional activation in patients with ADHD in ventrolateral prefrontal cortex may be specific to the disorder, at least when compared to patients with CD.

Reduced activation in lateral prefrontal cortex and anterior cingulate during attention and cognitive control functions in medication-naïve adolescents with depression compared to controls.

BACKGROUND: There is increasing recognition of major depressive disorder (MDD) in adolescence. In adult MDD, abnormalities of fronto-striatal and fronto-cingulate circuitries mediating cognitive control functions have been implicated in the pathogenesis and been related to problems with controlling negative thoughts. No neuroimaging studies of cognitive control functions, however, exist in paediatric depression. This study investigated whether medication-naïve adolescents with MDD show abnormal brain activation of fronto-striatal and fronto-cingulate networks when performing tasks of attentional and cognitive control. METHODS: Event-related functional magnetic resonance imaging was used to compare brain activation between 21 medication-naïve adolescents with a first-episode of MDD aged 14-17 years and 21 healthy adolescents, matched for handedness, age, sex, demographics and IQ. Activation paradigms were tasks of selective attention (Simon task), attentional switching (Switch task), and motor response inhibition and error detection (Stop task). RESULTS: In all three tasks, adolescents with depression compared to healthy controls demonstrated reduced activation in task-relevant right dorsolateral (DLPFC), inferior prefrontal cortex (IFC) and anterior cingulate gyrus (ACG). Additional areas of relatively reduced activation were in the parietal lobes during the Stop and Switch tasks, putamen, insula and temporal lobes during the Switch task and precuneus during the Simon task. CONCLUSIONS: This study shows first evidence that medication-naïve adolescents with MDD are characterised by abnormal function in ACG and right lateral prefrontal cortex during tasks of attention and performance monitoring, suggesting an early pathogenesis of these functional abnormalities attributed to MDD.

Rumination and negative symptoms in schizophrenia.

Rumination is thought to be an important maintaining factor in depression. Depressive symptomatology is also a prominent feature in schizophrenia. However, little is known about the relationship between rumination and symptoms, such as depression and negative symptoms, in schizophrenia. The present study examined associations between rumination and symptoms in a group of 37 stable medicated patients with schizophrenia. All participants were clinically assessed on their symptoms and completed self-reported measures of depression and rumination. The findings showed that negative symptoms, especially emotional withdrawal and stereotyped thinking, but not depressive symptomatology, were associated with rumination in the present sample of patients with schizophrenia. If the findings are replicated, interventions that reduce rumination and rigid thinking might be helpful to reduce some negative symptoms of psychosis.

Reduced activation in right lateral prefrontal cortex and anterior cingulate gyrus in medication-naïve adolescents with attention deficit hyperactivity disorder during time discrimination.

BACKGROUND: Patients with attention deficit hyperactivity disorder (ADHD) under-perform when discriminating between durations differing by several hundred milliseconds. This function involves right prefrontal and anterior cingulate (AC) brain regions, which are structurally and functionally compromised in this patient group during executive tasks. We investigated the neuro-anatomical substrates mediating fine temporal discrimination in adolescents with ADHD compared with controls, using functional magnetic resonance imaging (fMRI). METHODS: Twenty-one male medication-naïve adolescents aged 10-15 years with a DSM-IV diagnosis of ADHD (combined subtype) and without comorbid Axis I disorders (except conduct disorder) were compared to a group of 17 age- and IQ-matched healthy adolescents. Using fMRI on a 1.5T scanner, we compared brain activation and performance between adolescents with ADHD and controls during a time discrimination task contrasted with a temporal order task. RESULTS: Despite comparable performance, patients with ADHD showed decreased activation in right dorsolateral and inferior prefrontal cortex and AC during time discrimination compared with controls. CONCLUSIONS: Right hemispheric fronto-cingulate abnormalities in ADHD, previously observed during inhibitory and executive functions, are also associated with temporal perception. Furthermore, recruitment of medication-naïve patients precludes the possibility that deficits are attributable to stimulant exposure.

Cortisol levels in fingernails, neurocognitive performance and clinical variables in euthymic bipolar I disorder.

OBJECTIVES: Neurocognitive impairment has been found in bipolar patients. Hypercortisolemia is one possible cause but there has been no agreement on this. Previous sampling methods assessed only acute cortisol levels, whereas the association between cortisol and psychopathology might be better understood by investigating chronic levels. Fingernails are a novel method for measuring chronic cortisol concentration (CCC). Here, we measured CCC in euthymic bipolar disorder I (BD-I) patients and healthy controls using fingernails to investigate whether differences in CCC influenced neurocognitive performance. We also investigated whether differences in clinical illness variables influenced CCC in euthymic BD-I patients. METHODS: A previous study demonstrated neurocognitive impairment in euthymic BD-I patients. The current study included a portion of this sample: 40 BD-I versus 42 matched controls who provided fingernail samples. RESULTS: There was no statistically significant difference in CCC between controls and BD-I (P = .09). Logistic regression analyses revealed that euthymic bipolar I subjects with more than five years of current euthymia had decreased odds of having higher fingernail cortisol concentration (>71.2 pg/mg) compared to those with less than 1.5 years (P = .04). There was no association between CCC and cognitive impairment in all domains before and after adjustment for age and sex. CONCLUSIONS: The current evidence suggests CCC is not a trait biomarker in euthymic BD-I (BD-I). Longer periods of stability in affective disorders are associated with lower CCC. Fingernail cortisol does not seem to be implicated in neurocognitive impairment and BD-I. Future studies may investigate CCC in different illness phases of BD-I.

Does self-perceived mood predict more variance in cognitive performance than clinician-rated symptoms in schizophrenia?

Symptoms are known to account for a small variance in some cognitive functions in schizophrenia, but the influence of self-perceived mood remains largely unknown. The authors examined the influence of subjective mood states, psychopathology, and depressive symptoms in cognitive performance in a single investigation in schizophrenia. A group of 40 stable medicated patients with schizophrenia (20 men, 20 women) and 30 healthy comparison subjects (15 men, 15 women) were assessed on neurocognitive measures of verbal abilities, attention, executive functioning, language, memory, motor functioning, and information processing. All subjects provided self-ratings of mood prior to cognitive testing. Patients were also rated on psychopathology and depressive symptoms. Patients performed worse than comparison subjects on most cognitive domains. Within the patient group, subjective feelings of depression-dejection, fatigue-inertia, confusion, and tension-anxiety predicted (controlling for symptoms) poor performance on measures of attention, executive function, and verbal memory. In the same group of patients, clinician-rated symptoms of psychopathology and depression predicted significantly poor performance only on tests of motor function. In comparison subjects, vigor related to better, and fatigue and inertia to worse, spatial motor performance. Self-perceived negative mood state may be a better predictor of cognitive deficits than clinician-rated symptoms in chronic schizophrenia patients.

Cognitive impairment but preservation of sexual dimorphism in cognitive abilities in chronic schizophrenia.

Neurocognitive impairment in schizophrenia is well established, though sex differences on cognitive tasks have produced equivocal findings. The present study was designed to examine performance of schizophrenia patients on a sexually dimorphic cognitive battery. The cognitive battery comprising tests of spatial (mental rotation, computerized version of the Benton Judgment of Line Orientation) and verbal abilities (phonological and semantic fluency) was administered to men (n = 22) and women (n = 21) with schizophrenia and healthy controls (n = 21 men and 21 women). A series of multivariate analyses showed that the patient group performed worse than controls on all the cognitive tasks. Cognitive sexual dimorphism on all spatial tasks favoring men and verbal tasks favoring women remained. Within the patient sample, correlational data demonstrated that earlier age at onset of illness related to poorer spatial performance. It is concluded that normal sexual dimorphism is undisturbed on both spatial and verbal tasks by the schizophrenia disease process.

The Cognitive Remediation in Bipolar (CRiB) pilot study: study protocol for a randomised controlled trial.

BACKGROUND: People with bipolar disorder often show difficulties with cognitive functioning, and though these difficulties are identified as important targets for intervention, few treatment options are available. Preliminary evidence suggests that cognitive remediation therapy (a psychological treatment proven beneficial for people diagnosed as having schizophrenia) is helpful for people with bipolar disorders. We are conducting a pilot trial to determine whether individual, computerised, cognitive remediation therapy (CRT) for people with bipolar disorder 1) increases cognitive function; 2) improves global functioning, goal attainment and mood symptoms; 3) is acceptable and feasible for participants; and 4) can be addressed in a comprehensive, larger, randomised, controlled trial. METHODS/DESIGN: The study is designed as a two-arm, randomised, controlled trial comparing cognitive remediation therapy with treatment-as-usual (TAU) for euthymic bipolar patients. Participants are eligible to take part if aged between 18 and 65 with a diagnosis of bipolar disorder (type I) and currently in euthymic state, and no neurological, substance or personality disorder diagnoses. Sixty participants will be recruited (mainly through secondary and tertiary care) and will be block-randomised to receive either treatment-as-usual alone or in addition to a 12-week course of cognitive remediation therapy totalling 20-40 therapy hours. The intervention will comprise regular sessions with a therapist and computer-based training. Research assessments will take place before and after the intervention period and at a 12-week follow-up, and will include evaluation of neuropsychological, symptom-related, demographic and social factors, as well as collecting qualitative data regarding CRT expectations and satisfaction. Intention-to-treat analyses will examine the efficacy of cognitive remediation therapy primarily on cognition and additionally on functioning, quality of life and mood symptoms. Furthermore, we will examine the acceptability of CRT and undertake a preliminary health economics analysis to ascertain the cost of delivering the intervention. DISCUSSION: The results of this trial will provide valuable information about whether cognitive remediation therapy may be beneficial for people diagnosed with bipolar disorder in a euthymic state. TRIAL REGISTRATION: ISRCTN registry, ISRCTN32290525 . Registered on 2 March 2016.

The relationship of structural alterations to cognitive deficits in schizophrenia: a voxel-based morphometry study.

BACKGROUND: Region of interest studies have identified a number of structure-cognition associations in schizophrenia and revealed alterations in structure-cognition relationship in this population. METHODS: We examined the relationship of structural brain alterations, identified using voxel-based morphometry, to cognitive deficits in 45 schizophrenia patients relative to 43 healthy control subjects and tested the hypothesis that structure-cognition relationship is altered in schizophrenia. RESULTS: Patients had smaller total brain, gray matter, and white matter volumes. Regional alterations were left-hemisphere specific, including: gray matter reduction of inferior frontal, lingual, and anterior superior temporal gyri; white matter reduction of posterior and occipital lobes; and gray matter increase of the putamen and the precuneus. Smaller whole brain and gray matter volumes were associated with lower premorbid intelligence quotient (IQ) and poorer performance on IQ-dependent cognitive measures in patients and to a similar extent in control subjects. Larger precuneus was associated with better immediate verbal memory in patients, whereas verbal and nonverbal memory were positively associated with inferior frontal gyrus volume in control subjects. Smaller occipital white matter volume was associated with slower information processing speed in patients but not in control subjects. CONCLUSIONS: Regional volume alterations are associated with specific cognitive deficits in schizophrenia. Some structure-cognition relationships differentiate this population from healthy control subjects.

Sex differences and individual differences in cognitive performance and their relationship to endogenous gonadal hormones and gonadotropins.

Sexually dimorphic cognitive performance in men (n=42) and women (n=42) was related to testosterone, estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone binding globulin, measured in 10-ml blood samples collected between 0900 and 1030 and, among women, during the follicular phase of the menstrual cycle. Significant sex differences favored men on spatial tasks (Mental Rotation and Judgment of Line Orientation) and on an inhibition task and favored women on a verbal task (category fluency). However, there were no significant relationships between any of the hormones and cognitive performance, suggesting that there are few, if any, consistent, substantial relationships between endogenous, nonfluctuating levels of gonadal hormones or gonadotropins and these cognitive abilities in men or women.

Cognitive performance is impaired in euthymic Chinese patients with Bipolar 1 Disorder.

BACKGROUND: Data from euthymic patients with Bipolar Disorder (BD) has shown cognitive impairment and the notion that sufferers of BD achieve full recovery between illness episodes is questionable. These findings have not been replicated in a Chinese population. The present study examined the cognitive profile of euthymic Chinese patients with Bipolar 1 Disorder (BD-1) and matched healthy control participants. METHODS: Euthymic patients with BD-1 and matched controls (n=104 in total) completed serial measures to assess mood and also completed an IQ test and the Central Nervous System Vital Signs (CNSVS) computerized battery assessing memory (verbal and visual), executive functions, attention, psychomotor and processing speed. RESULTS: Patients with BD-1 performed worse than controls on all cognitive domains. When using 2 or more scores below the 5th percentile as a cutoff for neurocognitive impairment, 46.2% of the patients with BD-1 and none of the control sample scored in this range (p<.001). Correlational analysis among the illness variables in BD-1 revealed that cognitive performance was inversely correlated with the number of manic episodes and duration of illness. LIMITATIONS: It was not possible to determine the causal relationship between associated illness and performance. The effect of medication on cognitive performance requires further study. CONCLUSIONS: Euthymic Chinese patients with BD-1 demonstrate marked cognitive impairments and these correlated with illness parameters. Cognitive impairment in BD may be independent of language and culture.

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.

Fronto-striato-cerebellar dysregulation in adolescents with depression during motivated attention.

BACKGROUND: Pediatric major depressive disorder (MDD) is associated with deficits in sustained attention, thought to be related to underlying motivation deficits. This hypothesis, however, has never directly been tested using functional magnetic resonance imaging. In this study, we investigated the neurofunctional correlates of the interplay between attention and motivation in medication-naive pediatric MDD using a rewarded sustained attention task. METHODS: Functional magnetic resonance imaging was used to compare brain activation between 20 medication-naïve, noncomorbid, first-episode adolescents with MDD aged 13 to 18 years and 21 gender-, age-, and IQ-matched healthy adolescents. Participants performed a sustained attention task with and without a monetary reward to assess the impact of reward on sustained attention networks. RESULTS: During nonrewarded sustained attention, adolescents with MDD showed reduced activation compared with healthy control subjects in occipital cortex. When sustained attention was rewarded, however, the underactivation in adolescents with MDD was in an extensive right hemispheric network of inferior fronto-striato-thalamic attention and limbic hippocampus-anterior cingulate reward processing areas. Major depressive disorder patients showed increased activation in cerebellum, which correlated with reduced frontal activation and depressive symptoms, suggesting compensatory response. Further analysis showed that reward upregulated fronto-striatal and hippocampal/temporal activation in control subjects but deactivated these regions in MDD, with opposite effects in the cerebellum. CONCLUSIONS: Medication-naïve MDD adolescents show abnormalities in the regulation in fronto-striato-cerebellar brain regions involved in attention and reward during motivated but not unmotivated attention. This suggests a dysfunctional interplay between motivation and cognition in pediatric MDD, where motivation appears less capable of upregulating attention networks relative to healthy youths.

Methylphenidate normalizes frontocingulate underactivation during error processing in attention-deficit/hyperactivity disorder.

BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) have deficits in performance monitoring often improved with the indirect catecholamine agonist methylphenidate (MPH). We used functional magnetic resonance imaging to investigate the effects of single-dose MPH on activation of error processing brain areas in medication-naive boys with ADHD during a stop task that elicits 50% error rates. METHODS: Twelve medication-naive boys with ADHD were scanned twice, under either a single clinical dose of MPH or placebo, in a randomized, double-blind design while they performed an individually adjusted tracking stop task, designed to elicit 50% failures. Brain activation was compared within patients under either drug condition. To test for potential normalization effects of MPH, brain activation in ADHD patients under either drug condition was compared with that of 13 healthy age-matched boys. RESULTS: During failed inhibition, boys with ADHD under placebo relative to control subjects showed reduced brain activation in performance monitoring areas of dorsomedial and left ventrolateral prefrontal cortices, thalamus, cingulate, and parietal regions. MPH, relative to placebo, upregulated activation in these brain regions within patients and normalized all activation differences between patients and control subjects. During successful inhibition, MPH normalized reduced activation observed in patients under placebo compared with control subjects in parietotemporal and cerebellar regions. CONCLUSIONS: MPH normalized brain dysfunction in medication-naive ADHD boys relative to control subjects in typical brain areas of performance monitoring, comprising left ventrolateral and dorsomedial frontal and parietal cortices. This could underlie the amelioration of MPH of attention and academic performance in ADHD.