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PubMed2006

Remission versus response as the goal of therapy in ADHD: a new standard for the field?

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has a substantial negative impact; however, within long-term follow-up studies, a proportion of patients do very well, both symptomatically and functionally, suggesting that the lower the symptom burden, the greater the functional improvements. Studies in major depressive disorder have identified a relationship between symptomatic remission and restoration of normal functioning. OBJECTIVE: The purpose of this article was to propose a definition of remission in ADHD, review remission rates in clinical trials for commonly used medications, and explore the relationship between symptomatic remission and optimal functioning. METHODS: Remission and response rates for medications were obtained through MEDLINE searches of English-language citations (1999-2005) and meeting abstracts (2003-2005) using the terms amphetamine, atomoxetine, methylphenidate, ADHD, efficacy, effectiveness, and controlled trial, as well as hand searches of efficacy studies. Evidence from randomized controlled trials, as well as effectiveness studies, where the proportions of patients achieving predefined cutoff points for remission or response are reported, was reviewed. Because higher remission rates were identified with the oral, osmotic, controlled-release system (OROS) of methylphenidate, a relationship between symptomatic response/remission and optimal functioning was explored further. RESULTS: Remission in ADHD should be defined as a loss of diagnostic status, minimal or no symptoms, and optimal functioning when individuals are being treated with or without medication. Symptomatic remission can be operationalized as a mean total score of S1 on most standardized questionnaires. For the medications examined (OROS methylphenidate, immediate-release methylphenidate, atomoxetine, and mixed amphetamine salts), response rates were comparable at approximately 70% to 75%; however, remission rates were higher with OROS methylphenidate compared with either immediate-release methylphenidate or atomoxetine (remission rates with amphetamines were not found). Benefits, including decreased illness burden as well as improved psychosocial and academic functioning, were associated with treatment versus no treatment and were greater with medication that offered higher remission rates. CONCLUSIONS: The literature provided evidence that greater symptom improvements are associated with greater functional improvements, emphasizing that remission of ADHD as defined should be the goal of therapy. Treatment ought to include the early use of strategies with the greatest chance of achieving remission. Future clinical research should use remission as the primary outcome.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

Exanthematic diseases during pregnancy and attention-deficit/hyperactivity disorder (ADHD).

Rash causing viral diseases may be transmitted during pregnancy, causing severe congenital disease. Although neurological and psychiatric disorders are common consequences of congenital rubella, children born to women who developed a viral rash during pregnancy do not appear to be at increased risk of these disorders if they were asymptomatic at birth. In a case-control study conducted to evaluate risk factors for ADHD, we found an increased risk of this disorder among children born to women experiencing a viral rash during pregnancy. The viral rash (i.e. measles, varicella, or rubella) was reported by 4 of 71 mothers of children with ADHD and none of the 118 controls' mothers (P<0.01). The difference remained statistically significant after adjusting for potential confounders (i.e. other factors found associated with ADHD, such as gender and familiarity). Although, the viral disease reported by the mothers, in accordance with their physician's diagnosis, did not represent a homogeneous nosological group, the unexpectedly high rate found among ADHD cases' mothers suggest a role for viral diseases occurring during pregnancy in the development of ADHD.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Seasonality of mood disorders in adults with lifetime attention-deficit/hyperactivity disorder (ADHD).

BACKGROUND: The objective of this study was to estimate the prevalence of Seasonal Affective Disorder (SAD) in adults with lifetime Attention-Deficit/Hyperactivity Disorder (ADHD). METHOD: Patients eligible for this study had lifetime impairing symptoms of ADHD and a current and/or past co-morbid mood disorder according to their medical record. The Seasonal Pattern Assessment Questionnaire (SPAQ) was administered by a telephone interview to assess seasonality. RESULTS: The overall rate of SAD in this clinical population of adults with ADHD was estimated at 27%. Females were more at risk to develop SAD than men. LIMITATIONS: The SPAQ is a screening, not a diagnostic instrument. CONCLUSIONS: SAD symptoms are frequently comorbid with ADHD in adults. These results have clinical relevance for the recognition and treatment of SAD with bright light therapy in adults with ADHD.

Adolescent↗

PubMed2006

Algorithmically designed peptides ameliorate behavioral defects in animal model of ADHD by an allosteric mechanism.

This study exemplifies the use of three ADHD-relevant methodological innovations. (1) The use of novel, patented, computational peptide design techniques to generate peptides targeting the extra-cellular and para-transmembrane amino acid loops of the putatively ADHD-involved, D(2) dopamine receptor, D(2)DAR; (2) experimental evidence that these peptides in L-amino acid/ortho ordered or D-amino acid/reverse ordered (retro-inverso), D(2)DAR, hydrophobic eigenmode matched forms, evoked positive allosteric and indirect agonist influences on in vitro stably receptor transfected CHO and LtK cells and on in vivo, brain mediated activity; (3) a representative 15 residue all-D-amino acid, D(2) mode matched peptide, given parenterally, was found to "repair" a key aberrant ADHD behavioral characteristic in a standard animal model of ADHD, the Spontaneously Hypertensive Rat, SHR, relative to its progenitor species control, the Wistar-Kyoto rat, WKY. The representative, retro-inverso peptide, all-D-LLYKNKPRYPKRNRE, reversed SHR's relative deficiency in sensory motor gating (pre-pulse inhibition, PPI) while leaving SHR's nonselective attention (rearings), impulsive behavior (time in center), and activity level (timed total motor behavior) unchanged. Amphetamine also reversed SHRs sensory gating defect, but with significant increases in nonselective attention, impulsivity and hyperactivity. These preliminary results suggest the possibility of a new, "softer" pharmacological approach to ADHD: hydrophobic mode matched peptide allosteric augmentation of the activity of indigenous dopamine with respect to D(2)DAR mediated function, in place of stimulant drug-induced presynaptic dopamine release or impairment of dopamine uptake.

Acoustic Stimulation↗

PubMed2005

Temporal information processing in ADHD: findings to date and new methods.

The ability to perceive and represent time is a fundamental but complex cognitive skill that allows us to perceive and organize sequences of events and actions, and to anticipate or predict when future events will occur. It is a multidimensional construct, and a variety of methods have been used to understand timing performance in ADHD samples, which makes it difficult to integrate findings across studies. While further replication is needed, growing evidence links ADHD to problems in several aspects of temporal information processing, including duration discrimination, duration reproduction, and finger tapping. Neuroimaging studies of ADHD have also implicated cerebellar, basal ganglia, and prefrontal regions of the brain, which are believed to subserve temporal information processing. This line of research implicates more basic cognitive mechanisms than previously linked with ADHD and challenges researchers to develop and utilize innovative, multidisciplinary, scientific methods to dissect the various components of temporal information processing. Recent advances in neuroimaging, such as magnetoencephalography in collaboration with structural magnetic resonance imaging, can discriminate temporal processing at the level of a millisecond. This approach can lay the groundwork to provide a more precise understanding of neural network activity during different aspects and stages of temporal information processing in ADHD.

Attention Deficit and Disruptive Behavior Disorder↗

PubMed2026

The effect of tDCS on emotion-related risk-taking behavior and delay discounting in adults with ADHD.

INTRODUCTION: Adults with Attention Deficit Hyperactivity Disorder (ADHD) often engage in risky behaviors due to impaired decision-making processes. This study aims to investigate the effects of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC) on emotion-related risk-taking behavior and delay discounting in adults with ADHD. METHODS: Thirty adults with ADHD underwent three tDCS conditions, administered in a randomized order with at least one week between sessions: (1) left dlPFC anode/right vmPFC cathode, (2) left dlPFC cathode/right vmPFC anode, and (3) sham stimulation. In each session, participants completed the Delay Discounting Task (DDT) and the Modified Balloon Analogue Risk Task (mBART) under three emotional conditions (neutral, positive, and negative) which were induced using emotionally congruent photographs and sounds. Galvanic skin responses (GSR) were also recorded. In the DDT, both area under the curve (AUC) values and log-transformed discounting rates (log k) were calculated for small, medium, and large reward magnitudes (RM). Exploratory electric field modeling was also performed to characterize current distribution. RESULTS: The findings demonstrated task-specific effects of tDCS on decision-making. Although no overall tDCS effect was observed on DDT performance, significant tDCS × RM interactions emerged, particularly for smaller rewards. In contrast, exploratory analyses suggested that tDCS affected all mBART scores. Emotional condition did not influence consistently behavioral performance in either task, whereas both emotional stimulation and tDCS significantly affected GSR responses. However, exploratory electric field modeling indicated a broad prefrontal current distribution extending beyond the intended cortical targets. CONCLUSIONS: These findings suggest preliminary evidence that prefrontal tDCS can influence risk-related decision-making and autonomic responses in adults with ADHD. However, its effects on delay discounting appear to be context-dependent and limited to specific RMs. Future studies combining neuroimaging with individualized electric field modeling are needed to clarify the neural mechanisms underlying the observed effects of tDCS and to optimize stimulation protocols in adults with ADHD.

Humans↗

PubMed2003

The top and the bottom of ADHD: a neuropsychological perspective.

Five models of attention deficit/hyperactivity disorder (ADHD) are reviewed. It is proposed that the cognitive-energetic model provides a reasonably comprehensive account of ADHD by incorporating the features of both the inhibition and delay aversion models. It is suggested that ADHD can only be accounted for by an analysis at three levels: top-down control, specific cognitive processes and energetic factors. It is argued that a refined and conceptually comprehensive neuropsychological battery is needed to advance research in ADHD. A widely distributed neural network involving frontal, basal ganglia, limbic and cerebellar loci seem implicated in ADHD.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

ADHD and schizophrenia phenomenology: visual scanpaths to emotional faces as a potential psychophysiological marker?

Commonalities in the clinical phenomenology and psychopharmacology of ADHD and schizophrenia are reviewed. The potential of psychostimulants to produce psychotic symptoms emphasizes the need for objective psychophysiological distinctions between these disorders. Impaired emotion perception in both disorders is discussed. It is proposed that visual scanpaths to facial expressions of emotion might prove a potentially useful psychophysiological distinction between ADHD and schizophrenia. There is consistent evidence that both facial affect recognition and scanpaths to facial expressions are impaired in schizophrenia, with emerging empirical evidence showing that facial affect recognition is impaired in ADHD also. Brain imaging studies show reduced activity in the medial prefrontal and limbic (amygdala) brain regions required to process emotional faces in schizophrenia, but suggest more localized loss of activity in these regions in ADHD. As amygdala activity in particular has been linked to effective visual scanning of face stimuli, it is postulated that condition-specific breakdowns in these brain regions that subserve emotional behavior might manifest as distinct scanpath aberrations to facial expressions of emotion in schizophrenia and ADHD.

Amygdala↗

PubMed2005

Family-based association study of DAT1 and DRD4 polymorphism in Korean children with ADHD.

Although the etiology of Attention Deficit/Hyperactivity Disorder (ADHD) is not well understood, evidence from the family and twin studies suggest that ADHD is familial and highly heritable. The aim of the study was to test whether dopamine transporter gene (DAT1) and dopamine receptor D4 gene (DRD4) polymorphisms are in linkage disequilibrium with ADHD in Korean children, using a family-based association study. One hundred and twenty-six trios were studied and 87% of probands were boys (mean age=8.2 years, mean IQ=104). ADHD not otherwise specified (NOS) was the most common subtype and comorbidity rates were low. Descriptive analysis and the TDT test were the primary analyses. In exploratory analyses, logistic regression and QTDT were performed. The 10-repeat allele and 4-repeat allele were the most frequent for DAT1 and DRD4. TDT test for DAT1 and DRD4 did not show preferential transmission. Based on logistic regression and QTDT, the 5-repeat allele of DRD4 may confer protection for hyperactive-impulsivity symptom severity compared to the 4-repeat allele. The negative TDT finding between DAT1 and DRD4 VNTR polymorphisms and ADHD should be interpreted with caution; partly due to lack of power caused by low heterozygosity in the study population. Future studies are necessary to test the hypothesis generated in this study that the 5-repeat allele of DRD4 is protective for hyperactive-impulsivity symptom severity compared to the 4-repeat allele.

Analysis of Variance↗

PubMed2005

Atypical brain laterality in adults with ADHD during dichotic listening for emotional intonation and words.

Few studies directly examined the nature of hemispheric specialization and interaction in ADHD. The present experiment investigated left/right brain dynamics in unmedicated right handed adults with ADHD (n = 19) and in controls (n = 19), using a dichotic listening task to assess hemispheric differences in word and emotion recognition. We also assessed how focusing attention on a single ear modulated lateralized performance and affected cross-callosal interference effects. Analysis of variance indicated that ADHD subjects showed reduced left hemisphere specialization, were better at processing emotions, and worse at processing words compared to controls. These differences were eliminated during focused attention. Finally, during presumed right hemisphere processing of linguistic stimuli, subjects with ADHD showed reduced left hemisphere interference. We concluded that ADHD subjects demonstrated greater right hemisphere and reduced left hemisphere contribution during this task relative to controls. We posit that these hemispheric differences were due to management or use of available cognitive resources rather than inherent capacity.

Acoustic Stimulation↗

PubMed2005

Supplementation with flax oil and vitamin C improves the outcome of Attention Deficit Hyperactivity Disorder (ADHD).

Considerable clinical and experimental evidence now supports the idea that deficiencies or imbalances in certain highly unsaturated fatty acids may contribute to a range of common developmental disorders including Attention Deficit Hyperactivity Disorder (ADHD). Few intervention studies with LCPUFA supplementation have reported inconsistent and marginal results. This pilot study evaluates the effect of alpha linolenic acid (ALA)-rich nutritional supplementation in the form of flax oil and antioxidant emulsion on blood fatty acids composition and behavior in children with ADHD. Post-supplementation levels of RBC membrane fatty acids were significantly higher than pretreatment levels as well as the levels in control. There was significant improvement in the symptoms of ADHD reflected by reduction in total hyperactivity scores of ADHD children derived from ADHD rating scale.

Ascorbic Acid↗

PubMed2000

Smooth pursuit eye movements in schizophrenia and attentional dysfunction: adults with schizophrenia, ADHD, and a normal comparison group.

BACKGROUND: Smooth pursuit eye movement (SPEM) abnormalities are found in schizophrenia. These deficits often are explained in the context of the attentional and inhibitory deficits central to schizophrenia psychopathology. It remains unclear, however, whether these attention-associated eye movement abnormalities are specific to schizophrenia or are a nonspecific expression of attentional deficits found in many psychiatric disorders. Adult attention-deficit/hyperactivity disorder (ADHD) is an alternative disorder with chronic attentional and inhibitory dysfunction. Thus, a comparison of SPEM in adult schizophrenia and adult ADHD will help assess the specificity question. METHODS: SPEM is recorded during a 16.7 degrees per second constant velocity task in 17 adults with ADHD, 49 adults with schizophrenia, and 37 normal adults; all groups included individuals between ages 25-50 years. RESULTS: Smooth pursuit gain and the frequency of anticipatory and leading saccades are worse in schizophrenic subjects, with normal and ADHD subjects showing no differences on these variables. CONCLUSIONS: Many attention-associated SPEM abnormalities are not present in most subjects with ADHD, supporting the specificity of these findings to the attentional deficits seen in schizophrenia.

Adult↗

PubMed2003

Differential patterns of striatal activation in young children with and without ADHD.

BACKGROUND: Cognitive control, defined as the ability to suppress inappropriate thoughts and actions, is compromised in attention-deficit/hyperactivity disorder (ADHD). This study examines the neural basis of this deficit. METHODS: We used a paradigm that incorporates a parametric manipulation within a go/nogo task, so that the number of go trials preceding a nogo trial is varied to tax the neural systems underlying cognitive control with increasing levels of interference. RESULTS: Using this paradigm in combination with event-related functional magnetic resonance imaging (fMRI), we show that children without ADHD have increased susceptibility to interference with increasing numbers of go trials preceding a nogo trial, but children with ADHD have difficulty even with a single go trial preceding a nogo trial. In addition, children with ADHD do not activate frontostriatal regions in the same manner as normally developing children, but rather rely on a more diffuse network of regions, including more posterior and dorsolateral prefrontal regions. CONCLUSIONS: Normal immature cognition may be characterized as being susceptible to interference and supported by the maturation of frontostriatal circuitry. ADHD children show a slightly different cognitive profile at 6 to 10 years of age that is paralleled by a relative lack of or delay in the maturation of ventral frontostriatal circuitry.

Attention Deficit Disorder with Hyperactivity↗

PubMed2001

Evolutionary recasting: ADHD, mania and its variants.

This paper reviews clinical observations and evolutionary theory in relation to attention deficit hyperactivity disorder (ADHD) on the one hand and mania and its variants on the other. Both groups of disorders resemble each other in regard to high levels of motor activity, perhaps occurring together more often than not, and are confounded in most existing research. Making distinctions requires isolating the contribution of activity level from other characteristics such as those of flawed executive functions for ADHD or grandiosity and lapses in reciprocity for mania. High activity level is an asset throughout nature except in extreme intensities or when it amplifies the characteristics of psychopathology. Fitness, social displays, and behavioral adaptations for survival are clues to some aspects of hypomania and ADHD. While hypomania can be a competitive advantage in certain niches, it appears there can be few opportunities for ADHD to do so. Indeed, the impulsiveness seen in ADHD is probably the outcome of flaws in executive functions rather than being the cause of them. Neither lapses in executive functions nor in reciprocity are apt to be domain general but may interact sharply with each person's repertoire of psychological adaptations. The author submits that a theoretical orientation as outlined here would not only help in better understanding the disorders under consideration, but could be useful in providing new directions to treatment decisions.

Adaptation, Psychological↗

PubMed1998

Prepubertal and young adolescent bipolarity versus ADHD: assessment and validity using the WASH-U-KSADS, CBCL and TRF.

BACKGROUND: This addendum to 'Prepubertal and early adolescent bipolarity differentiate from ADHD by mania criteria; grandiose delusions; ultra-rapid or ultradian cycling' (in this volume) provides (1) a description of Washington University at St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) with sample sections (hypersexuality, rapid cycling); (2) a comparison of WASH-U-KSADS to KSADS-P/L and KSADS-1986 and (3) a comparison of WASH-U-KSADS to Child Behavior Checklist (CBCL) and Teachers Report Form (TRF) data. METHODS: Data were from the first 60 bipolar (BP) and first 60 ADHD subjects of 270 consecutively ascertained cases (90 BP, 90 ADHD and 90 community controls) in the NIMH funded 'Phenomenology and Course of Pediatric Bipolarity' study. Comprehensive assessments included the WASH-U-KSADS (administered blindly to mothers and separately to children), CBCL and TRF. RESULTS: As reported elsewhere in this volume, WASH-U-KSADS data significantly differentiated BP and ADHD groups. Significant differences were also found with the parent-rated CBCL and the teacher-rated TRF, thereby providing cross-modality and cross-informant validation of the WASH-U-KSADS. Because of the close agreement with published CBCL data from another investigator, cross-site validation also occurred. LIMITATIONS: Venues for consecutive ascertainment from the lowest socioeconomic status classes were unavailable due to current health care policies. CLINICAL RELEVANCE: CBCL and TRF data separated BP from ADHD groups, largely by non-specific externalizing dimensions (e.g., hyperactivity, aggressivity). Clinically relevant differentiation by categorical mania-specific criteria (e.g., elated mood, grandiosity, racing thoughts) occurred with WASH-U-KSADS data. Both types of data are crucial for genetic and neurobiological studies.

Adolescent↗

PubMed2000

Eye movement task measures inhibition and spatial working memory in adults with schizophrenia, ADHD, and a normal comparison group.

Schizophrenia and attention deficit/hyperactivity disorder (ADHD) are both associated with deficits in inhibition and working memory, although in ADHD the working memory deficit is hypothesized to be secondary to the inhibitory deficit. This similarity in cognitive processes has been paralleled by similarities across the two groups in the performance of working memory and inhibition tasks. The delayed oculomotor response task is an alternative task, which may allow greater separation of working memory from inhibitory components, and thus its use may provide additional information on primary vs. secondary deficits in these disorders. Ten young adult ADHD sufferers, 10 schizophrenic subjects, and 10 normal subjects were matched on age, gender, and education. Eye movements were recorded during delayed oculomotor response tasks with 1- and 3-s delays. Both the ADHD and the schizophrenic subjects demonstrated dis-inhibition (an increased percentage of premature saccades); however only schizophrenic subjects demonstrated an impaired working memory (decreased spatial accuracy of the remembered saccade). The results are consistent with the hypothesis that working memory is a primary deficit in schizophrenia, but secondary to the inhibitory deficit in ADHD.

Adult↗

PubMed2002

Attention-deficit/hyperactivity disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes.

Inattentiveness, overactivity and impulsiveness are presently regarded as the main clinical symptoms of attention-deficit/hyperactivity disorder (ADHD). Inattention is, however, a characteristic of most psychiatric disorders. It is argued that the ADHD Inattentive subtype may have heterogeneous origins and be qualitatively different from the ADHD Hyperactive/Impulsive subtype. At the neurobiological level, ADHD symptoms may to a large extent be caused by a dysfunctioning dopamine system: A dysfunctioning meso-limbo-cortical dopamine branch will produce altered reinforcement and extinction processes, on a behavioural level giving rise to deficient sustained attention, hyperactivity, motor and cognitive impulsiveness. A dysfunctioning nigro-striatal dopamine branch will cause 'extrapyramidal' symptoms. Our model disentangles the behaviours usually explained by 'executive functions' into cognitive impulsiveness, motor impulsiveness and deficient motor control. The various dopaminergic branches may not be equally dysfunctional in all individuals with ADHD. Etiologically, dopamine dysfunctioning will probably mainly be genetically determined while sometimes be induced by environmental factors like drugs of abuse or pollutants, which may explain geographical differences in prevalence rates.

Animals↗

PubMed2004

Response disinhibition may be explained as an extinction deficit in an animal model of attention-deficit/hyperactivity disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a disorder affecting between 2 and 12% of grade-school children disturbing social, academic, and occupational functioning. Problems related to social adjustment and functioning and/or psychiatric problems will exist in 50-70% of adolescents and young adults diagnosed with ADHD as children. It has been suggested that altered reinforcement and extinction processes may cause the symptoms of ADHD. The present study investigated extinction processes in spontaneously hypertensive rats (SHR), possibly the best-validated animal model of ADHD. Extinction was tested after either a variable interval (VI) or a fixed interval (FI) schedule of reinforcement with and without the presence of a conditioned reinforcer (light in the water cubicle). The results indicate a slower extinction process in the SHR compared to the normal controls, especially during the initial transition from scheduled reinforcement to extinction. Also, more responses were retained in the SHR during the later part of extinction. The extinction deficit in the SHR may be linked to reinforcer unpredictability and the presence of conditioned reinforcers, and may explain response disinhibition seen in children with ADHD.

Analysis of Variance↗