Paula Rothhammer

Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for attention-deficit/hyperactivity disorder in Chilean families.

Attention‐deficit/hyperactivity disorder, ADHD [MIM 126452], is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness, and/or inattentiveness. As part of an ongoing study of ADHD, we carried out a family‐based discordant sib‐pair analysis to detect possible associations between dopamine receptor D4 (DRD4) and dopamine transporter 1 (DAT1) polymorphisms and ADHD in Chilean families. Both loci individually classified as homozygotes or heterozygotes for the DRD4 7‐repeat and DAT1 10‐repeat alleles, did not exhibit genotype frequency differences between affected children and their healthy siblings (Fishers exact test P > 0.25 in both cases). However, the simultaneous presence of both DRD4 7‐repeat heterozygosity and DAT1 10 allele homozygosity were significantly higher (34.6%) in cases (26), compared with their unaffected siblings (25) (4%; Fishers exact test P = 0.0096; odds‐ratio, OR = 12.71). Increased density of dopamine transporter in ADHD brains, along with abundance of 7‐repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene–gene interaction worthy of further incisive studies.

Attention-deficit hyperactivity disorder involves differential cortical processing in a visual spatial attention paradigm

OBJECTIVE Inattention is undoubtedly one of the main characteristics of Attention-deficit hyperactivity disorder (ADHD). Nevertheless, a growing corpus of evidence shows that not all attentional processes are affected in this condition. This study aimed to explore the distribution of attentional resources in children with ADHD via a spatially shifted double-oddball visual task. METHODS We recorded event-related potentials (ERPs) for all visual stimuli. Subjects were instructed to allocate attention in a specific area of visual space while ignoring all stimuli presented outside. Ten male children (age: 9-14; mean = 11.6 +/- 2.1) who met DSM-IV criteria for the ADHD combined subtype participated in the study, along with ten age- and sex-matched healthy controls (9-14; mean = 11.2 +/- 2.3). RESULTS ADHD subjects showed late differential cortical responses to initially suppressed irrelevant stimuli. The amplitude of early N1-P1 components were mainly modulated by stimulus location and showed no significant differences between groups, but a late P300-like positivity was clearly evoked in the ADHD group by peripheral stimuli. CONCLUSIONS These results suggest that ADHD may not compromise the early attentional spatial filter but rather entails a different distribution of attentional resources at later stages of cortical processing. Perhaps these differences may be attributable to individual differences in attentional mechanisms. SIGNIFICANCE ADHD may not affect initial focusing of visual attention but rather the allocation of processing resources in later stages.

Effect of psychostimulants on distinct attentional parameters in attentional deficit/hyperactivity disorder.

Although there is extensive literature about the effects of stimulants on sustained attention tasks in attentional deficit/hyperactivity disorder (ADHD), little is known about the effect of these drugs on other attentional tasks involving different neural systems. In this study we measured the effect of stimulants on ADHD children, both in the electroencephalographic (EEG) activity during sustained attentional tasks and in psychometric performance during selective attentional tasks. These tasks are known to rely on different cortical networks. Our results in children medicated with 10 mg of d-amphetamine administered 60 min before the study indicate (i) a significant increase in amplitude but not latency of the P300 component of the event-related potential (ERP) during the sustained attentional task and (ii) a significant improvement in the reaction times and correct responses in the selective attentional task. In addition to supporting the use of stimulants in children with attentional deficit/hyperactivity disorder, these results show a multifocal activity improvement of cortical structures linked to dopamine, and interestingly, to attention. All these analyses are framed in a wider study of diverse attentional functions in this syndrome.

Electrophysiological Evidences of Inhibition Deficit in Attention-Deficit/Hyperactivity Disorder During the Attentional Blink

Previous studies on the distribution of attentional resources during time have yielded a differential performance in patients with Attention-Deficit/Hyperactivity Disorder (ADHD), in relation to healthy controls. The Attentional Blink (AB) experimental paradigm probes the ability to discriminate visual stimuli in close temporal proximity. The electro- physiological mechanisms underlying the AB have been intensively studied in healthy individuals, and seems to be very appropriate to evaluate the temporal distribution of attentional resources in ADHD. We recorded Event-Related Potentials (ERPs) to stimuli arranged in a rapid serial visual presentation task. Fourteen male children (age: 11.6±2.1) who met DSM-IV criteria for ADHD of the combined subtype participated in the study, along with fourteen age and sex-matched healthy controls (11.2±2.3). They were all screened to discard comorbidites. Behavioral responses showed an increased number of commission and omission errors in the ADHD group. Nonetheless, both groups exhibited a significant AB for probes presented in close temporal proximity to targets. ERP waveforms in ADHD showed a P300 component of reduced amplitude, elicited both by detected and undetected probes. However, in the control group the P300 was only elicited by detected probes and its amplitude was larger. As the P3 component is considered to reflect context updating in working memory, its elicitation by missed probes during the attentional blink suggests a failure of an inhibitory selection mecha- nism in ADHD.

Riesgo de déficit atencional/hiperactividad en escolares Aymara, Rapa-Nui y de Santiago de Chile: Posible contribución de polimorfismos genéticos del sistema dopaminérgico

BACKGROUND Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness or inattentiveness. AIM To search for differences in risk for ADHD and its components among Chilean native and mixed populations and to look forpossible associations with dopamine receptor D4 (DRD4) and dopamine transporter 1 (DAT1) polymorphisms. MATERIAL AND METHODS School teachers were requested to complete the Conners test, which uses DSM-IV criteria, to screen for ADHD risk among Aymara and Rapa-Nui students. RESULTS Rapa-Nui children from Easter Island had the highest risk of hyperactivity/impulsiveness. Aymara children from the Arica-Parinacota Region had lower scores. Although inattentiveness scores had lower differences between groups, overall ADHD score differences among studied populations were highly significant. DRD4 and DAT1 alleles had a heterogeneous distribution. Easter islanders had more divergent frequencies, mostprobably as a result of separate migration routes utilized at different timeperiods during the colonization of America and Polynesia. CONCLUSIONS The comparison of ADHD risk parameters between Rapa-Nui and Aymara children showed marked differences. Allele distri-bution of dopamine polymorphisms in Easter Island was also significantly different from northern Chile, due probably to different colonization histories. These findings suggest that higher ADHD risk scores in Easter Island children may be linked to the presence of different DRD4 alleles.

DRD4 dopamine receptor alleles in Chilean students of different ethnic origin and its relation with the risk for attention deficit/hyperactivity disorder

BACKGROUND Worldwide diversity of alleles of D4 receptor gene (DRD4), linked to attention deficit hyperactivity disorder (ADHD), is mostly the result of length and single nucleotide polymorphisms in a 48-bp tandem repeat (VNTR). Alleles containing from two (2R) to eleven (11R) repeats have been identified. The most common are 4R, 7R and 2R. AIM To study the association of ADHD risk with DRD4 genotypes in Chilean students. SUBJECTS AND METHODS ADHD risk data were obtained through the abbreviated Conners Scale for School Teachers in 66 Aymara children (11 cases and 55 controls), 91 Rapa-Nui children (60 cases ad 31 controls) and 96 children from a mixed urban population from Santiago (51 cases and 45 controls). DNA extracted from saliva was amplified by polymerase chain reaction (PCR) to genotype the DRD4 VNTR. RESULTS The distribution of DRD4 alleles reveals that, beneath the 4R allele, 7R exhibits the second highest frequencies in Aymara and Santiago children. In Polynesian children, 2R ranks after 4R. A statistically significant association between ADHD risk and 2R/4R genotype was identified in Polynesian children (p < 0.05; odds ratio = 3.7). CONCLUSIONS Different DRD4 genotypes are associated with ADHD phenotype in Chilean populations, probably as a consequence of their initial colonization history.

Trastorno por déficit de atención e hiperactividad en niños aymara: primera aproximación clínica

BACKGROUND The assessment of Attentional Deficit Hyperactivity Disorder (ADHD) among ethnic groups may reveal environmental or cultural variables that influence the appearance of this disorder. AIM To assess the presence and characteristics of ADHD in two communities of the inland Arica valleys (Azapa and Lluta), where the Aymara population predominates. MATERIAL AND METHODS Starting from a screening based on the Conners test, we evaluated 79 children aged 8 to 13 years. Sixty children were of Aymara origin and 19 children were of non-Aymara origin. Twenty Aymara and 9 non-Aymara children had ADHD. They were compared with a group of patients from Santiago, Chile (110 children) that were previously assessed. RESULTS Patients from Azapa/Lluta displayed similar characteristics to those from Santiago. However the former had significantly less psychiatric comorbidities than the latter. On the other hand, the non-Aymara subgroup of Azapa/Lluta displayed an increased rate of comorbidities and was exclusively of the combined subtype, although their sample size is too small to draw strong conclusions. CONCLUSIONS Although we cannot dismiss biological variables, the importance of family values and the respect to authorities may be protective factors for ADHD, associated to Aymara culture. Our findings suggest that the clinical characteristics of ADHD are not uniform among ethnic groups and cultures. The relative contribution of environmental and genetic factors in this variability remain to be determined.

Déficit atencional con hiperactividad trastorno multicausal de la conducta con heredabilidad y comorbilidad genética moderadas

This review aims to summarize information about the genetic etiology of attention deficit disorder with hyperactivity (ADHD), with particular reference to the contributions of our research group. We also discuss the genetic comorbidity estimated from genome-wide single nucleotide polymorphisms (SNP´s) between ADHD and major psychiatric disorders such as schizophrenia (E), major depressive disorder (MDD), bipolar disorder (BD) and autism spectrum disorders (ASD). A high genetic comorbidity was found between E and BD (46%), a moderate comorbidity between MDD and E, MDD and BD and MDD and ADHD (18%, 22% and 10% respectively) and a low comorbidity between E and ASD (2.5%). Furthermore, we show evidence concerning the genetic determination of psychiatric diseases, which is significantly lower when it is estimated from genome-wide SNP´s rather than using traditional quantitative genetic methodology (ADHD = E = 23%, BD = 25%, MDD = 21% and ASD = 17%). From an evolutionary perspective, we suggest that behavioral traits such as hyperactivity, inattention and impulsivity, which play a role in ADHD and perhaps also other hereditary traits which are part of major psychiatric disorders, could have had a high adaptive value during the early stages of the evolution of Homo sapiens. However, they became progressively less adaptive and definitively disadvantageous, to the extreme that they are involved in frequently diagnosed major psychiatric disorders.This review aims to summarize information about the genetic etiology of attention deficit disorder with hyperactivity (ADHD), with particular reference to the contributions of our research group. We also discuss the genetic comorbidity estimated from genome-wide single nucleotide polymorphisms (SNP´s) between ADHD and major psychiatric disorders such as schizophrenia (E), major depressive disorder (MDD), bipolar disorder (BD) and autism spectrum disorders (ASD). A high genetic comorbidity was found between E and BD (46%), a moderate comorbidity between MDD and E, MDD and BD and MDD and ADHD (18%, 22% and 10% respectively) and a low comorbidity between E and ASD (2.5%). Furthermore, we show evidence concerning the genetic determination of psychiatric diseases, which is significantly lower when it is estimated from genome-wide SNP´s rather than using traditional quantitative genetic methodology (ADHD = E = 23%, BD = 25%, MDD = 21% and ASD = 17%). From an evolutionary perspective, we suggest that behavioral traits such as hyperactivity, inattention and impulsivity, which play a role in ADHD and perhaps also other hereditary traits which are part of major psychiatric disorders, could have had a high adaptive value during the early stages of the evolution of Homo sapiens. However, they became progressively less adaptive and definitively disadvantageous, to the extreme that they are involved in frequently diagnosed major psychiatric disorders.

Genetic and Evolutionary Contributions to the Etiology of Attention Deficit Hyperactivity Disorder

We review progress made concerning the participation of candidate genes in the determination of attention deficit disorder with hyperactivity (ADHD) as well as recent evidence on its genetic determination based on molecular methodology. In addition to linkage analyses, we discuss recent results obtained through genome-wide association studies (GWAS). We also discuss the genetic comorbidity estimated between ADHD and major psychiatric disorders such as schizophrenia (E), major depressive disorder (MDD), bipolar disorder (BD), and autism spectrum disorders (ASD). Furthermore, we examine both the geographical distribution of DRD4 and cross-ethnic variation of ADHD risk in Chilean children. Finally, visualizing ADHD from an evolutionary perspective, we suggest that behavioral traits such as hyperactivity, inattention, impulsivity, and sexual arousal, which play a role in ADHD could have had a high adaptive value during the early stages of the evolution of Homo sapiens but turned progressively less adaptive and more recently definitively disadvantageous.Attention deficit hyperactivity disorder (ADHD) is classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) as a neurodevelopmental disorder characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity. This disorder is often associated with school learning difficulties and adjustment problems in children and adolescents and psychotropic substance consumption, alcohol abuse and risky behavior in adults. ADHD is one of the most frequently diagnosed neuropsychiatric disorders with a prevalence between 2 and 7% worldwide [1]. As with several psychiatric disorders, there is a diversity of approaches and/or positions concerning their presumed etiology. At one end of the spectrum are authors who still deny its existence as a disorder of biological origin and on the other, researchers who argue that it is a predominantly genetic disease with very high heritability [2].