Ximena Carrasco

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.

The alien hand syndrome: classification of forms reported and discussion of a new condition

Abstract.The term “alien hand” refers to a variety of clinical conditions whose common characteristic is the uncontrolled behavior or the feeling of strangeness of one extremity, most commonly the left hand. Acommon classification distinguishes between the posterior or sensory form of the alien hand, and the anterior or motor form of this condition. However, there are inconsistencies, such as the phenomenon of diagonistic dyspraxia, which is largely a motor syndrome despite being more frequently associated with posterior callosal lesions. We discuss critically the existing nomenclature and we also describe a case recently reported by us which does not fit any previously reported condition, termed agonistic dyspraxia. We propose that the cases of alien hand described in the literature can be classified into at least five broad categories: (i) diagonistic dyspraxia and related syndromes, (ii) alien hand, (iii) way-ward hand and related syndromes, (iv) supernumerary hands and (v) agonistic dyspraxia.

Plasticity in primary somatosensory cortex resulting from environmentally enriched stimulation and sensory discrimination training

We studied primary-somatosensory cortical plasticity due to selective stimulation of the sensory periphery by two procedures of active exploration in adult rats. Subjects, left with only three adjacent whiskers, were trained in a roughness discrimination task or maintained in a tactile enriched environment. Either training or enrichment produced 3-fold increases in the barrel cortex areas of behaviorally-engaged whisker representations, in their zones of overlap. While the overall areas of representation expanded dramatically, the domains of exclusive principal whisker responses were virtually identical in enriched vs normal rats and were significantly smaller than either group in roughness discrimination-trained rats. When animals were trained or exposed to enriched environments with the three whiskers arrayed in an are or row, very equivalent overlaps in representations were recorded across their greatly-enlarged whisker representation zones. This equivalence in distortion in these behavioral preparations is in contradistinction to the normal rat, where overlap is strongly biased only along rows, probably reflecting the establishment of different relations with the neighboring cortical columns. Overall, plasticity phenomena are argued to be consistent with the predictions of competitive Hebbian network plasticity.

Irrelevant stimulus processing in ADHD: catecholamine dynamics and attentional networks.

A cardinal symptom of attention deficit and hyperactivity disorder (ADHD) is a general distractibility where children and adults shift their attentional focus to stimuli that are irrelevant to the ongoing behavior. This has been attributed to a deficit in dopaminergic signaling in cortico-striatal networks that regulate goal-directed behavior. Furthermore, recent imaging evidence points to an impairment of large scale, antagonistic brain networks that normally contribute to attentional engagement and disengagement, such as the task-positive networks and the default mode network (DMN). Related networks are the ventral attentional network (VAN) involved in attentional shifting, and the salience network (SN) related to task expectancy. Here we discuss the tonic–phasic dynamics of catecholaminergic signaling in the brain, and attempt to provide a link between this and the activities of the large-scale cortical networks that regulate behavior. More specifically, we propose that a disbalance of tonic catecholamine levels during task performance produces an emphasis of phasic signaling and increased excitability of the VAN, yielding distractibility symptoms. Likewise, immaturity of the SN may relate to abnormal tonic signaling and an incapacity to build up a proper executive system during task performance. We discuss different lines of evidence including pharmacology, brain imaging and electrophysiology, that are consistent with our proposal. Finally, restoring the pharmacodynamics of catecholaminergic signaling seems crucial to alleviate ADHD symptoms; however, the possibility is open to explore cognitive rehabilitation strategies to top-down modulate network dynamics compensating the pharmacological deficits.

A New Sign of Callosal Disconnection Syndrome: Agonistic Dyspraxia. A Case Study

We report a patient with callosal haemorrhage and no extracallosal involvement who developed a unique form of intermanual conflict. In the acute phase the patient showed a mild speech disturbance and right hemiparesis, and in her right hand, a grasp reflex and compulsive manipulation of tools, all attributable to transient frontal involvement. In the chronic phase there was intermanual conflict occasionally associated with the sensation of a second left hand. The patient also presented a sign consisting of compulsive, automatic execution of orders by one hand (the left or the right) when the patient was specifically asked to perform the movement with the other hand (the right or the left, respectively). There was no left-right confusion in this patient. We call this condition agonistic dyspraxia. In contrast with diagonistic dyspraxia, this consists of the agonistic behaviour of the other hand under conditions in which the hand that has been instructed to respond cannot execute the request.

Temporal constraints of behavioral inhibition: relevance of inter-stimulus interval in a Go-Nogo task.

The capacity to inhibit prepotent and automatic responses is crucial for proper cognitive and social development, and inhibitory impairments have been considered to be key for some neuropsychiatric conditions. One of the most used paradigms to analyze inhibitory processes is the Go-Nogo task (GNG). This task has been widely used in psychophysical and cognitive EEG studies, and more recently in paradigms using fMRI. However, a technical limitation is that the time resolution of fMRI is poorer than that of the EEG technique. In order to compensate for these temporal constraints, it has become common practice in the fMRI field to use longer inter-stimulus intervals (ISI) than those used in EEG protocols. Despite the noticeable temporal differences between these two techniques, it is currently assumed that both approaches assess similar inhibitory processes. We performed an EEG study using a GNG task with both short ISI (fast-condition, FC, as in EEG protocols) and long ISI (slow-condition, SC, as in fMRI protocols). We found that in the FC there was a stronger Nogo-N2 effect than in the SC. Moreover, in the FC, but not in the SC, the number of preceding Go trials correlated positively with the Nogo-P3 amplitude and with the Go trial reaction time; and negatively with commission errors. In addition, we found significant topographical differences for the Go-P3 elicited in FC and SC, which is interpreted in terms of different neurotransmitter dynamics. Taken together, our results provide evidence that frequency of stimulus presentation in the GNG task strongly modulates the behavioral response and the evoked EEG activity. Therefore, it is likely that short-ISI EEG protocols and long-ISI fMRI protocols do not assess equivalent inhibitory processes.

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.

Pupil Size Tracks Attentional Performance In Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) diagnosis is based on reported symptoms, which carries the potential risk of over- or under-diagnosis. A biological marker that helps to objectively define the disorder, providing information about its pathophysiology, is needed. A promising marker of cognitive states in humans is pupil size, which reflects the activity of an ‘arousal’ network, related to the norepinephrine system. We monitored pupil size from ADHD and control subjects, during a visuo-spatial working memory task. A sub group of ADHD children performed the task twice, with and without methylphenidate, a norepinephrine–dopamine reuptake inhibitor. Off-medication patients showed a decreased pupil diameter during the task. This difference was no longer present when patients were on-medication. Pupil size correlated with the subjects’ performance and reaction time variability, two vastly studied indicators of attention. Furthermore, this effect was modulated by medication. Through pupil size, we provide evidence of an involvement of the noradrenergic system during an attentional task. Our results suggest that pupil size could serve as a biomarker in ADHD.

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.