[Neurobiology of attention deficit hyperactivity disorder]. / Neurobiologische Grundlagen der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung.

The origin of ADHD is multifactorial and both the aetiology and pathophysiology of ADHD are as yet incompletely understood. The monoamine deficit hypothesis of ADHD postulates a dysbalance in the interaction of the neurotransmitters dopamine, noradrenaline and serotonin. Pathophysiological mechanisms involved in ADHD include alterations in fronto-striatal circuits. The currently proposed animal models of ADHD are heterogeneous with regard to their pathophysiological alterations and their ability to mimic behavioural symptoms and to predict response to medication. Some evidence points to a genetic basis for ADHD which is likely to involve many genes of small individual effects. In summary, specific neurobiological substrates of ADHD are unknown and multiple genetic and environmental factors appear to act together to create a spectrum of neurobiological liability.

Reduced memory and attention performance in a population-based sample of young adults with a moderate lifetime use of cannabis, ecstasy and alcohol.

Regular use of illegal drugs is suspected to cause cognitive impairments. Two substances have received heightened attention: 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') and delta-9-tetrahydrocannabinol (THC or 'cannabis'). Preclinical evidence, as well as human studies examining regular ecstasy consumers, indicated that ecstasy use may have negative effects on learning, verbal memory and complex attentional functions. Cannabis has also been linked to symptoms of inattention and deficits in learning and memory. Most of the published studies in this field of research recruited participants by means of newspaper advertisements or by using word-of-mouth strategies. Because participants were usually aware that their drug use was critical to the research design, this awareness may have caused selection bias or created expectation effects. Focussing on attention and memory, this study aimed to assess cognitive functioning in a community-based representative sample that was derived from a large-scale epidemiological study. Available data concerning drug use history allowed sampling of subjects with varying degrees of lifetime drug experiences. Cognitive functioning was examined in 284 young participants, between 22 and 34 years. In general, their lifetime drug experience was moderate. Participants completed a neuropsychological test battery, including measures for verbal learning, memory and various attentional functions. Linear regression analysis was performed to investigate the relationship between cognitive functioning and lifetime experience of drug use. Ecstasy and cannabis use were significantly related to poorer episodic memory function in a dose-related manner. For attentional measures, decrements of small effect sizes were found. Error measures in tonic and phasic alertness tasks, selective attention task and vigilance showed small but significant effects, suggesting a stronger tendency to experience lapses of attention. No indication for differences in reaction time was found. The results are consistent with decrements of memory and attentional performance described in previous studies. These effects are relatively small; however, it must be kept in mind that this study focussed on assessing young adults with moderate drug use from a population-based study.

The long-term effects of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) on cognitive performance in rats.

The neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) has been reported, both in vitro and in vivo models, to produce neurodegeneration and parkinsonian symptoms after prolonged exposure in rats. The aim of the present study was to investigate the effects of TaClo on the cognitive performance of rats. We used the COGITAT hole board system where rats can find hidden pellets by exploring the board. TaClo-treated rats found as many pellets as control rats treated with saline. Furthermore, their search was as efficient as that of control animals since there were no differences between the groups regarding explorative activity, visits to non-baited holes and time needed to find the pellets. These results suggest that there is no deficit in spatial memory following the chronic administration of TaClo to rats.

Interaction of attention and graphomotor functions in children with attention deficit hyperactivity disorder.

The present article provides a review of a series of studies in children with attention deficit hyperactivity disorder (ADHD) concerning (1) the effects of methylphenidate on various attentional functions, (2) the stimulant-induced changes of both qualitative and quantitative (i.e. kinematic) aspects of handwriting, (3) the interaction between conscious control of handwriting and fluency of handwriting movements, and (4) possible therapeutic approaches to graphomotor disturbances. Children with ADHD showed impairments in various aspects of attentional functioning. Pharmacological treatment of ADHD children with methylphenidate resulted in marked improvements of various components of attentional functioning. In comparison to the performance following the withdrawal of methylphenidate, children with ADHD on methylphenidate displayed a significant improvement in task accuracy in the areas of vigilance, divided attention, selective attention (inhibition, focused attention and integration of sensory information) and flexibility. However, the comparison with healthy children revealed considerable deficits regarding vigilance, divided attention, flexibility and selective attention (focused attention and integration of sensory information) in children with ADHD on methylphenidate. The comparison of writing movements of children on and off methylphenidate revealed that medication resulted in a better handwriting, but a deterioration in handwriting fluency as assessed by kinematic analysis. Children with ADHD may use their increased attentional capacities to focus on skills (e.g. handwriting) that are independent of conscious control or may even be disturbed by attention. The findings summarized in this paper indicate, therefore, that administration of methylphenidate alone is insufficient in the treatment of children with ADHD. Children with ADHD may benefit from instructions on how to best use their improved attentional capacities.

Association of Parkinson's disease with symptoms of attention deficit hyperactivity disorder in childhood.

Methylphenidate (MPH) is a centrally acting (psycho)stimulant which reversibly blocks the dopamine re-uptake transporter. At present MPH is one of the most frequently prescribed drugs for the symptomatic treatment of attention deficit hyperactivity disorder (ADHD). Although MPH has been in use for about 50 years, there is no information available concerning the long-term benefits and risks of medication. Based on experiments in rats it has been suggested that MPH treatment may affect the maturation of central dopaminergic systems and may be a risk factor for the development of Parkinson's disease (PD). The aim of the present case-control study was to gain information about (1) ADHD-like symptoms that may precede PD motor symptoms, and (2) the exposure to psychostimulants in childhood. We used a German short version of the Wender Utah Rating Scale (WURS-k, Retz-Junginger et al., 2002) which is a reliable measure for the retrospective diagnosis of childhood ADHD, and another questionnaire including a rating scale for symptoms of ADHD in childhood (Q-ADHD-Child) according to DSM-IV and ICD-10 criteria. A total of 92 patients with PD and 115 control subjects were enrolled in this study. Ninety-six percentage of PD patients (N = 88) completed the two rating scales. The data of these patients and of 88 randomly selected individuals of the controls were included for analysis. In the WURS-k, the PD group showed higher total scores compared to control subjects. In addition, we found increased scores in PD patients regarding the items attention deficit, hyperactivity and anxious and depressive symptoms, but not regarding impulsivity, oppositional behaviour and deficits in social adaptation. The results of the Q-ADHD-Child also showed increased scores in PD patients regarding attention deficit and hyperactivity. However, one cannot conclude that the PD patients enrolled in this study had suffered from childhood ADHD, since the average total WURS-k score of (14.4) was far below the cut-off score of 30 or higher which is considered to identify childhood ADHD. Finally, we found no evidence that PD patients had been exposed to psychostimulants such as MPH and amphetamine.

Dopamine/glutamate interactions in Parkinson's disease.

In Parkinson's disease, the tonic inhibition by basal ganglia output structures may be exacerbated by the action of the subthalamic nucleus. As expected, the reduction of excitatory impact from this structure has been shown to reduce akinesia in monkeys with experimental parkinsonism. The findings of receptor binding studies supporting an increased neuronal activity of efferents of the subthalamic nucleus in patients with Parkinson's disease, suggest that subthalamic nucleotomy or pallidotomy may be effective lesions in the neurosurgical treatment of Parkinson's disease. Systemic administration of glutamate antagonists has been shown to have anti-akinetic effects in animal models of Parkinson's disease. Other observations in monkeys indicate that excitatory amino acids such as glutamate are involved in the pathophysiological cascade of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neuronal cell death. The neuroprotective effects of competitive and non-competitive NMDA (N-methyl-D-aspartate) receptor antagonists against MPTP toxicity support the hypothesis that NMDA receptor-mediated events are involved in the neurotoxicity of MPTP. Glutamate antagonists may therefore be able to retard the progression and to improve the symptomatology of Parkinson's disease. Several compounds with anti-parkinsonian effects such as amantadine, memantine, budipine and orphenadrine have been shown to be non-competitive NMDA receptor antagonists and are candidates for clinical trials on the neuroprotective efficacy of NMDA receptor antagonism. Furthermore, glutamate antagonists are useful in the treatment of the akinetic parkinsonian crisis, a severe form of clinical deterioration in patients with Parkinson's disease.

Iron, copper, zinc, magnesium, and calcium in postmortem brain tissue from schizophrenic patients.

The regional distribution of iron, copper, zinc, magnesium, and calcium in postmortem brain of schizophrenic patients was compared with that of matched controls. In none of the brain regions investigated (caudate nucleus, hippocampus, amygdala, cortex, corpus mamillare, gyrus cinguli, and hypothalamus) were significant differences observed between these two groups. In the total group, region-specific differences were found for iron, copper, zinc, and calcium, but not for magnesium. Gender differences were observed only for zinc. There was no correlation between a neuroleptic-free period before death and the content of any of the metals investigated, except for a positive correlation between copper in the hippocampus and a neuroleptic-free period. The results of the present study suggest that there are no profound differences in the content of iron, copper, zinc, magnesium, and calcium in postmortem brains between controls and schizophrenic patients.

Biochemical actions of l-deprenyl (selegiline).

l-Deprenyl is a selective, irreversible monoamine oxidase (MAO) type B inhibitor. Dopamine is a relatively good MAO-B substrate in the human brain. Because Parkinson's disease is characterized by a decrease in dopaminergic neurotransmission in the basal ganglia, the selective inhibition of MAO-B should lead to diminished metabolism of dopamine in the nigrostriatal system and a significant increase in the concentration of the neurotransmitter. MAO-B inhibition explains the clinical efficacy of l-deprenyl in the treatment of Parkinson's disease and the prevention of the conversion of protoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is oxidized by MAO-B and can cause a parkinsonian syndrome, to their active neurotoxin. In addition, l-deprenyl appears to exhibit other biochemical actions that are independent of its MAO-B activity. These actions may be the basis of the neuroprotective effects of l-deprenyl and may include the inhibition of oxidative stress, an indirect influence on the polyamine binding site of the N-methyl-d-aspartate receptor and the stimulation of neurotrophic factors.

Vulnerability of the nigrostriatal system as detected by transcranial ultrasound.

OBJECTIVE: To assess the incidence of a hyperechogenic substantia nigra (SN) by transcranial sonography (TCS) in healthy people and to evaluate whether an enlarged hyperechogenic SN area is associated with functional impairment of the nigrostriatal system. BACKGROUND AND METHODS: Until now, preclinical impairment of the nigrostriatal system could be identified only by functional neuroimaging techniques such as PET in selected groups of patients. TCS is a new, noninvasive ultrasound technique that has demonstrated an increased echogenicity of the SN in patients with PD, whereas in most healthy individuals, the SN is either barely detectable or undetectable by TCS. RESULTS: Of 330 healthy volunteers, 8.6% exhibited an increased echogenicity of the SN. From these, 10 clinically healthy individuals with distinct unilateral or bilateral hyperechogenic signals in the SN region (SN area above 0.25 cm2) underwent comprehensive motor testing, neuropsychological assessment, MRI, and [18F]-dopa PET examination. With regard to motor functions, these individuals did not differ from 10 age- and sex-matched controls with a low echogenic SN and an area of echogenic signals below 0.2 cm2. Enlargement of hyperechogenic areas in the 10 healthy individuals was associated with a marked decrease in the accumulation of [15F]-dopa in the caudate nucleus and putamen. CONCLUSIONS: Substantia nigra hyperechogenicity appears to indicate a functional impairment of the nigrostriatal system. Transcranial sonography may be a suitable method of identifying persons at risk of nigrostriatal alterations, making possible the introduction of early neuroprotective therapy.

Cognitive dysfunction and subjective complaints of cancer patients. a cross-sectional study in a cancer rehabilitation centre.

Although the neurotoxicity of many anticancer therapies is well documented, the impact of cancer treatment on cognitive functioning has been studied less frequently. The present study examines deficits in cognitive functioning and their correlation with medical data as well as with psychosocial variables. A standardised neuropsychological test battery and several questionnaires were administered to a random sample of 119 patients. 24% of our patients fulfilled our criterion for cognitive impairment. There were no significant associations between the results of the neuropsychological testing and the current affective status or self-reports of attentional deficits in daily life. Cognitive impairment occurs in a clinically relevant percentage of cancer patients and cannot be explained exclusively due to depression or anxiety. Since subjective and objective cognitive impairment data showed little correlation, neuropsychological evaluation should not only be based on subjectively-reported complaints, but also on objective measurements.

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets.

In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-1 antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apomorphine, were weakly inhibited by SCH 23390. The selective D-1 partial agonist SKF 38393 decreased motor activity and did not induce grooming, oral movements or other behaviours. SKF 38393 inhibited motor activity induced by the administration of quinpirole but did not alter apomorphine-induced motor behaviour. Locomotor activity in normal common marmosets appears to be mediated mainly via D-2 systems. In contrast to rodents, administration of SKF 38393 does not induce behavioural activation and there does not appear to be a facilitating effect of D-1 systems on D-2 function in the normal common marmoset. However, the ability of both SKF 38393 and SCH 23390 to inhibit quinpirole locomotor activity suggests some interaction between D-1 and D-2 systems to occur in this species.

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to MPTP-treated common marmosets.

The ability of selective D-1 agonist and antagonist drugs to alter motor deficits and locomotor activity was studied in MPTP-treated common marmosets. Both the D-2 agonist quinpirole and the mixed D-1/D-2 agonist apomorphine reversed the motor impairments and induced locomotor activity. The D-1 antagonist SCH 23390 and the D-2 antagonist raclopride given alone further reduced motor function in MPTP-treated animals. The actions of quinpirole were potently and completely inhibited by raclopride but only partially and inconsistently by SCH 23390. In contrast, the effects of apomorphine were markedly but incompletely inhibited by both raclopride and SCH 23390. The D-1 agonist SKF 38393 alone caused a dose related reduction in motor activity. SKF 38393 weakly and partially inhibited the improvements in motor function produced by quinpirole but had a more pronounced effect on apomorphine induced motor activity. The induction of motor activity in MPTP treated common marmosets may separately involve both D-1 and D-2 receptors. Comparison with our previous data on the effect of the same drugs in normal common marmosets provides some evidence for a breakdown of linkage between D-1 and D-2 systems following MPTP treatment. The actions of SKF 38393 in MPTP-treated common marmosets contrasts with its ability to induce behavioural activation and a facilitation of D-2 mediated behaviour in rodents. SKF 38393 may not be the compound with which to delineate the role of D-1 receptors in primates.

L-dopa withdrawal in Parkinson's disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction.

A group of ten patients with idiopathic Parkinson's disease (PD) was tested on a series of automated tests of learning, memory, planning and attention whilst either on or off L-dopa medication. Controlled withdrawal of L-dopa interfered with aspects of performance on three of the tests that had previously been shown to be sensitive to frontal lobe dysfunction; a spatial working memory task, the Tower of London planning test, and a visual discrimination paradigm that also included intra- and extra-dimensional shift tests of selective attention. More specifically, errors were increased in the spatial working memory test, and both the accuracy and latency of thinking were impaired. Thinking time was significantly slowed following L-dopa withdrawal, even though the possible contaminating effects on motor slowing were fully controlled by a yoked control procedure. Nine out of ten patients reached a further stage of the visual discrimination, set-shifting paradigm when on, rather than off, L-dopa medication. Spatial span was also impaired off medication, but there were no effects of L-dopa withdrawal on tests of pattern and spatial recognition memory, simultaneous and delayed matching to sample or visuospatial conditional associative learning. Comparisons with a large control group confirmed previous findings that PD is associated with deficits on the majority of these tests. The results are discussed in terms of the fronto-striatal, dopamine dependent nature of some of the cognitive deficits found in PD, but the apparent dopamine-independent nature of deficits in other aspects of cognitive functioning, notably in tests of visual recognition memory and associative learning.

Stroke-blind for colors, faces and locations: Partial recovery after three years.

Purpose. To study and follow-up achromatopsia, prosopagnosia, and topographagnosia in a patient who suffered a bilateral stroke of the posterior cerebral arteries. Methods. Ophthalmological, neuropsychological and neuroradiological examinations were conducted over a span of 3 years to assess the amount of brain damage and look for signs of functional recovery. Results. After the onset of achromatopsia, perception of the color green re-appeared first, followed by red, yellow, and brown. Blue which had appeared entirely black was last to return. While reading and color naming have largely recovered, color discrimination after three years remains poor especially in dim lighting. Similarly, with prosopagnosia, while the patient has learn to identify people (including photographs) by individual features, his ability to perceive and recognize faces and facial expressions holistically remains severely impaired. Recognition of streets, houses, and topographical layouts also continues to be affected, while the perception of speed and distance has somewhat improved. Perimetry further suggests a mild improvement of the superior hemianopia in his visual fields. Conclusions. Although major deficits in color, face and place perception remain, some functions impaired by the stroke have returned par-alleling a partial recovery from the brain lesion as demonstrated by NMR.

Regional distribution and characterization of nitric oxide synthase activity in the brain of the common marmoset.

The distribution of nitric oxide synthase (NOS) within the brain of the common marmoset, a non-human primate species, was investigated using the [3H]L-citrulline formation assay and Western blot analysis. No hemispheric asymmetry of specific NOS activity was shown. The highest levels of NOS were found in the putamen and caudate nucleus--more than twice those in the cortex and the cerebellum, the brain regions with the lowest activities. The regional distribution pattern was similar to that in the ferret brain and contrasted to that in the mouse and bovine brain. Analysis of NOS catalytic activities in subcellular fractions revealed marked differences in the subcellular localization. Neuronal NOS accounted mainly for the measured catalytic activity in the brain. Differences in the regional distribution pattern of brain NOS activity among species may be indicative of diversities in the functional role of nitric oxide and NOS in mammals.

Brain muscarinic cholinergic receptors in Huntington's disease.

Muscarinic cholinergic receptors and choline acetyltransferase (ChAT) activity were studied in postmortem brain tissue from patients with Huntington's disease and matched control subjects. In comparison with controls, reductions in ChAT activity were found in the hippocampus, but not in the temporal cortex in Huntington's disease. Patients with Huntington's disease showed reduced densities of the total number of muscarinic receptors and of M-2 receptors in the hippocampus while the density of M-1 receptors was unaltered. Muscarinic receptor binding was unchanged in the temporal cortex. These results indicate a degeneration in Huntington's disease of the septo-hippocampal cholinergic pathway, but no impairment of the innominato-cortical cholinergic system.

Depression in Parkinson's disease: brainstem midline alteration on transcranial sonography and magnetic resonance imaging.

Recent studies using transcranial sonography (TCS) have provided evidence of alterations in the mesencephalic midline structures in patients with unipolar depression and depression in Parkinson's disease (PD), suggesting an involvement of the basal limbic system in primary and secondary mood disorders. This study tested the hypothesis of brainstem midline abnormality in depression and investigated 31 PD patients by magnetic resonance imaging (MRI) and TCS. Signal intensity of the pontine and mesencephalic brainstem midline was rated on T2-weighted images and measured by relaxometry. In addition, two blinded investigators assessed the echogenicity of the brainstem midline by TCS. The severity of motor symptoms and depression were graded independently using standard research scales. Rating of signal intensity and T2 relaxometry of the pontomesencephalic midline structures revealed significant difference between depressed and nondepressed PD patients (P < 0.05). This corresponded to a significant reduction in mesencephalic midline echogenicity of depressed PD patients on TCS images. No correlation was found between raphe signal intensity, T2 relaxation times, or TCS echogenicity and the severity of motor symptoms or depression. This study is the first to show changes in signal intensity and T2 relaxation time of the pontomesencephalic midline structures on MRI in depressed PD patients confirming previous TCS findings. As these midline structures comprise fiber tracts and nuclei of the basal limbic system, the findings may support the hypothesis of an alteration in the basal limbic system in mood disorders.

Behavioural effects and supersensitivity in the rat following intranigral MPTP and MPP+ administration.

Unilateral intranigral injections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ (1-methyl-4-phenylpyridine) were given to young rats and unilateral intranigral injections of MPTP were given to old rats. MPTP in old rats and MPP+ in young rats induced ipsiversive circling for at least one week after injection and contraversive circling after the systemic administration of apomorphine; the number of D-2 receptors (Bmax) in the striatum of the injected hemisphere increased compared with that of control rats. MPTP in young rats induced only short-lasting ipsiversive circling and no contraversive circling after apomorphine; the number of striatal D-2 receptors did not increase. These results suggest that the neurotoxicity of MPTP is age-dependent in the rat, and that MPTP has neurotoxic effects on the nigrostriatal dopaminergic system in old rats and induces dopamine receptor supersensitivity in the denervated striatum.

Unilateral intranigral injection of MPTP in the rat induces contraversive turning.

Unilateral injection of MPTP into the pars compacta of the substantia nigra in rats induced contraversive turning immediately after the injection. Contraversive turning decreased, and reversed its direction after about 30 min. Ipsiversive turning was still present 24 h after the injection of MPTP. These results suggest that MPTP has an initial stimulatory effect on dopaminergic neurons followed by a depression of the activity of these cells.