Showing papers in "Journal of Neural Transmission in 2008"

Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies

Abstract: A genome-wide association (GWA) study with pooled DNA in adult attention-deficit/hyperactivity disorder (ADHD) employing ~500K SNP markers identifies novel risk genes and reveals remarkable overlap with findings from recent GWA scans in substance use disorders. Comparison with results from our previously reported high-resolution linkage scan in extended pedigrees confirms several chromosomal loci, including 16q23.1-24.3 which also reached genome-wide significance in a recent meta-analysis of seven linkage studies (Zhou et al. in Am J Med Genet Part B, 2008). The findings provide additional support for a common effect of genes coding for cell adhesion molecules (e.g., CDH13, ASTN2) and regulators of synaptic plasticity (e.g., CTNNA2, KALRN) despite the complex multifactorial etiologies of adult ADHD and addiction vulnerability.

Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA

Abstract: Decreased blood–brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson’s disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.

Motor coordination problems in children and adolescents with ADHD rated by parents and teachers: effects of age and gender

Abstract: Objective. ADHD is frequently accompanied by motor coordination problems. However, the co-occurrence of poor motor performance has received less attention in research than other coexisting problems in ADHD. The underlying mechanisms of this association remain unclear. Therefore, we investigated the prevalence of motor coordination problems in a large sample of children with ADHD, and the relationship between motor coordination problems and inattentive and hyperactive/impulsive symptoms. Furthermore, we assessed whether the association between ADHD and motor coordination problems was comparable across ages and was similar for both genders. Method. We investigated 486 children with ADHD and 269 normal controls. Motor coordination problems were rated by parents (Developmental Coordination Disorder Questionnaire) and teachers (Groningen Motor Observation Scale). Results. Parents and teachers reported motor coordination problems in about one third of children with ADHD. Problems of fine and gross motor skills, coordination skills and motor control were all related to inattentive rather than hyperactive/impulsive symptoms. Relative to controls, motor coordination problems in ADHD were still present in teenagers according to parents; the prevalence diminished somewhat according to teachers. Boys and girls with ADHD were comparably affected, but motor performance in controls was better in girls than in boys. Conclusions. Motor coordination problems were reported in one third of children with ADHD and affected both boys and girls. These problems were also apparent in adolescents with ADHD. Clinicians treating children with ADHD should pay attention to co-occurring motor coordination problems because of the high prevalence and the negative impact of motor coordination problems on daily life.

Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice.

Abstract: The relative contribution of the two tryptophan hydroxylase (TPH) isoforms, TPH1 and TPH2, to brain serotonergic system function is controversial. To investigate the respective role of TPH2 in neuron serotonin (5-HT) synthesis and the role of 5-HT in brain development, mice with a targeted disruption of Tph2 were generated. The preliminary results indicate that in Tph2 knockout mice raphe neurons are completely devoid of 5-HT, whereas no obvious alteration in morphology and fiber distribution are observed. The findings confirm the exclusive specificity of Tph2 in brain 5-HT synthesis and suggest that Tph2-synthesized 5-HT is not required for serotonergic neuron formation.

Bladder and bowel dysfunction in Parkinson's disease.

Abstract: Bladder dysfunction (urinary urgency/frequency) and bowel dysfunction (constipation) are common non-motor disorders in Parkinson’s disease (PD). In contrast to motor disorder, the pelvic autonomic dysfunction is often non-responsive to levodopa treatment. Brain pathology mostly accounts for the bladder dysfunction (appearance of overactivity) via altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. In contrast, peripheral enteric pathology mostly accounts for the bowel dysfunction (slow transit and decreased phasic contraction) via altered dopamine-enteric nervous system circuit, which normally promotes the peristaltic reflex. In addition, weak strain and paradoxical anal contraction might be the results of brain pathology. Pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore it might aid the differential diagnosis. Drugs to treat bladder dysfunction in PD include anticholinergic agents. Drugs to treat bowel dysfunction in PD include dietary fibers, peripheral dopaminergic antagonists, and selective serotonergic agonists. These treatments might be beneficial not only in maximizing patients’ quality of life, but also in promoting intestinal absorption of levodopa and avoiding gastrointestinal emergency.

Temporal reward discounting and ADHD: task and symptom specific effects.

Abstract: This study investigated a new aspect of the association between ADHD symptoms and delay aversion. Participants were 55 undergraduate Psychology students with varying levels of self-reported ADHD symptoms. Various delay aversion tasks were used, including real and hypothetical temporal discounting tasks previously used in the field of ADHD. ADHD symptoms, specifically hyperactivity/impulsivity, were associated with steep discounting, but only when rewards and delays were real. These data suggest that (1) real temporal discounting tasks are more sensitive to ADHD-related delay aversion than hypothetical ones; (2) delay aversion may be a causal mechanism specifically associated with ADHD-Combined and Hyperactive/Impulsive Types but not Inattentive Type. These findings may help refine behavioral treatment approaches and models of ADHD.

Increased EEG gamma band activity in Alzheimer's disease and mild cognitive impairment

Abstract: High frequency (30–70 Hz) gamma band oscillations in the human electro-encephalogram (EEG) are thought to reflect perceptual and cognitive processes. It is therefore interesting to study these measures in cognitive impairment and dementia. To evaluate gamma band oscillations as a diagnostic biomarker in Alzheimer’s disease (AD) and mild cognitive impairment (MCI), 15 psychoactive drug naive AD patients, 20 MCI patients and 20 healthy controls participated in this study. Gamma band power (GBP) was measured in four conditions viz. resting state, music listening, story listening and visual stimulation. To evaluate test–retest reliability (TRR), subjects underwent a similar assessment one week after the first. The overall TRR was high. Elevated GBP was observed in AD when compared to MCI and control subjects in all conditions. The results suggest that elevated GBP is a reproducible and sensitive measure for cognitive dysfunction in AD in comparison with MCI and controls.

Evidence-based systematic review on the efficacy and safety of botulinum toxin-A therapy in post-stroke spasticity.

Abstract: Background. Botulinum toxin type A (BoNTA) has been suggested as an effective anti-spastic drug. In this article, we summarized the data of randomized, placebo-controlled, double- blind trials and conducted a meta-analysis to assess if BoNTA is an adequate treatment for spasticity following stroke. Objectives. To evaluate the relevant literature and assess the effectiveness and safety of BoNTA in (1) reducing spasticity based on mean change in the Modified Ashworth Scale (MAS) for upper and lower limb spasticity from baseline; (2) reducing spasticity based on the percent of patients having > or = 1point(s) change in the MAS; (3) improving the patient’s or caregivers’ Global Assessment Scale (GAS); and (4) total adverse events. Method. We selected all randomized, placebo controlled, double-blind clinical trials or previous meta-analyses evaluating the efficacy and safety of BoNTA (Botox® or Dysport®) for the treatment of spasticity in both upper and lower limbs after stroke. Validity assessment of studies was performed, and Revman 4.2.7 from Cochrane Collaboration and SPSS (statistical package for the social sciences), v 9.0, were applied for analysis. Results. Overall analysis showed clinical improvement between baseline and 4–6 weeks after application of BoNTA of the patient’s spasticity score using the MAS (weighted mean difference [WMD] = 0.87, 95% CI = 0.52–1.22). The odds ratio of the MAS spasticity score showing one or more points improvement at 4–6 weeks after giving BoNTA showed clinically significant improvement (OR = 4.5, 95% CI = 2.79–7.25). The odds ratio of having an improved GAS at 4–6 weeks after injecting BoNTA showed clinically significant improvement (Odds ratio = 5.85, 95% CI = 3.12–10.95). The odds ratio of having an adverse event during the entire study did not show any significant difference between placebo and BoNTA (odds ratio = 0.84, 95% CI = 0.55–1.28). Reviewers’ conclusions. BoNTA improves muscle tone in upper and lower limb spasticity following stroke. A global assessment of improvement was noted by the patients or the caregivers following BoNTA injection. BoNTA is considered a safe therapeutic agent.

Slow cortical potential neurofeedback in attention deficit hyperactivity disorder : is there neurophysiological evidence for specific effects?

Abstract: This study compared changes in quantitative EEG (QEEG) and CNV (contingent negative variation) of children suffering from ADHD treated by SCP (slow cortical potential) neurofeedback (NF) with the effects of group therapy (GT) to separate specific from non-specific neurophysiological effects of NF. Twenty-six children (age: 11.1 +/- 1.15 years) diagnosed as having ADHD were assigned to NF (N = 14) or GT (N = 12) training groups. QEEG measures at rest, CNV and behavioral ratings were acquired before and after the trainings and statistically analyzed. For children with ADHD-combined type in the NF group, treatment effects indicated a tendency toward improvement of selected QEEG markers. We could not find the expected improvement of CNV, but CNV reduction was less pronounced in good NF performers. QEEG changes were associated with some behavioral scales. Analyses of subgroups suggested specific influences of SCP training on brain functions. To conclude, SCP neurofeedback improves only selected attentional brain functions as measurable with QEEG at rest or CNV mapping. Effects of neurofeedback including the advantage of NF over GT seem mediated by both specific and non-specific factors.

Spasticity treatment with botulinum toxins.

Abstract: Spasticity is a physiological consequence of an insult to the brain or spinal cord, which can lead to life-threatening, disabling and costly consequences This typically occurs following stroke, brain injury, spinal cord injury, multiple sclerosis and other disabling neurological diseases and cerebral palsy It is but one feature of the upper motor neurone syndrome and there have been considerable developments in its management through new drugs and technology The sole indication for treating spasticity is when it is causing harm and interferes with active or passive functioning Successful treatment strategies have now been developed and there is good evidence of treatment effectiveness Treatment is essentially aimed at reducing abnormal sensory inputs, which have an impact on excessive and uncontrolled alpha-motor neuron activity Attending to the physical characteristics of muscle shortening is the basis of spasticity management All pharmacological interventions are adjunctive to a programme of physical intervention and there is a good evidence base for this in relation to botulinum toxin treatment Management therefore centres around the development of a formal treatment plan is important to document the intended outcomes, which should be written and agreed upon with the patient Anti-spastic drugs treat spasticity They do not treat contractures and they will not make hemiplegic limbs function, unless the patient's function is impeded by the spasticity The management of spasticity is physical and all pharmacological interventions are adjunctive to that This article therefore deals with the principles of management of spasticity and treatment with botulinum toxin It covers treatment planning, patient assessment, goal setting and covers the range of available treatments It also describes how botulinum toxin works, the evidence for its use in spasticity management and practical aspects of treatment, such as muscle location, the injection procedure and post-injection care Finally, there is a word on the organisation of services The contribution of botulinum toxin to spasticity management is now well recognised The trick in clinical management is to use it intelligently and to know when and when not to use it It is a useful short-term means of improving patients' function and the distressing features of spasticity following an insult to the central nervous system This is usually against the background of a long-term condition, for which a long-term management strategy is required Botulinum toxin provides a window of opportunity to improve the outcomes from physical management of the focal and multi-focal problems of spasticity

From poison to remedy: the chequered history of botulinum toxin

Abstract: Botulinum toxin poisoning has afflicted mankind through the mists of time. However, the first incident of food-borne botulism was documented as late as the 18th century, when the consumption of meat and blood sausages gave rise to many deaths throughout the kingdom of Wurttemberg in South Western Germany. The district medical officer Justinus Kerner (1786–1862), who was also a well-known German poet, published the first accurate and complete descriptions of the symptoms of food-borne botulism between 1817 and 1822 and attributed the intoxication to a biological poison. Kerner also postulated that the toxin might be used for treatment purposes. In 1895, an outbreak of botulism in the small Belgian village of Ellezelles led to the discovery of the pathogen “Clostridium botulinum” by Emile Pierre van Ermengem. Modern botulinum toxin treatment was pioneered by Alan B. Scott and Edward J. Schantz in the early 1970s, when the type-A serotype was used in medicine to correct strabismus. Other preparations of the type-A toxin were developed and manufactured in the United Kingdom, Germany, and China, whereas a therapeutic type-B toxin was prepared in the United States. To date, the toxin has been used to treat a wide variety of conditions associated with muscular hyperactivity, glandular hypersecretions and pain.

Decision-making on an explicit risk-taking task in preadolescents with attention-deficit/hyperactivity disorder

Abstract: Inappropriate risk-taking and disadvantageous decision-making have been described as major behavioural characteristics of patients with attention-deficit/hyperactivity disorder (ADHD). However these behaviours are difficult to measure in laboratory contexts and recent studies have yielded inconsistent results which might be related to task characteristics. The present study adopted the Game of Dice Task, a test procedure in which risks are made explicit and the load on working memory is minimal. As a result, preadolescents with ADHD (N = 23) made significantly more risky choices and suffered major losses of money compared to normal controls (N = 24) but only when they played the game a second time. Differences in risk-taking correlated significantly with hyperactivity as rated by parents and with inhibitory control, but not with working memory performance. The results are discussed in the context of current theories of ADHD.

Antidepressant-like activity of zinc: further behavioral and molecular evidence.

Abstract: Zinc exhibits antidepressant-like activity in preclinical tests (the forced swim test and tail suspension test) and in olfactory bulbectomy and chronic unpredictable stress; two models of depression. Zinc also enhances the treatment of depression in humans. In the present study we evaluated the antidepressant activity of zinc in another model of depression-chronic mild stress (CMS) and the effect of zinc treatment on BDNF protein and the mRNA level. In CMS zinc hydroaspartate (10 mg/kg) exhibited a rapid (after 1 week of treatment) antidepressant-like effect. Chronic treatment with zinc induced a 17-39% increase in the BDNF mRNA and protein level in the hippocampus. These data indicate a rapidly acting antidepressant-like activity of zinc in CMS and the involvement of zinc in the regulation of BDNF.

Botulinum toxin in the treatment of blepharospasm and hemifacial spasm

Abstract: Blepharospasm and hemifacial spasm are the two most common craniofacial movement disorders. Blepharospasm is a syndrome characterized by excessive or continuous eye closure related to overactivity of the orbicularis oculi and adjacent muscles bilaterally. Hemifacial spasm is a peripherally-induced movement disorder typically caused by vascular compression of cranial nerve VII (CN VII) leading to involuntary unilateral contractions of muscles used in facial expression. Treatment options for both conditions include medications, botulinum toxin, and various surgical interventions. This article summarizes the existing medical literature which indicates that botulinum toxin is the treatment of choice for blepharospasm and hemifacial spasm.

The Janus-face kynurenic acid

Abstract: Kynurenic acid is an endogenous product of the tryptophan metabolism. Studies on the mechanism of its action have revealed that kynurenic acid at high concentrations is a competitive antagonist of the N-methyl-D-aspartate receptor and acts as a neuroprotectant in different neurological disorders. This in vitro investigation was designed to show that kynurenic acid acts differently at low concentrations. In vitro electrophysiological examinations on the young rat hippocampus confirmed the well-known finding that kynurenic acid in micromolar concentrations exerts an inhibitory effect. However, in nanomolar concentrations, kynurenic acid does not give rise to inhibition, but in fact facilitates the field excitatory postsynaptic potentials. The results available so far are compatible with the idea that kynurenic acid in the concentration range between a few hundred nanomolar and micromolar displays different effects. Its probable action on different receptors, inducing the different mechanisms, is discussed. The findings strongly suggest the neuromodulatory role of kynurenic acid under both physiological and pathological circumstances.

Intake of copper has no effect on cognition in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial

Abstract: Disturbed copper (Cu) homeostasis may be associated with the pathological processes in Alzheimer's disease (AD). In the present report, we evaluated the efficacy of oral Cu supplementation in the treatment of AD in a prospective, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild AD for 12 months. Sixty-eight subjects were randomized. The treatment was well-tolerated. There were however no significant differences in primary outcome measures (Alzheimer's Disease Assessment Scale, Cognitive subscale, Mini Mental Status Examination) between the verum [Cu-(II)-orotate-dihydrate; 8 mg Cu daily] and the placebo group. Despite a number of findings supporting the hypothesis of environmental Cu modulating AD, our results demonstrate that oral Cu intake has neither a detrimental nor a promoting effect on the progression of AD.

Psychiatric disorders in adults diagnosed as children with atypical autism. A case control study.

Abstract: The prevalence and types of psychiatric disorders were studied in a clinical sample of 89 individuals with atypical autism (AA) first seen as children, and 258 matched controls from the general population using data from the nationwide Danish Psychiatric Central Register. The average observation time was 36.9 years, and mean age at follow-up 45.3 years. A total of 61 persons with AA (68.5%) had been in contact with psychiatric hospitals during the follow-up period, compared with 10.9% in the comparison group. A whole range of significantly elevated psychiatric disorders was found, so AA is not seen to be associated with any specific mental disorder. Schizophrenia spectrum disorders were the most commonly associated psychiatric disorders, diagnosed at least one time in 34.8% of the AA cases. Our findings underscore that it is important for clinicians working in adult psychiatric services to be aware that AA and a wide range of psychiatric disorders often co-exist.

Response inhibition in borderline personality disorder: event-related potentials in a Go/Nogo task

Abstract: Borderline personality disorder (BPD) has been related to a dysfunction of anterior cingulate cortex, amygdala, and prefrontal cortex and has been associated clinically with impulsivity, affective instability, and significant interpersonal distress. We examined 17 patients with BPD and 17 age-, sex-, and education matched control participants with no history of Axis I or II psychopathology using event-related potentials (ERPs). Participants performed a hybrid flanker-Go/Nogo task while multichannel EEG was recorded. Our study focused on two ERP components: the Nogo-N2 and the Nogo-P3, which have been discussed in the context of response inhibition and response conflict. ERPs were computed on correct Go trials (button press) and correct Nogo trials (no button press), separately. Groups did not differ with regard to the Nogo-N2. However, BPD patients showed reduced Nogo-P3 amplitudes. For the entire group (n = 34) we found a negative correlation with the Barratt Impulsiveness Scale (BIS-10) and Becks's depression inventory (BDI). The present study is the first to examine Nogo-N2 and Nogo-P3 in BPD and provides further evidence for impaired response inhibition in BPD patients.

Abnormal short latency afferent inhibition in early Alzheimer’s disease: a transcranial magnetic demonstration

Abstract: The pathogenesis of Alzheimer’s disease (AD) appears to involve several different mechanisms, the most consistent of which is an impairment of cholinergic neurotransmission; however, there is controversy about its relevance at the early stage of disease. A transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with motor cortex TMS (short latency afferent inhibition, SAI) may give direct information about the function of some cholinergic pathways in the human motor cortex. We evaluated SAI in a group of patients with early diagnosis of AD and compared the data with that from a control group. The amount of SAI was significantly smaller in early AD patients than in controls. This study first provides physiological evidence that a central cholinergic dysfunction occurs in the earlier stages of AD. Identification of SAI abnormalities that occur early in the course of AD will allow earlier diagnosis and treatment with cholinergic drugs.

Neuropsychological assessment of attention in adults with different subtypes of attention-deficit/hyperactivity disorder

Abstract: There is only little information about varying attention functions of adults with different DSM-IV subtypes of attention-deficit/hyperactivity disorder (ADHD). In the present study groups of adult patients with ADHD - predominantly inattentive type, ADHD - predominantly hyperactive-impulsive type or ADHD - combined type and three healthy control groups were compared regarding multiple components of attention. Assessment of attention was performed using a computerized neuropsychological test battery for attentional functions. In comparison with healthy subjects, the three patient groups displayed impairments of vigilance, selective attention, divided attention, and flexibility. These impairments of attention of ADHD subgroups were primarily observed with regard to reaction time. With regard to tonic and phasic alertness no differences between patient and control groups could be found. Comparison between ADHD subgroups revealed that DSM-IV subtypes of ADHD differ in measures of divided attention, selective attention and flexibility. Differences between ADHD subgroups were primarily observed with regard to task accuracy. The results suggest that while distinct profiles of attentional functioning were observed between adult patients with ADHD and healthy adults indicating gross disturbances of various attention functions in patients with ADHD, differences between ADHD subgroups were only weak.

A 1H magnetic resonance spectroscopy study in adults with obsessive compulsive disorder: relationship between metabolite concentrations and symptom severity

Abstract: 1H magnetic resonance spectroscopy (1H MRS) studies exploring brain metabolites, especially glutamine + glutamate (Glx), in obsessive compulsive disorder (OCD) are of vital interest for trying to understand more about the pathophysiology of OCD. Therefore, we conducted the present 1H MRS study with the aims of (1) comparing MRS metabolites in a group of adult patients with OCD and a group of healthy controls, and (2) examining the relationship between MRS metabolite concentrations and symptom severity in the patient group. Three brain regions were studied, the right caudate nucleus, the anterior gyrus cinguli and the occipital cortex bilaterally. Since multivariate analysis is a highly useful tool for extraction of 1H MRS data, we applied principal component analysis (PCA) and partial least square projection to latent structures (PLS) to the MRS data. PLS disclosed a strong relationship between several of the metabolites and OCD symptom severity, as measured with Yale-Brown obsessive-compulsive scale (YBOCS): the YBOCS score was found to be positively correlated to caudate creatine, Glx, glutamate, and choline compounds as well as occipital cortex myoinositol, and negatively correlated to occipital cortex Glx. The negative correlation between occipital cortex Glx and YBOCS was the most impressive. PCA did not reveal any tendency for a separation between the patients with OCD and controls with respect to MRS metabolites. The results are discussed in relation to corticostriatothalamocortical feedback and previous observations of poor visuospatial ability in OCD.

CBCL-pediatric bipolar disorder phenotype: severe ADHD or bipolar disorder?

Abstract: Background. In children with pediatric bipolar disorder (PBD), a consistent pattern of elevations in hyperactivity, depression/anxiety, and aggression has been identified on the child behavior checklist (CBCL-PBD profile). The aim of the present study was to estimate the prevalence of the CBCL-PBD profile in a child psychiatric sample, and to determine ICD-10 diagnoses in CBCL-PBD patients.

Cortical control of gait in healthy humans: an fMRI study

Abstract: This study examined the cortical control of gait in healthy humans using functional magnetic resonance imaging (fMRI). Two block-designed fMRI sessions were conducted during motor imagery of a locomotor-related task. Subjects watched a video clip that showed an actor standing and walking in an egocentric perspective. In a control session, additional fMRI images were collected when participants observed a video clip of the clutch movement of a right hand. In keeping with previous studies using SPECT and NIRS, we detected activation in many motor-related areas including supplementary motor area, bilateral precentral gyrus, left dorsal premotor cortex, and cingulate motor area. Smaller additional activations were observed in the bilateral precuneus, left thalamus, and part of right putamen. Based on these findings, we propose a novel paradigm to study the cortical control of gait in healthy humans using fMRI. Specifically, the task used in this study—involving both mirror neurons and mental imagery—provides a new feasible model to be used in functional neuroimaging studies in this area of research.

Co-transmission of conduct problems with attention-deficit= hyperactivity disorder: familial evidence for a distinct disorder

Abstract: Common disorders of childhood and adolescence are attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). For one to two cases in three diagnosed with ADHD the disorders may be comorbid. However, whether comorbid conduct problems (CP) represents a separate disorder or a severe form of ADHD remains controversial. We investigated familial recurrence patterns of the pure or comorbid condition in families with at least two children and one definite case of DSM-IV ADHDct (combined-type) as part of the International Multicentre ADHD Genetics Study (IMAGE). Using case diagnoses (PACS, parental account) and symptom ratings (Parent/Teacher Strengths and Difficulties [SDQ], and Conners Questionnaires [CPTRS]) we studied 1009 cases (241 with ADHDonly and 768 with ADHD + CP), and their 1591 siblings. CP was defined as ≥4 on the SDQ conduct-subscale, and T ≥ 65, on Conners’ oppositional-score. Multinomial logistic regression was used to ascertain recurrence risks of the pure and comorbid conditions in the siblings as predicted by the status of the cases. There was a higher relative risk to develop ADHD + CP for siblings of cases with ADHD + CP (RRR = 4.9; 95%CI: 2.59–9.41); p < 0.001) than with ADHDonly. Rates of ADHDonly in siblings of cases with ADHD + CP were lower but significant (RRR = 2.9; 95%CI: 1.6–5.3, p < 0.001). Children with ADHD + CP scored higher on the Conners ADHDct symptom-scales than those with ADHDonly. Our finding that ADHD + CP can represent a familial distinct subtype possibly with a distinct genetic etiology is consistent with a high risk for cosegregation. Further, ADHD + CP can be a more severe disorder than ADHDonly with symptoms stable from childhood through adolescence. The findings provide partial support for the ICD-10 distinction between hyperkinetic disorder (F90.0) and hyperkinetic conduct disorder (F90.1).

Neuropsychological characteristics as predictors of SSRI treatment response in depressed subjects

Abstract: Studies suggest that neuropsychological measures may provide prognostic information regarding SSRI treatment response, yet it is unclear which specific cognitive domains are the most effectual predictors. The aim of this study was to characterize the cognitive profile associated with SSRI nonresponse using a comprehensive set of neuropsychological tests. Participants (N = 32) met criteria for current major depressive episode. Assessment followed pre-treatment medication washout. Clinical response was measured after 3-month open-label SSRI treatment. Groups did not differ by demographic characteristics, intelligence or depression severity. Responders outperformed nonresponders across all cognitive domains, with the largest differences observed in executive, language and working memory functions. Results indicate poorer global cognitive functioning is predictive of treatment nonresponse. Deficits were most pronounced in tests demanding greater mental search and manipulation rather than speeded motor output. Cognitive slowing may mediate the working memory and executive function deficits found in nonresponders. These findings can inform exploration for pharmacogenetic endophenotypes.

Impulsiveness and ERP components in a Go/Nogo task

Abstract: Impulsiveness has been linked to fast guesses and premature responses in reaction time tasks like the Eriksen flanker task or the Go/Nogo task. In the present study, healthy subjects without history of DSM-IV Axis I or II psychopathology were examined. Impulsiveness was determined by calculating individual reaction times (as a function of general response speed) in order to split the entire group (n = 26) in a subgroup with a more controlled response style (low impulsiveness [LI] group; n = 13) and a subgroup with a more impulsive response style (high impulsiveness [HI] group; n = 13). Subjects performed a Go/Nogo task while a multi-channel EEG was recorded. Two event-related potentials (ERP) were of special interest: the Nogo-N2 and -P3 component. HI subjects had significantly reduced (less positive) Nogo-P3 amplitudes compared to LI subjects whereas groups did not differ with regard to the Nogo-N2. These results corroborate previous findings of reduced Nogo-P3 amplitudes in samples with enhanced levels of impulsiveness. Moreover, present data suggest that there is a broader range of impulsiveness even in healthy subjects which might mask or pronounce between-group differences in clinical studies. Therefore, different levels of impulsiveness in control groups should be carefully taken into account in further ERP studies.

Externally provoked freezing of gait in open runways in advanced Parkinson's disease results from motor and mental collapse.

Abstract: Freezing of gait (FOG) in Parkinson's disease (PD) is defined as a sudden inability to maintain effective stepping movements. However, its pathophysiology remains unclear. The objectives are: (1) To assess the contribution of both spatial (walking speed, stride length) and temporal parameters (cadence, stride time) and their coefficients of variation to the genesis of FOG in PD. (2) To evaluate whether and how externally imposed modifications of self-determined gait would elicit FOG. We included ten patients with advanced PD, and with daily off drug FOG episodes. We focused on walking in an open runway. For each subject, we manipulated gait by externally imposing four changes in walking speed and four changes in cadence. FOG episodes, often with a long duration of more than 5-s, were observed mostly under conditions with a high imposed cadence. The steps that immediately preceded these episodes were mainly characterized by an increase in cadence and an increase in stride length variability. The results also underscore that FOG can be elicited in a laboratory setting when patients are placed under considerable strain, at least in advanced stages of PD. Patients were unable to adequately negotiate the extreme imposed cadence condition, and this resulted in frequent FOG episodes, even while walking in an open runway. Placing advanced PD patients into extreme imposed conditions leads to a motor wise and mental collapse response, culminating in FOG. Future work should establish the relevance of these findings for the more common forms of FOG, including brief episodes during turning or gait initiation.

Genetic aspects in attention-deficit/hyperactivity disorder.

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder among children and adolescents with high heritability. Molecular genetic findings support the thesis that dopaminergic, serotonergic, and noradrenergic neurotransmission pathways account for the etiology of this complex disease. Genetic research comprises formal genetic studies, candidate gene studies, linkage analyses, and recently large-scale genome wide association studies, gene-environement interaction studies, and pharmacogenetics. This article comprehensively reviews the latest findings on the genetics of ADHD.

Effects of (-)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization.

Abstract: Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (−)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (−)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (−)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (−)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (−)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (−)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.

Appearance of antidepressant-like effect by sildenafil in rats after central muscarinic receptor blockade: evidence from behavioural and neuro-receptor studies.

Abstract: The phosphodiesterase (PDE) 5 inhibitor sildenafil has been shown to display psychotropic actions in humans and animals, and has been used for the treatment of antidepressant-associated erectile dysfunction. However, its effects on the neurobiology of depression are unknown. Nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) inhibition is anti-depressant in animals, and increasing cGMP with sildenafil is anxiogenic in rodents. Substantial cholinergic-nitrergic interaction exists in the brain, while sildenafil shows modulatory actions on cholinergic transmission. Depression is also associated with increased cholinergic drive. Here we report that sildenafil increases muscarinic acetylcholine receptor (mAChR) signaling in human neuroblastoma cells. We also show that fluoxetine (20 mg/kg/day × 7 days), as well as a combination of sildenafil (10 mg/kg/day × 7 days) plus the antimuscarinic atropine (1 mg/kg/day × 7 days) demonstrates significant, comparable antidepressant-like effects in the rat forced swim test (FST) and also reduces cortical β-adrenergic receptor (β-AR) density, while sildenafil or atropine alone did not. Importantly, sildenafil did not modify fluoxetine’s response. Sildenafil thus demonstrates antidepressant-like effects but only after central muscarinic receptor blockade, providing evidence for cholinergic-nitrergic interactions in the neurobiology of depression.