Search

A measure of auditory prepulse inhibition (PPI) or sensory gating is the reduction of the scalp-recorded P1 event-related potential (ERP) after a sound that is preceded by 100-300 ms by a click as prepulse. This measure of sensory gating was adapted to study the effect of a prepulse on processing tones that were part of a "Go/no-go" discrimination. Methods: ERPs were recorded at right and left frontal and temporal sites on the scalp of groups of patients with schizophrenia (SCH, 8), obsessive compulsive disorder (OCD, 10) and healthy controls (CON, 19). Results: a) Both patient groups responded slower and showed more errors of omission than controls. b) A prepulse presented 100 ms (but not at 500 ms) before either tone reduced the P1 or P50 ERP amplitude on healthy controls, but showed a right temporal shift in the SCH patients. c) If the tone was the 'no-go' stimulus in the tone discrimination the prepulse reduced the N1 amplitude in both normal controls and SCH patients. This N100 amplitude was similar in records from over the left and right hemisphere of controls but was shifted to right temporal sites in the SCH group. d) OCD patients showed a relative predominance of the left hemisphere in the gating of frontal P1, N100 and P300 components, but early gating was not significantly impaired in this group. Conclusions: These results show a reduction of a PPI-like effect on early processing (e.g. P50/P1) that is more marked in the left hemisphere of SCH patients, and may affect channel selection for processing information about task-relevant sounds (e.g. N100)

Event-related potentials (ERPs) in schizophrenics have been reported to show a reduced P3 on the left and less frontal mismatch negativity. But the specificity of such findings to component, its locus, the type of eliciting event and patient group remains uncertain. Hence, we examined ERP topography for P3, N2 and 3 precursor peaks according to stimulus (3-tone oddball), attention condition (diffuse/focused) and four types of difference-waves (Mismatch negativity, Processing negativity, Negative difference (Nd) and the 'Goodin-Waveform'). Method: We contrasted ERPs in a 3-tone oddball task-form in 24 healthy (mean 18.5y of age) and 13 OCD (mean age 16.3 y) subjects with schizophrenic patients with high versus low ratings of active delusions and hallucinations (12 paranoid-hallucinatory, PH [mean age 18.5y]; 12 nonparanoid, NP [mean age 18.9y]) Results: 1. P3 peaks were delayed and reduced in NP and PH groups. Peaks in the midline were usual in the focused attention condition, but a right bias in diffuse attention (passive presentation). 2. P3 responses to irrelevant non-targets remained lateralised in NP, and small in OCD patients. All showed a small left and anterior bias in the P3-like peak recorded after subtraction in the difference waves. 3. Mismatch negativity (MMN) peaks shifted to the right in OCD, laterally to both sides in PH and more posteriorly in NP patients. 4. Frontal processing negativity was biased to the left (early) in NP and to the right (late) in PH groups. 5. Early peak topography in the difference waveforms reflected some of these later changes (e.g., for PH and NP groups the normal right bias in the P1-like peak was absent; the N1-like peak was reduced and widely distributed: for the NP group, the P2-like peak appeared smaller on the left). 6. In OCD patients, the peak latencies were topographically undifferentiated for P1 and P2, or delayed in the case of the N2 component. Conclusions: A) The OCD group showed an unusual regional allocation of processing effort. B) Before 200 ms, fronto-central activity was more widespread in both the PH and NP groups. C) NP patients, in particular, treated irrelevant stimuli anomalously. D) Lateralisation of negativity in target- and nontarget-derived difference waves may reflect differential disruption of the frontal-temporal dialogue in registering important vs. unimportant features. Indeed, the apparent left/right differences of negative difference (Nd) or processing negativity amplitude may not so much reflect amplitude differences as a delayed latency over left frontal areas in PH and over the right frontal areas in NP patients with schizophrenia.

Conditioned blocking (CB) refers to a delay in learning that a new stimulus, added during learning, has the same consequences as the conditioned stimulus already present. In animals such "learned inattention" depends on monoaminergic and limbic function and, thus, CB performance should be informative on selective information processing impairments found in subgroups of psychotic patients. Attenuated CB in acute schizophrenia has been reported to normalize rapidly. Method: This study examines in young patients the specificity of CB performance to illness, and its associations with symptoms, personality traits and monoaminergic metabolic status. Results: Performance: CB was attenuated in psychotic patients with nonparanoid symptoms (NP: n=12, mean age 17 years) with respect to obsessive compulsive (OCD: n=13, mean age 16 years) and healthy subjects (CON; n=29, mean age 18 years), but only a transient attenuation was observed in paranoid hallucinatory patients (PH: n=14, mean age 19 years). The severity of negative symptoms in psychosis and specific negative/positive symptoms in the NP/PH groups were associated with reduced CB. Outgoing personality traits in CON and OCD subjects correlated with CB. In NP patients attenuated CB was associated with increasing neurotic lability. In PH patients CB correlated positively with "manic" but negatively with psychotic or neurotic scores. Monoamines: Increased dopamine activity (24h urine samples) correlated positively with CB, but relative increases of noradrenaline metabolism in NP and serotonin metabolism in OCD patients interfered. Conclusions: Marked psychotic or neurotic traits and some negative symptom states were associated with reduced CB. The particular selective processing problems of NP patients may reflect inappropriate NA activity.

Objectives: Care planning should define care at the end of life in advance. At a later stage, when patients are no longer able to do this themselves, it should serve as a guideline for health care. The aim of this article is to give a first insight into the discussions around this social instrument., Study Design: The study design was comparing the arguments of proponents and critics., Methods: This is a critical discourse analysis., Results: A discussion of proponents and critics shows how closely this social instrument is interwoven with the areas of biopolitics, economics and governmentality., Conclusions: Further research should address the question of what quality assurance can look like., (Copyright © 2021 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Freezing of gait is a common phenomenon of advanced Parkinson's disease. Besides locomotor function per se, a role of cognitive deficits has been suggested. Limited evidence of associated dopaminergic deficits points to caudatal denervation. Further, altered functional connectivity within resting-state networks with importance for cognitive functions has been described in freezers. A potential pathophysiological link between both imaging findings has not yet been addressed. The current study sought to investigate the association between dopaminergic pathway dysintegrity and functional dysconnectivity in relation to FOG severity and cognitive performance in a well-characterized PD cohort undergoing high-resolution 6-[18F]fluoro-L-Dopa PET and functional MRI. The freezing of gait questionnaire was applied to categorize patients (n = 59) into freezers and non-freezers. A voxel-wise group comparison of 6-[18F]fluoro-L-Dopa PET scans with focus on striatum was performed between both well-matched and neuropsychologically characterized patient groups. Seed-to-voxel resting-state functional connectivity maps of the resulting dopamine depleted structures and dopaminergic midbrain regions were created and compared between both groups. For a direct between-group comparison of dopaminergic pathway integrity, a molecular connectivity approach was conducted on 6-[18F]fluoro-L-Dopa scans. With respect to striatal regions, freezers showed significant dopaminergic deficits in the left caudate nucleus, which exhibited altered functional connectivity with regions of the visual network. Regarding midbrain structures, the bilateral ventral tegmental area showed altered functional coupling to regions of the default mode network. An explorative examination of the integrity of dopaminergic pathways by molecular connectivity analysis revealed freezing-associated impairments in mesolimbic and mesocortical pathways. This study represents the first characterization of a link between dopaminergic pathway dysintegrity and altered functional connectivity in Parkinson's disease with freezing of gait and hints at a specific involvement of striatocortical and mesocorticolimbic pathways in freezers., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Basal ganglia (BG) circuitry plays a crucial role in the control of movement. Degeneration of its pathways and imbalance of dopaminergic signalling goes along with movement disorders such as Parkinson's disease. In this study, we explore the interaction of degeneration in two BG pathways (the nigro-striatal and dentato-pallidal pathway) with D2 receptor signalling to elucidate an association to motor impairment and medication response. Included in the study were 24 parkinsonian patients [male, 62 years (± 9.3 SD)] compared to 24 healthy controls [male, 63 years (± 10.2 SD)]; each participant passed through three phases of the study (i) acquisition of metadata/clinical testing, (ii) genotyping and (iii) anatomical/diffusion MRI. We report a decline in nigro-striatal (p < .003) and dentato-pallidal (p < .0001) connectivity in the patients compared to controls, which is associated with increasing motor impairment (relating to nigro-striatal, r = -0.48; p < .001 and dentato-pallidal connectivity, r = -0.36; p = .035). Given, that variations of the ANKK1 Taq1 (rs 1,800,497) allele alters dopamine D2-dependent responses, all participants were genotyped respectively. By grouping patients (and controls) according to their ANKK1 genotype, we demonstrate a link between D2 receptor signalling and decline in connectivity in both investigated pathways for the A1- variant (nigro-striatal pathway: r = -0.53; p = .012, dentato-pallidal pathway: r = -0.62; p = .0012). In patients with the A1+ variant, we only found increased brain connectivity in the dentato-pallidal pathway (r = 0.71; p = .001) correlating with increasing motor impairment, suggesting a potentially compensatory function of the cerebellum. Related to medication response carriers of the A1+ variant had a better drug effect associated with stronger brain connectivity in the nigro-striatal pathway (r = 0.54; p < .02); the A1- group had a good medication response although nigro-striatal connectivity was diminished (r = -0.38; p < .05); these results underscore differences in receptor availability between both groups in the nigro-striatal pathway. No effect onto medication response was found in the dentato-pallidal pathway (p > .05). Interplay between basal ganglia connectivity and D2 receptor availability influence the clinical presentation and medication response of parkinsonian patients. Furthermore, while current models of basal-ganglia function emphasize that balanced activity in the direct and indirect pathways is required for normal movement, our data highlight a role of the cerebellum in compensating for physiological imbalances in this respect., (Copyright © 2019. Published by Elsevier Inc.)

We report on a case of epilepsia partialis continua with rapid response to intravenous bolus administration of levetiracetam. A 60-year-old woman presented with continuous jerking of the right foot and hallux persisting for more than two days. She had a 9-year history of epilepsy due to a left temporoparietal oligodendroglioma with occasional focal seizures clinically presenting as speech arrest, which was treated with levetiracetam and oxcarbazepine administered orally. After hospital admission, the twitching of the foot and toe was refractory to add-on treatment with lorazepam and diazepam but stopped within 15 min after intravenous bolus administration of 2000 mg levetiracetam. This observation suggests that intravenous bolus administration of levetiracetam may be an effective therapeutic option in epilepsia partialis continua.

High resolution positron emission tomography (PET) with the newly developed HRRT scanner (Siemens/CTI) permits the reliable quantification of 18-Fluorodeoxyglucose (FDG) uptake as a marker of neuronal activity in small subcortical nuclei which are involved in the pathophysiology of Parkinson's disease (PD). We investigated the normalized cerebral metabolic rates of glucose (nCMRGlc) with HRRT PET in basal ganglia (BG) nuclei of 10 early-stage PD patients and in 9 healthy volunteers. PET data were co-registered to magnetic resonance images and analyzed in a three-dimensional volume-of-interest (VOI) approach. After normalization for global brain activity, PD patients showed a significantly higher nCMRGlc than controls bilaterally in the BG output nuclei (pallidum, substantia nigra) and unilateral in the caudate and putamen. The metabolic activity of the nucleus accumbens, the subthalamic nucleus, the corpus amygdaloideum and the red nucleus was normal. These first HRRT PET data in living parkinsonian humans extend previous brain imaging findings of abnormal network activity in the BG and confirm output nuclei and striatal overactivation also in early stage PD patients.

In this study we surveyed a total of 218 cerebrospinal fluid (CSF) samples from patients with different neurological diseases including Alzheimer disease, non-Alzheimer forms of dementia, other neurodegenerative diseases without dementia and normal controls to quantitate by capture ELISA the concentrations of the immunoglobulin superfamily adhesion molecules L1 and NCAM, and characterized by immunoblot analysis the molecular forms of L1 and NCAM. We found a significant increase of L1 and a strong tendency for increase of the soluble fragments of NCAM in the CSF of Alzheimer patients compared to the normal control group. The proteolytic fragments of L1, but not NCAM were also elevated in patients with vascular dementia and dementia of mixed type. Higher L1 concentrations were observed irrespective of age and gender. NCAM concentrations were independent of gender, but positively correlated with age and, surprisingly, also with incidence of multiple sclerosis. Thus, there was an influence of Alzheimer and non-Alzheimer dementias and neurodegeneration on L1, whereas age and neurodegeneration influenced NCAM concentrations. These observations point to an abnormal processing and/or shedding of L1 and NCAM in dementia-related neurodegeneration and age, respectively, reflecting changes in adhesion molecule-related cell interactions.

Ecotin is a homodimeric protein from Escherichia coli that inhibits many serine proteases of the chymotrypsin fold, often with little effect from the character or extent of enzyme substrate specificity. This pan-specificity of inhibition is believed to derive from formation of a heterotetrameric complex with target proteases involving three types of interface: the dimerization interface, a primary substrate-like interaction, and a smaller secondary interaction between the partner ecotin subunit and the protease. A monomeric ecotin variant (mEcotin) and a single-chain ecotin dimer (scEcotin) were constructed to study the effect of a network of protein interactions on binding affinity and the role of dimerization in broad inhibitor specificity. mEcotin was produced by inserting a beta-turn into the C-terminal arm, which normally exchanges with the other subunit. While the dimerization constant (K(dim)) of wild-type (WT) ecotin was found to be picomolar by subunit exchange experiments using FRET and by association kinetics, mEcotin was monomeric up to 1 mM as judged by gel filtration and analytical centrifugation. A crystal structure of uncomplexed mEcotin to 2.0 A resolution verifies the design, showing a monomeric protein in which the C-terminal arm folds back onto itself to form a beta-barrel structure nearly identical to its dimeric counterpart. The kinetic rate constants and equilibrium dissociation constants for monomeric and dimeric ecotin variants were determined with both trypsin and chymotrypsin. The effect of the secondary binding site on affinity was found to vary inversely with the strength of the interaction at the primary site. This compensatory effect yields a nonadditivity of up to 5 kcal/mol and can be explained in terms of the optimization of binding orientation. Such a mechanism of adaptability allows femtomolar affinities for two proteases with very different specificities., (Copyright 2001 Academic Press.)

Objective: The problems children with attention-deficit/hyperactivity disorder (ADHD) encounter in tasks measuring inhibitory control are often theoretically related to deficits in cognitive processes. This study investigated the effects of different motivational incentives on the ability of children to inhibit intended or ongoing actions., Method: In a large German industrial town, 33 children with ADHD were compared with 33 members of a combined group of children with major depressive disorder, anxiety disorders, oppositional defiant disorder, or conduct disorder, and 33 children without any psychiatric disorder with respect to their performances in a stop-signal task. The children received continuous feedback under high- or low-incentive conditions. The children's performance was compared in terms of qualitative (inhibition rate) and quantitative (reaction time) measures., Results: There were no indications of deficits in sustained attention in children with ADHD. Under conditions of low incentives, children with ADHD were less able to inhibit their reactions and had longer stop-signal reaction times. But when given high incentives, children with ADHD performed the task as well as both other groups., Conclusions: Supposed deficits in children with ADHD should be regarded from a perspective that differentiates performance from ability. Furthermore, the findings support a motivational explanation of the origins of lowered inhibitory control in children with ADHD.

A patient had a paraneoplastic autonomic, then sensory, then sensory-motor neuropathy with small cell lung carcinoma and a high titer Anti-Hu antibody to nuclei of neuronal cells. As an unusual finding there was electrophysiological and pathological evidence of demyelination and a peripheral nerve microvasculitis. The relationship of microvasculitis and peripheral nerve demyelination is discussed and their occurrence with paraneoplastic anti-Hu-associated sensory neuropathy is suggested not to be by chance.

Event-related potentials (ERPS) in schizophrenics have been reported to show a reduced P3 on the left and less frontal mismatch negativity (MMN). But the specificity of such findings to component, its locus, the type of eliciting event and patient group remains uncertain. Hence, we examined ERP topography for P3, N2 and 3 precursor peaks according to stimulus (3-tone oddball), attention condition (diffuse/focused) and four types of difference-waves. We contrasted 24 healthy and 13 OCD subjects with schizophrenic patients with high versus low ratings of active delusions and hallucinations (12 paranoid-hallucinatory, PH; 12 nonparanoid, NP). P3 peaks were delayed and reduced in NP and PH groups. Midline peaks were usual in focused attention and a right bias in diffuse attention. P3 responses to irrelevant standards remained lateral in NP and small in OCD patients. All showed a small left and anterior bias in the P3-like peak in difference-waves. Mismatch negativity waveform (MMN) peaks shifted to the right in OCD, to both sides in PH and posteriorly in NP patients. Frontal processing negativity was biased to the left (early) in NP and to the right (late) in PH groups. Early peak topography reflected some later changes (e.g. PH and NP groups; P1-like peak, right bias absent; N1-like peak depressed and widely distributed; NP group, P2-like peak smaller on the left). In OCD patients, peak latencies were topographically undifferentiated (P1, P2) or delayed (N2). The OCD group showed an unusual regional allocation of processing effort. Before 200 ms frontocentral activity was more widespread in Ph and NP groups. Lateralization of negativity in target- and nontarget-derived difference-waves may reflect differential disruption of the frontal-temporal dialogue in registering important vs unimportant features. NP patients, in particular, treated irrelevant stimuli anomalously.

We have established a precise and accurate high-performance liquid chromatographic method for the simultaneous assay of carbamazepine, phenytoin, phenobarbital, primidone and their principal metabolites. This method has been used for the analysis of these drugs and the metabolites in serum, saliva and urine samples. Acetonitrile is used for the deproteinization of serum and saliva samples while solid-phase extraction is utilized for urine sample pretreatment. Samples of 2 microliters are injected onto a 3-microns ODS-Hypersil column (250 mm x 2 mm I.D.) with a column temperature of 40 degrees C. The drugs and metabolites are eluted with a mobile phase containing potassium phosphate buffer-acetonitrile-methanol (110:50:30, v/v/v) at a flow-rate of 0.2 ml/min. Signals are monitored by a photodiode-array detector at a sample wavelength of 200 nm with a bandwidth of 10 nm. These four commonly used antiepileptic drugs and their six metabolites are well separated from one another within 15 min. Within-day coefficients of variation (C.V.) are within 5% in most cases and between-day C.V. are from 2.32 to 4.75%. The recovery rates range from 95.12 to 104.42%. This method has the necessary sensitivity and linearity for routine therapeutic monitoring of both total and free drug levels and may be employed for pharmacokinetics studies of drug interactions and metabolism as well.

The derivatization of valproic acid and undecylenic acid with 4-bromomethyl-7-methoxycoumarin is described. The derivatives were detected by photodiode-array and fluorescence detectors. The optimum monitoring conditions and the stability of the suspension solution and derivatives were investigated. A high-performance liquid chromatographic (HPLC) method with isocratic or gradient elution has been established for the analysis. This method has been used for the determination of total and free valproic acid in serum. There is a satisfactory correlation between the results obtained by this HPLC method and those measured by the enzyme immunoassay. Some other common anti-epileptic drugs did not interfere with the analysis. The method is simple and fast and has better sensitivity and linearity than enzyme immunoassay. It is suited for routine therapeutic drug monitoring.