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Skizofreni udvikles typisk over adskillige år. Symptomerne vedrører i reglen selv-bevidstheden og erkendelsesevnen. Der kan opstilles testbare hypoteser om sammenhængen mellem nervesystemets udvikling, kognitivt fysiologiske undersøgelsesresultater og forløbet af skizofreni. Med udgangspunkt i en arvelig/tidlig exogen biologisk fejl kan sygdomsprocessen forstås via sekundære patogetiske mekanismer på det neuroplastiske, det kliniske og det sociale niveau.

Aim: Fewer patient encounters and diminished bedside teaching pose a challenge to medical students’ opportunity to learn during clinical clerkships in psychiatry. Videos can be used for close examination of signs and symptoms and to increase engagement and recall. A video library holding recordings of psychiatric patients with mental status examinations were prepared. We explored the students’ use of this library during their clerkships. Methods and materials: The video library was introduced to three rotations of medical students and made accessible on hospital computers. Four students volunteered as key informants and were followed daily throughout the clerkship by the first author, using the ethnographic method of participant observation. At the end of the clerkship, group interviews were conducted with each rotation of students, including the key informants. Twelve students participated in the study. Field notes taken during participant observation and the transcribed interviews were merged in a thematic analysis. Results: The analysis reveals the students’ autonomous and arbitrary use of the video library. Creatively extending the use of the videos, they scheduled their video sessions according to their individual needs. The students furthermore blended experiences gained from the library and in the ward, thus coping in various ways with the shortcomings of the video library. Conclusions: The medical students felt they benefited from the simplified learning situation offered by the video library. Their frequent shortcuts through the videos during sessions highlighted weaknesses in the feedback and reflection processes occasioned by the library.

Background: The Mental Status Examination (MSE) is a core element of the psychiatric assessment. To investigate the current level of psychopathological knowledge, the reliability of the MSE can be ...

Objective During psychiatric rotation, clerkship students must learn the clinical skill of recording an accurate Mental Status Examination (MSE). The authors built a video e-library consisting of 23 authentic patient videos that were accessible on a secure website during the rotation period, aimed at assisting students’ acquisition of MSE skills. Methods The authors conducted a prospective case comparison study investigating the impact of the video e-library as “add-on” intervention, on acquisition of MSE skills, as measured by a test consisting of three videos with adjoining forced choice questionnaires. Eighty-five clerkship students had instructions and access to the video e-library whereas 82 did not. A group of clinicians, unfamiliar with the video e-library, was also subjected to the new MSE skills test and they served as a reference group. Outcome was defined as scores of MSE skills measured by the purpose made MSE skills test and entailed evaluation questions on the students’ use of the e-library. Results The MSE skill test score differed between the three groups, and the clinicians scored higher than both student groups (clinicians mean score (M) 12.6; p < 0.001). However, the students with video access scored higher compared to students without access (M 10.7 versus M 9.9, p = 0.04). The e-library was appreciated by the students as helpful (83.6%) and they used it not only for practicing the MSE but also for observation of interviewing techniques. Conclusion The e-library with video vignettes of authentic patients strengthens MSE skills as “add-on” to the psychiatric rotation, and evaluations by the students were positive.

Autoregulation of cerebral blood flow (CBF) was studied in anaesthetized rats during acute ethanol intoxication (blood alcohol concentration 2.5 to 3 g/l). For each rat an autoregulation curve was determined: 8-10 CBF measurements were made over the mean arterial pressure range 129 mmHg to 20 mmHg. MAP was raised above the resting level by angiotension II infusion, then lowered by controlled haemorrhage. In control rats, CBF autoregulation was demonstrated within the MAP range 129 mmHg to 70 mmHg: at lower pressure autoregulation was inadequate and CBF fell. In ethanol intoxicated rats CBF autoregulation was demonstrated within the MAP range 129 mmHg to 50 mmHg: at lower pressure CBF fell. Although the lower limit of CBF autoregulation was thus at an MAP 20 mmHg less than in control rats, this probably reflects suppression of cerebral metabolism, rather than an effect of ethanol on CBF autoregulation per se.

The effect of the central depressants nitrous oxide, halothane, pentobarbital and ethanol upon cerebral blood flow (CBF), cerebral oxygen consumption (CMRO2) and cerebral vascular reactivity to carbon dioxide were measured using the rapid and repetitive intraarterial 133Xenon injection technique modified for rat studies. The cerebrovascular resistance (CVR) during normocapnia in the pentobarbital group was significantly higher (P less than 0.01) than in the nitrous oxide group thus indicating a vasoconstrictor effect of pentobarbital that may be clinically important, because the ability of barbiturates to contract vessels in healthy brain regions may partly explain the protective properties of these drugs against cerebral ischemia. The results indicated that pentobarbital and ethanol may act synergistically with carbon dioxide in depressing CMRO2 and cerebral vascular reactivity. Finally, it is concluded that nitrous oxide anaesthesia (70% N2O: 30% O2) is suitable as a reference situation in rat studies of the effect of pharmocological agents on CBF, CMRO2 and cerebrovascular reactivity.

Clinically, patients with Delirium Tremens (DT) and acute alcohol hallucinosis (impending DT) appear excited with vivid false perception. Cerebral blood flow and eeg correspondingly point to hyperexcitability in the CNS during these conditions. Clinical trials with barbital treatment in alcohol withdrawal shows that the amount of drug and the drug plasma concentration is the same no matter whether the physical signs of withdrawal are accompanied by hallucinations and clouding of consciousness. The psychotic signs in DT and acute alcoholic hallucinosis develops after many years of alcoholism as does seizures. We hypothesize that physical withdrawal is determined by the degree of physical dependence developed during the most recent drinking period whereas the psychotic signs and seizures are due to a cumulated CNS hyperactivity developed over many years of repeated alcohol intoxication and withdrawal. Changes of electrolyte concentrations in plasma or CSF do not play an important role in the pathogenesis of DT and related clinical states except that changes in calcium and inorganic phosphate metabolism indirectly point to changes in membrane excitability. A new model for a study of rapidly repeated intoxication and withdrawal episodes in rats has shown that repetition of episodes augments the convulsive component of withdrawal whereas the non-convulsive signs are dependent on the most recent episode only. The augmentation of the convulsive component correlates with regional differences in brain glucose consumption. Furthermore, synaptic proteins and acidic phospholipids may be involved in the development of CNS hyperexcitability during alcohol withdrawal. In conclusion both clinical and experimental studies indicate that severe alcohol withdrawal reactions may consist of two components: 1) Physical withdrawal signs determined by recent physical dependence. 2) A long term cumulated CNS hyperexcitability relating to seizures and psychotic signs during withdrawal. This state is elicited by alcohol withdrawal but it represents a cumulated and permanent or long lasting CNS dysfunction in alcoholics. The precise biochemical/pathophysiological mechanisms for the development of the two-component dysfunction still remain to be clarified in detail.

The present study examined basal ganglia volumes in drug-naive first-episode schizophrenic patients before and after treatment with either a specific typical or atypical antipsychotic compound. Sixteen antipsychotic drug-naive and three minimally medicated first-episode schizophrenic patients and 19 matched controls participated. Patients were randomly assigned to treatment with either low doses of the typical antipsychotic drug, zuclopenthixol, or the atypical compound, risperidone. High-resolution magnetic resonance imaging (MRI) scans were obtained in patients before and after 12 weeks of exposure to medication and in controls at baseline. Caudate nucleus, nucleus accumbens, and putamen volumes were measured. Compared with controls, absolute volumes of interest (VOIs) were smaller in patients at baseline and increased after treatment. However, with controls for age, gender and whole brain or intracranial volume, the only significant difference between patients and controls was a Hemisphere x Group interaction for the caudate nucleus at baseline, with controls having larger left than right caudate nuclei and patients having marginally larger right than left caudate volumes. Within patients, the two medication groups did not differ significantly with respect to volume changes after 3 months of low dose treatment in any of the VOIs. Nevertheless, when medication groups were examined separately, a significant volume increase in the putamen was evidenced in the risperidone group. The altered asymmetry in caudate volume in patients suggests intrinsic basal ganglia pathology in schizophrenia, most likely of neurodevelopmental origin.

In an attempt to delineate the prefrontal cortex (PFC) in the Göttingen minipig brain the distribution of reciprocal thalamocortical projections was investigated using anterograde and retrograde tracing techniques and evaluated in relation to the specific cytoarchitectonic organization. Tracers were visualized using standard immunohistochemistry or evaluated in vivo using manganese (Mn2+) as an MRI paramagnetic tracer. The in vivo tract tracing turned out to be very sensitive with a high correspondence to the histological labelling. Tracers injected into the mediodorsal thalamus labelled the medial and rostral pole of the frontal lobe as well as the anterior cingulate, anterior insular and dorsomedial frontal cortices. Subsequently, the reciprocity and specificity of these connections were tested from injections into the traced frontal cortices indicating that the PFC has cortical connections to different parts of the MD nucleus. Although the granular layer IV, characteristic of primate PFC could not be identified, both cytoarchitectonic and connectional data suggests that the Göttingen minipig has a structurally divided prefrontal cortex. Stereological estimates of PFC volume showed that the Göttingen minipig PFC constitutes about 24% of the total neocortex volume and 10% of the total brain volume.

The postnatal development of total number and perikaryon volume of cerebellar Purkinje cells was estimated in the Göttingen minipig cerebellar cortex using a new stereological approach, the vertical bar fractionator. Data were obtained from the brains of five neonate and five adult female Göttingen minipigs. The total number of Purkinje cells ranged from 1.83 x 10(6) in the neonate to 2.82 x 10(6) in the adult Göttingen minipig. The number-weighted mean perikaryon volume of Purkinje cells increased concurrently from around 6,800 microm(3) in the neonate to 17,600 microm(3) in the adult. The study demonstrates that a pronounced postnatal neurogenesis in Purkinje cell number and perikaryon volume is part of the growth and development of the cerebellum in the Göttingen minipig. The Purkinje cells of the Göttingen minipig were found to be substantially large compared with human and represents the largest cells described hitherto from mammalian cerebella. The vertical fractionator is a new sampling technique, which allows the combination of a fractionator design on vertical bar sections excluding exhaustive sampling and bias from artificial edges. By design, the sections are perfect stereological vertical sections and provide the basis for unbiased estimates of total number of structural entities in the brain, including surface area, fibre length and particle volume.

The 32-bp deletion allele in chemokine receptor CCR5 has been associated with several immune-mediated diseases and might be implicated in schizophrenia as well.The authors genotyped DNA samples from 268 schizophrenia patients and 323 healthy subjects. Age at first admission to a psychiatric hospital department served as a measure of disease onset.Patients and comparison subjects differed marginally in their genotype distribution, with a slightly higher frequency of the deletion allele seen in the patients. The authors found the deletion allele to be associated with higher age at first admission. After age at first admission was analyzed as a continuous variable, it was dichotomized using 40 years as the cutoff. With this approach the authors found that genotype distributions of patients with age at first admission above the cutoff (possible cases of late-onset schizophrenia) and healthy subjects differed significantly. This was reflected in an increased frequency of the deletion allele in the patient subgroup. Patients with ages at first admission below and above 40 years significantly differed in distribution of genotypes and alleles, with an overrepresentation of the deletion allele in the latter subgroup of patients.These findings suggest that the CCR5 32-bp deletion allele is a susceptibility factor for schizophrenia with late onset. Alternatively, the CCR5 32-bp deletion allele may act as a modifier by delaying the onset of schizophrenia without affecting the disease susceptibility.

Udgivelsesdato: 2005-Nov-7 Behavioral response to novelty in rats has been linked both to dopamine transmission in the ventral striatum, and to propensity to self-administer psychostimulant drugs. In order to probe the relationship between behavioral response to novelty and dopamine systems we have developed a behavioral model for correlation with positron emission tomography (PET) of dopamine transmission in brain of Göttingen minipigs. In the present study, we measured exploration of a novel object by recording the number of contacts, and duration of contact with a novel object, in groups of six male and six female adult minipigs. We hypothesized that these novelty scores would correlate with the amphetamine-evoked dopamine release in ventral striatum, measured 2 weeks later in a PET study of the availability of binding sites for the dopamine D2/3 antagonist [11C]raclopride. There were significant correlations between duration of contact with a novel object and the amphetamine-evoked reductions in binding potential (DeltapB) in the left ventral striatum of the 12 animals; Comparison of results by gender revealed that the correlation was driven mainly by the male group, and was not present in the female group. We interpret these results to show that propensity to explore an unfamiliar object is relatively elevated in pigs with low basal occupancy of dopamine D2/3 receptors by endogenous dopamine, and with high amphetamine-induced occupancy of released dopamine in the male pigs.

Prepulse inhibition (PPI) is used as a measure for sensorimotor gating. Studies in animals have indicated that hippocampus and entorhinal cortex, structures which are affected in mild Alzheimer's disease (AD), are involved in the regulation of PPI. The objectives of this study were to determine if patients with very mild AD had altered PPI, and to study possible correlations between PPI and cognitive performance or neuropsychiatric symptoms. A passive acoustic PPI paradigm was applied in 48 patients with either mild AD or Mild Cognitive Impairment (MCI) and in 49 healthy controls. No differences were found between patients and healthy controls regarding PPI. Further, PPI was not found to correlate with cognitive performance or neuropsychiatric symptoms. PPI is significantly altered in patients with neuropsychiatric disorders associated with dopaminergic, glutamatergic and/or serotonergic dysfunctions, such as schizophrenia. Since mild AD is primarily associated with loss of cholinergic markers in the limbic regions this study suggests that acetylcholine only plays a minor role in the regulation of PPI.

Göttingen minipigs were trained on a set-shifting procedure involving discriminations, reversals, and extra-dimensional shifts. The discriminations used were black-white discriminations and right-left discriminations. The initial visual and spatial discrimination seemed equally difficult, and only for the visual modality was reversal found to be more difficult than the initial discrimination. Visual reversal was more difficult than spatial reversal, and a larger number of perseverative sessions were found for visual reversal compared to spatial reversal. The acquisition of the extra-dimensional shift from the visual to the spatial dimension was not inferior to the learning of spatial reversal. Neither was the acquisition of the extra-dimensional shift from the spatial to the visual dimension inferior to the learning of visual reversal. Thus, no evidence was found for attention to stimulus dimensions in discrimination learning of the pigs.

Background: Studies on the effects of antipsychotics on cognitive deficits in schizophrenia mostly suggest a superior effect of atypical over typical compounds, although findings are inconsistent and effect sizes small. Several methodological issues, such as heterogenous patient samples, incomparable drug doses, effects of prior medication, construct validity, and retest effects on neuropsychological tasks, confound most results and the comparability between studies. Consequently, the conclusion concerning effects of antipsychotics on cognition is still equivocal.Objective: The present randomized clinical trial examined the effects on cognition of comparatively low doses of a typical antipsychotic (zuclopenthixol) and an atypical antipsychotic (risperidone) in a homogenous group of drug-naïve first-episode schizophrenic patients in a longitudinal setting.Methods: First-episode schizophrenic patients who had never previously been exposed to antipsychotic treatment (N-25) were randomly allocated to treatment with flexible doses of zuclopenthixol or risperidone in an open-label design. Cognitive functions were examined both when patients were drug-naïve, and after 13 weeks of treatment. A comprehensive neuropsychological battery was used in order to optimize construct validity, and principal components of cognitive functions were extrapolated in order to reduce type I errors. A healthy control group was tested at baseline and after 13 weeks, in order to examine retest effects. The cognitive domains studied were executive functions, selective attention, and reaction time.Results: The patients showed considerable cognitive deficits when drug-naïve. There were few differential effects of risperidone and zuclopenthixol on cognitive deficits, except for a differential significance, respectively, tendency towards improved reaction and movement times in the risperidone group, and a lack of such in the zuclopenthixol group. These differences were no longer significant after covarying for extrapyramidal side effects and anticholinergic medication that were more prevalent in the zuclopenthixol group and the increases after medication were comparable with retest effects in controls.Conclusion: The study underscores the importance of examining impact of factors, such as clinical improvement, extrapyramidal side effects, anticholinergic medication and retest effects in longitudinal efficacy studies. This study does not support efficacy of either risperidone or zuclopenthixol on cognitive functions in drug-naïve schizophrenia patients after 3 months of medication, because neither could be distinguished from retest effects of the healthy control group.

Pre-pulse inhibition (PPI) of the startle response is a measure of sensorimotor gating which has been frequently shown to be deficient in schizophrenic patients. In humans it is typically measured as the attenuation of the startle eye-blink reflex EMG when a startle eliciting noise is preceded by a weak white noise pre-pulse (PP), the interval between the PP and the startle noise stimulus (SNS) determining the degree of inhibition. Aiming at developing a new animal model of schizophrenia, we have investigated the acoustic startle eye-blink and PPI in 10 Göttingen minipigs. The stimuli and the block design of the stimulation were similar to paradigms used in human research. Initially the startle habituation across trials and blocks, secondarily the PPI at PP to SNS intervals of 30, 60, 120, 220, 520, 1020 and 2020 ms was investigated. One pig out of ten did not have a startle response, and three other pigs did not have a startle response of a sufficient magnitude to demonstrate the PPI seen in the other six pigs at the expected PP intervals of 60, 120, and 220 ms. Maximal inhibition was seen at the 220 ms interval (mean PPI 58.6%, range -18.4 to 94.6%, N = 9). Most of the results in the pigs are in accordance with findings in studies of the human startle eye-blink EMG and this initial study promotes further studies and the use of the PPI measure in the validation of minipig models of psychiatric disorders.

Objectives: To estimate the prevalence of psychiatric morbidity and the effect of systematic psychiatric evaluation in patients referred to a memory clinic in a neurological setting. Design: Descriptive case-series study in consecutive referrals to a memory clinic. Setting: An outpatient multidisciplinary memory clinic in a neurological setting. Participants: An index group of 100 consecutive patients (aged 60–89) referred for diagnostic evaluation of cognitive symptoms during a period of 8 months and a reference group of 686 consecutive patients (aged 60–98) referred during a previous period of 54 months. In the index group, a systematic psychiatric evaluation was performed in addition to the neurological evaluation and routine investigations. In the reference group, patients had the same basic evaluation, but psychiatric evaluation was optional and was performed in 21% of the patients. Measurements: Prevalence of primary psychiatric morbidity in the index and reference groups according to international clinical criteria and multidisciplinary consensus report and three key psychiatric symptoms: delusions, hallucinations, and affective symptoms in the index group. Results: Twenty-three percent of patients in the index group had a primary psychiatric disease. A primary psychiatric disease was diagnosed in 8% of patients in the reference group (P

The purpose of the study was to evaluate psychiatric emergency outreach after functioning for a period of 2 years in Copenhagen, Denmark. Psychiatric emergency outreach was staffed by a psychiatrist and an ambulance driver, and the target group was defined as mentally ill and persons in severe crisis. For each of 935 calls covering 777 different patients, a registration form with social and clinically relevant data was filled out. After the 2-year period, patients were looked up in the National Cause of Death Register and the National Psychiatric Case Register. A total of 66% were previously registered as psychiatric patients, and in 37% of all calls, the patient had psychotic symptoms. In 25% of the calls, the patient was admitted to psychiatric hospital; 38% of the admissions were involuntary. Forty-eight per cent of the calls were initiated by relatives, friends or neighbours. Suicidal behaviour was frequent. There were significantly more calls in socially deprived areas. Standard Mortality Rates were high for all causes of death (5.00), and especially for suicide (31.98). In conclusion, psychiatric emergency outreach seems to fulfil some of its purpose.

Significant somatosensory evoked potential (SEP) P50 gating has previously been found in young healthy men by the use of identical paired stimuli. In this study, the exploration of the gating paradigm was extended with the addition of a mixed modality paradigm where three different pairs of identical stimuli (clicks, right median nerve electric stimulations and proprioceptive stimuli of changing load on a handheld weight) were presented over a 12-s cycle. In both modalities repeated measures analyses of variance demonstrated no effect of paradigm. This mixed-modality recording paradigm could be used in further experiments to examine gating deficits across modalities.

We studied cerebral evoked potentials on the scalp to the stimulation of the right hand from a change in weight of 400-480 g in ten subjects. Rise-time was 20g/10 ms, Inter Stimulus Interval 2s and stimulus duration was 100 ms. The cerebral activations were a double positive contralateral C3'/P70, P190, and a single negative frontal Fz/N70 component. We conclude that a brisk change of a hand held load elicits a significant evoked potential (EP) unlike the electrical somato-sensory EP (SEP). The stimulus is perceived as applied force. For this reason we call it a proprioceptive EP (PEP). Further studies of the PEP are needed to assess the influence of load manipulations and of muscle contraction and to explore the effect of attentional manipulation.

Objective: To compare two levels of stress (solitary confinement (SC) and non-SC) among remand prisoners as to incidence of psychiatric disorders in relation to prevalent disorders. Method: Longitudinal repeated assessments were carried out from the start and during the remand phase of imprisonment. Both interview-based and self-reported measures were applied to 133 remand prisoners in SC and 95 remand prisoners in non-SC randomly selected in a parallel study design. Results: Incidence of psychiatric disorders developed in the prison was significantly higher in SC prisoners (28%) than in non-SC prisoners (15%). Most disorders were adjustment disorders, with depressive disorders coming next. Incident psychotic disorders were rare. The difference regarding incidence was primarily explained by level of stress (i.e. prison form) rather than confounding factors. Quantitative measures of psychopathology (Hamilton Scales and General Health Questionnaire) were significantly higher in subjects with prevalent and incident disorders compared to non-disordered subjects. Conclusion: Different levels of stress give rise to different incidence of psychiatric morbidity among remand prisoners. The surplus of incident disorders among SC prisoners is related to SC, which may act as a mental health hazard.

Madsen AL, Vorstrup S, Rubin P, Larsen JK, Hemmingsen R. Neurological abnormalities in schizophrenic patients: a prospective follow-up study 5 years after first admission. Acta Psychiatr Scand 1999: 100: 119–125. © Munksgaard 1999. Objective: The aim of this study was to examine the temporal stability of neurological abnormalities in first-episode schizophrenic patients, and to clarify the relationships between such abnormalities and psychopathology. Method: A total of 18 schizophrenic patients, 11 non-schizophrenic patients and 10 healthy volunteers were examined neurologically at first admission and 5 years later. Results: A significant increase in the number of neurological abnormalities was seen in schizophrenic patients with genetic predisposition and in patients with a non-remitting course of disease. Birth complications had an impact on the occurrence of neurological abnormalities at first admission. Conclusion: The association between a deteriorating course of disease and neurological impairment supports the theory that any possible impairment of the brain in schizophrenia is aggravated during the first 5 years of disease.

Two random samples of Danish prisoners on remand (solitary confinement (SC) and non-SC)) were examined using semistructured and standardized psychiatric and social interviews, cognitive tests, and questionnaires. Heroin dependence was divided into injection heroin dependence (IHD) and smoke heroin dependence (SHD). Comparisons corrected for confounders were made with regard to IHD versus SHD and dependent versus non-dependent subjects. Thirty-two per cent of the sample had lifetime heroin dependence, and the IHD versus SHD ratio was 3:1. The IHD subjects were more severely strained than SHD with regard to somatic complications (blood-transferred infections), early social strain, psychiatric comorbidity (mood disorders), personality dimensions (introversion), and cognitive performance (low performance scale score). The IHD subjects were considered more vulnerable than SHD subjects, both premorbid and during the dependence. SHD subjects may be recruited from other groups than the traditional (that is, IHD) ...

In order to investigate whether alcohol-withdrawal kindling is an irreversible process, male Wistar rats were exposed to 12 episodes, each consisting of 2 days of severe alcohol intoxication and 5 days of alcohol withdrawal. Spontaneous withdrawal seizures were found in 15% of the animals during episodes 10-12. After an alcohol-free period of 26 days, the animals were subjected to three more episodes of alcohol dependence (i.e. episodes 13-15) in which 12% of the animals developed spontaneous withdrawal seizures. Based on several statistical tests, we concluded that there was no true difference between the seizure activity in episodes 10-12 and episodes 13-15, indicating that alcohol-withdrawal kindling is a long-lasting and perhaps irreversible process. In a second experiment, an alcohol-withdrawal kindled group was first exposed to seven episodes of alcohol dependence. A diazepam group went through the same alcohol regimen, but each withdrawal reaction was blocked by diazepam treatment. Finally, a single episode group was included which was fed isocalorically with the kindled animals. After an alcohol-free period of 11 days, all three groups were subjected to 4 days of severe alcohol intoxication. During the subsequent withdrawal reaction seizures were observed in 22-26% of the animals with no significant differences across the groups. These results call for a modification of the kindling hypothesis of alcohol withdrawal and suggest that kindling-induced alterations may be overlooked if convulsive behaviour is tested during a relatively strong withdrawal reaction.

Neural network modeling is situated between neurobiology, cognitive science, and neuropsychology. The structural and functional resemblance with biological computation has made artificial neural networks (ANN) useful for exploring the relationship between neurobiology and computational performance, i.e., cognition and behavior. This review provides an introduction to the theory of ANN and how they have linked theories from neurobiology and psychopathology in schizophrenia, affective disorders, and dementia.

During repeated alcohol withdrawal, convulsive withdrawal behavior has been shown to be increased in a kindling-like manner in both clinical and experimental studies. In the present experiment, quantitative autoradiography was used to investigate binding of tritiated ligands to glutamate receptor subtypes and the benzodiazepine/GABA (BZ/GABA) receptor complex in rats exposed to 14 episodes of alcohol withdrawal. Seizures were detected in 25% of the animals during withdrawal episode 10-13. Repeated alcohol withdrawal resulted in a decrease in the number of [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]-AMPA) binding sites in striatum and sub-regions of the entorhinal cortex, the cerebellum and the hippocampus, while the [3H]-flunitrazepam binding was down-regulated in the frontal cortex. There was no differences between the controls and the multiple withdrawal animals regarding the [3H]-dizocilpine ([3H]-MK801) binding and the [3H]-kainic acid binding. However, within the latter group, those animals in which withdrawal seizures were observed had increased [3H]-MK801 binding sites in focal regions of entorhinal cortex and hippocampus, compared to those in which seizures were not observed. The decreased AMPA binding suggested impaired glutamate neurotransmission. As such, this receptor probably did not contribute to alcohol withdrawal kindling, but rather was involved in seizure protective mechanisms during this process.

The purpose of the present experiment was to study the "kindling" hypothesis of alcohol withdrawal stating that exposure to repeated episodes of alcohol withdrawal results in an increased severity of subsequent withdrawal reactions. Two groups of male Wistar rats were subjected to 13 episodes of 2 days severe alcohol intoxication and 5 days alcohol withdrawal. Animals in the control group (n = 80) developed clinical withdrawal signs following each intoxication episode. In the diazepam group (n = 80) the withdrawal reactions during episodes 1-9 were blocked by intraperitoneal diazepam administration (0-30 mg/kg) 8, 11 and 15 h into withdrawal. During episode 10-13 diazepam treatment was terminated and convulsive withdrawal behaviour was observed 9-15 h after last alcohol dose. The probability of seizure activity during these four withdrawal episodes was calculated as 0.239 and 0.066 in the control and the diazepam groups, respectively. Based on Monte Carlo simulation techniques, this difference was found to be statistically significant (P0.05). No differences in the non-convulsive alcohol withdrawal symptoms tremor, hyperactivity and rigidity were detected between controls and diazepam animals after diazepam treatment. It was concluded that the increased convulsive behaviour in the control group was caused by cumulated kindling-like cerebral alterations during the previous repeated alcohol withdrawal phases.

Forty-six patients with schizophrenia or schizophreniform disorder admitted to hospital for the first time were compared with 21 healthy volunteers on neuropsychological tests reflecting prefrontal and left respectively right hemisphere function. The patients with schizophrenia or schizophreniform disorder had a poorer performance on neuropsychological tests (such as Wisconsin Card Sorting) compared with healthy volunteers. Both left and right hemisphere seemed to be involved. Especially poor performance was found on somewhat complicated tests requiring ability of analysis, abstraction and memory, thus indicating dysfunction of prefrontal and temporohippocampal regions. Signs of sulcal enlargement and size of lateral ventricles on computed tomographic scan correlated with poor test performance on some tests both in patients and in healthy volunteers. No correlations were found between performance on neuropsychological test and negative symptoms.

OBJECTIVE: The hypothesis of a sensory gating defect in schizophrenia has been supported by studies demonstrating deficient auditory P50 gating in patients. P50 gating is the relative attenuation of P50 amplitude in the auditory evoked potential following the second auditory stimulus of a stimulus pair. METHOD: Auditory evoked potentials of 12 unmedicated male patients with schizophrenia and 24 healthy men were recorded during three runs of 40 click pairs. Three alternative waveform-processing strategies were used to analyze the data. RESULTS: Regardless of strategy used, the differences between subject groups regarding P50 amplitude and gating were nonsignificant. CONCLUSIONS: The P50 gating in the patient group was normal. The results do not support the concept of the P50 gating defect as a general trait marker of schizophrenia.

Thirty-seven patients with delirium tremens or other signs of alcohol withdrawal were included in a double-blind randomized study of the effect of phenobarbital (19 patients) versus barbital (18 patients). Since 1909 barbital has been considered the preferred drug for treatment of alcohol withdrawal in Denmark. The patients were treated with tablets of phenobarbital, 100 mg, or barbital, 250 mg, to terminate symptoms of the withdrawal reaction and induce sleep. The groups were comparable as to age, sex distribution, severity of disease, and anamnestic information about drinking habits. The course of treatment was monitored by the Delirum Tremens Rating Scale and by the following outcome measures: medication to sleep, hours to sleep, total medication doses, and hours to last dose. There were no statistically significant differences between phenobarbital- and barbital-treated patients in any of the measures applied. Sleep was induced within a few hours in both groups, and there were no adverse effects of th...

Rats were treated intermittently or continuously with the dopamine D1 receptor antagonist NNC-756 for 15 weeks. Two weeks after withdrawal they were challenged with the dopamine D1 receptor agonist SKF 38393, either alone or after pretreatment with NNC-756. Neither treatment regimen resulted in irreversible increases in oral activities when treated rats were compared with controls; however, transient elevations were observed in the beginning of treatment in the continuously treated group and in the withdrawal phase in the discontinuously treated group. Furthermore, discontinuous treatment resulted in within-group elevations in vacuous chewing movements and tongue protrusions after withdrawal. Dopamine D1 receptor supersensitivity was not observed after challenge with the dopamine D1 receptor agonist. NNC-756 efficiently blocked the behavioural response to stimulation with SKF 38393. Both treatment regimens resulted in the development of rigidity and catalepsy. The present study suggests that treatment with selective dopamine D1 receptor antagonists is less likely to cause irreversible oral dyskinesia than is treatment with classical neuroleptic drugs.

Intermittent as opposed to continuous treatment of rats with haloperidol resulted in a long-lasting potentiation of oral activity. To examine if this behavioural sensitization to discontinuous neuroleptic treatment facilitates seizure development in electrical kindling, rats treated either intermittently or continuously with haloperidol for 15 weeks were kindled in the nucleus amygdala. Development of kindled seizures was significantly faster in the intermittently treated group (P0.01) than in controls or continuously treated rats. Furthermore, discontinuously treated animals displayed electroencephalographic afterdischarges in the substantia nigra from the beginning of treatment. The findings of cross-sensitivity between electrical amygdala kindling and pharmacological sensitization and of early appearance of epileptiform nigral activity have implications for the pathogenesis of both conditions. We suggest that depressed gamma-aminobutyric acid activity in substantia nigra could be a common mechanism.

Recent investigations with functional brain mapping have shown that prefrontal brain dysfunction during mental challenge prevails in early schizophrenia; there are indications of an impaired striatal modulation as well. Macroscopically, the frontotemporal cortical regions including limbic structures are impaired, whereas subcortical loss of tissue may be less pronounced, at least in the early stages of disease. Impaired temporo-limbic and thalamic functions in establishing semantic (non-biographic) memory and during build-up and release of language may correlate with the basic psychopathologic phenomena of thought disorder and autism in schizophrenia. The patients may have to rely on experiental (personal, individual, biographic) memory; this is cognitively demanding and imprecise as far as common rules in the outside world are concerned. Several neurotransmittors in multiple feed-back circuits regulate frontal, cortico-limbic, and thalamic activity, and current pathogenetic models must include arousal, “...

We present results from a prospective 1-year random sample investigation of visitors to psychiatric emergency services covering the city of Copenhagen as a whole. The services are free of charge, are open 24 h a day, and offer psychiatric evaluation, acute treatment, and overnight stay for the population in each of the four catchment areas in the city. Every 10th day throughout 1985 all visits were registered. The demographic characteristics of 1969 visits (covering 1595 persons) are as follows: 75% were 20–50 years old, 59% were males, 65% were unmarried/divorced, and 37% were receiving disability pension. The predominant diagnoses were alcohol dependence (31%) and schizophrenia (20%). Among the repeat visitors these diagnoses were even more frequent. The results demonstrate that emergency services are necessary to prevent admission to a psychiatric ward, both for chronic patients and non-psychiatric individuals who need immediate assistance because of crisis reactions. Coordination of the emergency unit...

Ethanol withdrawal is associated with neuronal hyperexcitability and increased hippocampal glutamate release. Neuropeptide Y (NPY) appears to play an important role in regulation of hippocampal neuronal excitability by inhibiting glutamate release. Expression of NPY and its receptors Y1, Y2, and Y5 was studied in hippocampal areas of rats during ethanol withdrawal after repeated intragastric ethanol administration for 2 or 4 days using in situ hybridization. Withdrawal was associated with decreased hippocampal expression of NPY and each of its receptors, particularly Y2, after 2 and/or 4 days of ethanol compared to control rats. These data suggest that the hippocampal NPY system is downregulated during ethanol withdrawal and these neuroadaptational changes could play a role in mediating withdrawal hyperexcitability.

SummaryIt was first suggested that disordered proprioception was a core feature of schizophrenia by Sandor Rado in 1953. Using a recently designed proprioceptive event-related potential paradigm based on a change of load, we studied 12 unmedicated male out-patients with schizophrenia and 24 controls. In the patients, the early contralateral parietal activity was delayed and later central activity had increased amplitude, but gating was unaffected. The results could be understood within the ‘deficiency of corollary discharge’ model of schizophrenia but not within the ‘filtering’ theory. Further studies, including psychiatric controls, are necessary to verify the specificity of the abnormality.

Objective: Patients with psychoses often suffer from affective symptoms. The originally broad concept of schizoaffective disorder (SAD) has been significantly narrowed, transformed into a convoluted set of criteria both in the ICD-10 and DSM-IV. We examined the reliability of the clinical use of this diagnosis in university settings. Method: All patients discharged from two university hospitals in Copenhagen in year 2002 with a diagnosis of ICD-10 SAD (n = 59) were re-evaluated using the Operational Criteria (OPCRIT) checklist expanded by additional items and applied to hospital chart material. Diagnoses were allocated by OPCRIT algorithm and by consensus of two psychiatrists. Results: No patients fulfilled the SAD lifetime diagnosis according to DSM-IV criteria and the raters diagnosed only six patients as possible ICD-10 SAD. Conclusion: A moratorium on the clinical use of the SAD diagnosis is suggested.

Background. Brain morphometry in children and adolescents with first-episode psychosis offer a unique opportunity for pathogenetic investigations. Methods. We compared high-resolution 3D T1-weighted magnetic resonance images of the brain in 29 patients (schizophrenia, schizotypal disorder, delusional disorder or other non-organic psychosis), aged 10–18 to those of 29 matched controls, using optimized voxel-based morphometry. Results. Psychotic patients had frontal white matter abnormalities, but expected (regional) gray matter reductions were not observed. Post hoc analyses revealed that schizophrenia patients (n = 15) had significantly larger lateral ventricles as compared to controls. Duration and dose of antipsychotics correlated negatively with global gray matter volume in minimally medicated patients (n = 18). Conclusion. Findings of white matter changes and enlarged lateral ventricles already at illness onset in young schizophrenia spectrum patients, suggests aberrant neurodevelopmental processes in the pathogenesis of these disorders. Gray matter volume changes, however, appear not to be a key feature in early onset first-episode psychosis.

Cognitive deficits have been found to be prevalent in early onset schizophrenia. Whether these deficits also characterise other early onset psychotic disorders to a similar degree is unclear, as very few comparative studies have been done. The primary purpose of this study was to compare the profile and severity of cognitive impairments in first-episode early onset psychotic patients who received the schizophrenia diagnosis to those diagnosed with other non-organic, non-affective psychotic disorders. The secondary purpose was to examine whether the profile of cognitive deficits, in terms of intelligence, executive functions, memory, attention and processing speed was global or specific. First-episode psychotic adolescents (N = 39) between the ages 11 and 17 years were included, 18 of whom were diagnosed with schizophrenia, and 21 with other non-organic, non-affective psychoses, using ICD-10 criteria. A healthy control group (N = 40) was included, matched on gender and age. Cognitive functions were assessed using WISC-III/R, the CANTAB battery, WCST, Trail Making B, fluency tasks, and Buschke's selective reminding task. A similar profile and level of impairment was found on measures of attention, executive functions, reaction time, and memory in the schizophrenic and psychotic adolescent groups. However, analyses of WISC-III factor profiles suggested that early onset schizophrenia patients may have more global IQ deficits than non-organic, non-affective psychoses when examined recently after illness onset. Compared to the deficits of adult schizophrenia described in the literature, the results suggest relatively spared simple reaction times in early onset patients.

Accumulating evidence implicates deficiencies in apolipoprotein D (ApoD) function and arachidonic acid signaling in schizophrenic disorders. We addressed two hypotheses in relation to ApoD: first, polymorphisms in the ApoD gene confer susceptibility to or are markers of disease, and, second, genetic variation in the ApoD is associated with long-term clinical outcome to antipsychotic treatment. We genotyped two single-nucleotide polymorphisms in the ApoD gene in 343 chronic patients with schizophrenia spectrum disorders (ICD-10) and 346 control subjects of Danish origin. We did not find ApoD alleles, genotypes or haplotypes to be associated with disease. However, we did find that long-term clinical outcome was associated with the ApoD polymorphism rs7659 (P = 0.041) following adjustment for lifetime clinical global impression, age at first admission and gender.

SUMMARYThe first mathematically unbiased estimates of neocortical cell numbers are presented from the developing pig brain, including a full description of tissue processing and optimal sampling for application of the stereological optical fractionator method in this species. The postnatal development of neocortical neurons and glial cells from the experimental Göttingen minipig was compared with the postnatal development of neocortical neurons in the domestic pig. A significant postnatal development was observed in the Göttingen minipig brain for both neuronal (28%; P=0.01) and glial cells (87%; P

Neuregulin 1 has been implicated as a susceptibility gene in schizophrenia. Several research groups have reported association with the 5′ end of the gene although no causative variant has been reported. We have investigated whether there is association with the 5′ end of the gene in Danish schizophrenia patients. We found that the at-risk haplotype initially reported in the Icelandic population was not found in significant excess (or = 1.4, p = 0.12). The haplotype structure in the Danish sample was similar to that of other reported in other Caucasian populations and highly different from that of Chinese.

BackgroundThe families of patients with first-episode psychosis often play a major role in care and often experience lack of support.AimsTo determine the effect of integrated treatment v. standard treatment on subjective burden of illness, expressed emotion (EE), knowledge of illness and satisfaction with treatment in key relatives of patients with a first episode of schizophrenia-spectrum disorder.MethodPatients with ICD-10 schizophrenia-spectrum disorders (first episode) were randomly assigned to integrated treatment or to standard treatment. Integrated treatment consisted of assertive community treatment, psychoeducational multi-family groups and social skills training. Key relatives were assessed with the Social Behaviour Assessment Schedule (SBAS, burden of illness), the 5-min speech sample (EE), and a multiple choice questionnaire at entry and after 1 year.ResultsRelatives in integrated treatment felt less burdened and were significantly more satisfied with treatment than relatives in standard treatment. There were no significant effects of intervention groups on knowledge of illness and EE.ConclusionsThe integrated treatment reduced family burden of illness and improved satisfaction with treatment.