Brain donation in psychiatry: results of a Dutch prospective donor program among psychiatric cohort participants.

BACKGROUND: Human brain tissue is crucial to study the molecular and cellular basis of psychiatric disorders. However, the current availability of human brain tissue is inadequate. Therefore, the Netherlands Brain Bank initiated a program in which almost 4.000 participants of 15 large Dutch psychiatric research cohorts were asked to register as prospective brain donors. METHODS: We approached patients with schizophrenia, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder, families with a child with autism or Attention Deficit Hyperactivity Disorder, healthy relatives and healthy unrelated controls, either face-to-face or by post. We investigated whether diagnosis, method of approach, age, and gender were related to the likelihood of brain-donor registration. RESULTS: We found a striking difference in registration efficiency between the diagnosis groups. Patients with bipolar disorder and healthy relatives registered most often (25% respectively 17%), followed by unrelated controls (8%) and patients with major depressive disorder, post-traumatic stress disorder, and obsessive-compulsive disorder (9%, 6% resp. 5%). A face-to-face approach was 1.3 times more effective than a postal approach and the likelihood of registering as brain donor significantly increased with age. Gender did not make a difference. CONCLUSIONS: Between 2013 and 2016, our prospective brain-donor program for psychiatry resulted in an almost eightfold increase (from 149 to 1149) in the number of registered psychiatric patients at the Netherlands Brain Bank. Based on our results we recommend, when starting a prospective brain donor program in psychiatric patients, to focus on face to face recruitment of people in their sixties or older.

Suicide Behavior Before and After the Start with Antidepressants: A High Persistent Risk in the First Month of Treatment Among the Young.

BACKGROUND: A causal relationship between antidepressants (ADs) and a high risk of suicidal behavior at a young age has been suggested. We analyzed the rates of suicide attempts during treatment with AD in comparison with the rates before treatment initiation for different ages. METHODS: Claims of insurance company Achmea were linked to the population registry of Statistics Netherlands. Episodes of AD use were defined for those with their first registered prescription in 2006-2011 (n = 66,196). Rates were analyzed in a Poisson model. Correlates of attempts in the first month of AD use were assessed in a logistic model. RESULTS: Among those aged <25 years, a high rate of suicide attempts during the month before the start of ADs was found (376.3/10 000 person yrs). A non-significant increase in the first month (p = 0.212) was found and a non-significant trend to lower values was determined thereafter (p = 0.3050). Among those ≧ 25 years, a clear decrease to lower rates immediately after the start was observed (p < 0.025). The highest rates of suicide were found among those >40 years during the first month. Female gender was, but treatment characteristics were not, associated with early attempts at a young age. CONCLUSIONS: Among young AD users, a high pre-treatment risk of suicide attempts was present and persisted during the early phases after the start. This contrasted with the clear decrease in risk among those aged ≧ 25 years, suggesting lower effectiveness of ADs to prevent suicidal behavior at young ages. Caution should be exercised to infer a causal relationship or to use data on attempts to predict risk of suicide during AD use.

Serious Games as Potential Therapies: A Validation Study of a Neurofeedback Game.

Serious (biofeedback) games offer promising ways to supplement or replace more expensive face-to-face interventions in health care. However, studies on the validity and effectiveness of EEG-based serious games remain scarce. In the current study, we investigated whether the conditions of the neurofeedback game "Daydream" indeed trained the brain activity as mentioned in the game manual. EEG activity was assessed in 14 healthy male volunteers while playing the 2 conditions of the game. The participants completed a training of 5 sessions. EEG frequency analyses were performed to verify the claims of the manual. We found significant differences in α- to ß-ratio between the 2 conditions although only in the amplitude data, not in the power data. Within the conditions, mean α-amplitude only differed significantly from the ß-amplitude in the concentration condition. Our analyses showed that neither α nor ß brain activity differed significantly between game levels (higher level requiring increased brain activity) in either of the two conditions. In conclusion, we found only marginal evidence for the proposed claims stated in the manual of the game. Our research emphasizes that it is crucial to validate the claims that serious games make, especially before implementing them in the clinic or as therapeutic devices.

Neurons in the fusiform gyrus are fewer and smaller in autism.

Abnormalities in face perception are a core feature of social disabilities in autism. Recent functional magnetic resonance imaging studies showed that patients with autism could perform face perception tasks. However, the fusiform gyrus (FG) and other cortical regions supporting face processing in controls are hypoactive in patients with autism. The neurobiological basis of this phenomenon is unknown. Here, we tested the hypothesis that the FG shows neuropathological alterations in autism, namely alterations in neuron density, total neuron number and mean perikaryal volume. We investigated the FG (analysing separately layers II, III, IV, V and VI), in seven post-mortem brains from patients with autism and 10 controls for volume, neuron density, total neuron number and mean perikaryal volume with high-precision design-based stereology. To determine whether these results were specific for the FG, the same analyses were also performed in the primary visual cortex and in the cortical grey matter as a whole. Compared to controls, patients with autism showed significant reductions in neuron densities in layer III, total neuron numbers in layers III, V and VI, and mean perikaryal volumes of neurons in layers V and VI in the FG. None of these alterations were found in the primary visual cortex or in the whole cerebral cortex. Although based on a relatively small sample of post-mortem brains from patients with autism and controls, the results of the present study may provide important insight about the cellular basis of abnormalities in face perception in autism.

The Netherlands Brain Bank for Psychiatry.

The Netherlands Brain Bank (NBB) performs rapid autopsies of donors who gave written informed consent during life for the use of their brain tissue and medical files for research. The NBB initiated the Netherlands Brain Bank for Psychiatry (NBB-Psy), a prospective donor program for psychiatric diseases. NBB-Psy wants to expand the tissue collections in order to provide a strong incentive to increase research in psychiatry. The ultimate goal of NBB-Psy is to reduce the burden of psychiatric disorders for patients, their families, and for society as a whole. NBB-Psy consists of an antemortem and postmortem donor program. This chapter focuses on the design of NBB-Psy and the antemortem donor program, where patients and relatives are actively informed on the possibility to become a brain donor. Since the initiation of NBB-Psy, the number of registered donors with a psychiatric diagnosis has increased from 149 in 2010 to 1018 in May 2016.

Caudate nucleus is enlarged in high-functioning medication-naive subjects with autism.

BACKGROUND: Autism is defined by three symptom clusters, including repetitive and stereotyped behavior. Previous studies have implicated basal ganglia in these behaviors. Earlier studies investigating basal ganglia in autism have included subjects on neuroleptics known to affect basal ganglia volumes. Therefore, we investigated these structures in medication-naive subjects with autism. METHODS: Volumetric magnetic resonance measures of caudate, putamen, and nucleus accumbens were compared in two independent samples of medication-naive, high-functioning subjects with autism or Asperger syndrome: 1) 21 affected children and adolescents and 21 matched control subjects; and 2) 21 affected adolescents and young adults and 21 matched control subjects. RESULTS: Caudate nucleus was enlarged in both samples. This result remained significant after correction for total brain volume. CONCLUSIONS: These results implicate caudate nucleus in autism, as an enlargement of this structure was disproportional to an increase in total brain volume in two independent samples of medication-naive subjects with autism.

Children seeking help for auditory verbal hallucinations; who are they?

BACKGROUND: Auditory Verbal Hallucinations (AVH) in children and adolescents are a relatively common and mostly transient feature in community samples. However, it should not be regarded as a merely benign phenomenon, as childhood AVH are associated with psychopathology. Little is known about the clinical group of children seeking help for AVH. This brings uncertainty on how to assess and treat these children. METHODS: This study describes the characteristics of 95 help-seeking children (aged 6 to 18years) with AVH attending an outpatient clinic specifically dedicated to help youth with this complaint. We aim to provide pointers regarding diagnostic assessment and interventions. RESULTS: Children seeking help for AVH suffered from a diversity of co morbid psychiatric diagnoses and consistently experienced high stress from AVH. When the DSM-IV-TR criteria for psychotic disorder NOS were used, all 95 children obtained this diagnosis. However, when a psychotic disorder was defined using the A-criterion of schizophrenia, only a minority of 11 cases (11.6%) was diagnosed as having a psychotic disorder. All children were in need of psycho-education and coping strategies and only the minority (11.6%) fulfilling criteria for a more narrowly defined psychotic disorder was prescribed antipsychotic medication. CONCLUSIONS: Children seeking help for AVH form a heterogeneous group with high stress and reduced functioning. Even though only a minority (11.6%) suffers from a psychotic disorder, all children warrant clinical care due to their burden and multi morbid psychopathology.

Neuropathological findings in autism.

Autism is currently viewed as a largely genetically determined neurodevelopmental disorder, although its underlying biological causes remain to be established. In this review, we examine the available neuropathological literature on autism and discuss the findings that have emerged. Classic neuropathological observations are rather consistent with respect to the limbic system (nine of 14 studied cases showed increased cell packing density and smaller neuronal size), the cerebellum (21 of 29 studied cases showed a decreased number of Purkinje cells, and in all of five cases that were examined for age-related morphological alterations, these changes were found in cerebellar nuclei and inferior olive) and the cerebral cortex (>50% of the studied cases showed features of cortical dysgenesis). However, all reported studies had to contend with the problem of small sample sizes, the use of quantification techniques not free of bias and assumptions, and high percentages of autistic subjects with comorbid mental retardation (at least 70%) or epilepsy (at least 40%). Furthermore, data from the limbic system and on age-related changes lack replication by independent groups. It is anticipated that future neuropathological studies hold great promise, especially as new techniques such as design-based stereology and gene expression are increasingly implemented and combined, larger samples are analysed, and younger subjects free of comorbidities are investigated.

[Suicide behavior before and after the start with antidepressants: a high persistent risk in the first month of treatment among the young]. / Suïcidaal gedrag vóór en na start antidepressiva: een hoog risico onder jongeren gedurende de eerste maand van behandeling.

OBJECTIVE: A causal relationship between antidepressants (ADs) and high risk of suicide behavior at young age has been suggested. We analyzed the rates of suicide attempts during treatment with AD in comparison with the rates before treatment initiation for different ages. DESIGN: Observational retrospective cohort study. METHOD: Claims of insurance company Achmea were used to establish the risk of a suicide attempt before and after start of treatment among patients with a first registered AD prescription in 2006-2011 (n = 66,196). RESULTS: Among those aged < 25 years, a high rate of suicide attempts during the month before the start was found (376.3/10,000 person yrs). A non-significant increase in the first month (p = 0.212) was found and a non-significant trend to lower values thereafter (p = 0.3050). Among those ≥ 25 years, a clear decrease to lower rates immediately after the start was observed (p < 0.025). The highest rates of suicide were found among those > 40 years during the first month. Female gender was, but treatment characteristics were not associated with early attempts at young age. CONCLUSION: Among young AD users, high pre-treatment risk of suicide attempts was present and persisted during the early phases after the start. This contrasted with the clear decrease in risk among those aged ≥ 25 years, suggesting lower immediate effectiveness of ADs to prevent suicidal behavior at young ages. Caution should be exercised to infer a causal relationship or to use data on attempts to predict risk of suicide during AD use.

Larger brains in medication naive high-functioning subjects with pervasive developmental disorder.

BACKGROUND: Are brain volumes of individuals with Pervasive Developmental Disorder (PDD) still enlarged in adolescence and adulthood, and if so, is this enlargement confined to the gray and/or the white matter and is it global or more prominent in specific brain regions. METHODS: Brain MRI scans were made of 21 adolescents with PDD and 21 closely matched controls. RESULTS: All brain volumes, except the white matter, were significantly larger in patients. After correction for brain volume, ventricular volumes remained significantly larger in patients. CONCLUSIONS: Patients showed a proportional, global increase in gray matter and cerebellum volume, and a disproportional increase in ventricular volumes. Thus, at least in high-functioning patients with PDD, brain enlargement may still be present in adult life.

No evidence for preferential involvement of medial temporal lobe structures in high-functioning autism.

BACKGROUND: Autism is a neurodevelopmental disorder associated with slight increases in brain volume. There has been some suggestion that medial temporal lobe structures may be preferentially involved in this disorder, although results have not always been consistent. Here, we investigate amygdala and hippocampus volumes in medication-naive subjects with high-functioning autism. METHOD: Whole-brain magnetic resonance imaging scans were acquired from 42 patients and 42 closely matched, healthy control subjects. RESULTS: Amygdala volume did not differ significantly between patients and controls. A significant increase in hippocampal volume was proportional to an increase in overall brain volume. CONCLUSIONS: These results argue against preferential involvement of medial temporal lobe structures in autism, at least in high-functioning medication-naive individuals.

Increased gray-matter volume in medication-naive high-functioning children with autism spectrum disorder.

BACKGROUND: To establish whether high-functioning children with autism spectrum disorder (ASD) have enlarged brains in later childhood, and if so, whether this enlargement is confined to the gray and/or to the white matter and whether it is global or more prominent in specific brain regions. METHOD: Brain MRI scans were acquired from 21 medication-naive, high-functioning children with ASD between 7 and 15 years of age and 21 comparison subjects matched for gender, age, IQ, height, weight, handedness, and parental education, but not pubertal status. RESULTS: Patients showed a significant increase of 6% in intracranium, total brain, cerebral gray matter, cerebellum, and of more than 40% in lateral and third ventricles compared to controls. The cortical gray-matter volume was evenly affected in all lobes. After correction for brain volume, ventricular volumes remained significantly larger in patients. CONCLUSIONS: High-functioning children with ASD showed a global increase in gray-matter, but not white-matter and cerebellar volume, proportional to the increase in brain volume, and a disproportional increase in ventricular volumes, still present after correction for brain volume. Advanced pubertal development in the patients compared to the age-matched controls may have contributed to the findings reported in the present study.

Brain anatomy in non-affected parents of autistic probands: a MRI study.

BACKGROUND: Autism is a neurodevelopmental disorder with an estimated genetic origin of 90%. Previous studies have reported an increase in brain volume of approximately 5% in autistic subjects, especially in children. If this increase in brain volume is genetically determined, biological parents of autistic probands might be expected to show brain enlargement, or at least intracranial enlargement, as well. Identifying structural brain abnormalities under genetic control is of particular importance as these could represent endophenotypes of autism. METHOD: Using quantitative anatomic brain magnetic resonance imaging, volumes of intracranial, total brain, frontal, parietal, temporal and occipital lobe, cerebral and cortical gray and white matter, cerebellum, lateral ventricle, and third ventricle were measured in biological, non-affected parents of autistic probands (19 couples) and in healthy, closely matched control subjects (20 couples). RESULTS: No significant differences were found between the parents of the autistic probands and healthy control couples in any of the brain volumes. Adding gender as a factor in a second analysis did not reveal a significant interaction effect of gender by group. CONCLUSIONS: The present sample of biological, non-affected parents of autistic probands did not show brain enlargements. As the intracranium is not enlarged, it is unlikely that the brain volumes of the parents of autistic probands have originally been enlarged and have been normalized. Thus, increased brain volume in autism might be caused by the interaction of paternal and maternal genes, possibly with an additional effect of environmental factors, or increased brain volumes might reflect phenotypes of autism.