Gerard J. den Heeten

Smaller hippocampal volume in Dutch police officers with posttraumatic stress disorder

BACKGROUND Previous magnetic resonance imaging studies of posttraumatic stress disorder (PTSD) have reported smaller hippocampal volume, especially in war and sexual abuse victims. Our aim was to assess hippocampal volume in traumatized police officers with and without PTSD in the absence of alcohol abuse and moderate to severe major depression. METHODS In a case-matched control study, 14 police officers with current PTSD and 14 traumatized police officers without lifetime PTSD were examined using magnetic resonance imaging. Three temporal lobe areas were manually segmented: hippocampus, amygdala, and parahippocampal gyrus. Volumetric analysis was used to measure gray matter, white matter, and cerebrospinal fluid. RESULTS After controlling for total brain volume, the hippocampal volume in the PTSD group was significantly smaller in comparison with the traumatized control group (total 10.6%; left 12.6%). Volumes of amygdala, parahippocampal gyrus, gray matter, white matter, and cerebrospinal fluid were not significantly altered. A significant negative correlation was found between reexperiencing symptoms and hippocampal volume in the PTSD group. CONCLUSIONS We confirmed previous findings of smaller hippocampal volume in PTSD in a new population made up of police officers, excluding comorbidity as a confounder. The finding of smaller hippocampal volume was specific to PTSD.

Effects of psychotherapy on hippocampal volume in out-patients with post-traumatic stress disorder: a MRI investigation

BACKGROUND Magnetic resonance imaging (MRI) studies have especially reported smaller hippocampal volume in patients with post-traumatic stress disorder (PTSD), most of them war or sexual abuse victims. The present study compares the hippocampal volumes of out-patients with PTSD who had low co-morbidity rates to those of trauma-exposed control subjects without PTSD, and measures hippocampal volume changes in these patients after brief eclectic psychotherapy. We hypothesized that smaller hippocampal volumes are specific to PTSD and that hippocampal volume changes after effective psychotherapy would be measurable. METHOD Eighteen patients with PTSD and 14 traumatized control subjects were examined with MRI. In a randomized clinical trial, the PTSD patients were assigned to treatment (n = 9) or waiting-list group (n = 9). After the former received psychotherapy for 4 months, the MRI was repeated on both PTSD groups. Three temporal lobe structures were manually segmented: hippocampus, amygdala, and parahippocampal gyrus. Volumetric analysis was used to measure grey matter, white matter, and cerebrospinal fluid. RESULTS PTSD patients had significantly smaller hippocampal volumes at baseline (total 13.8%, right 13.5%, left 14.1%) compared to the control subjects. After effective psychotherapy, however, no volume changes were found in the smaller hippocampi. CONCLUSIONS We confirmed previous findings of smaller hippocampal volume in PTSD in a new population made up of out-patients who experienced different types of traumas, reducing co-morbidity to a minimum. Smaller hippocampal volumes did not change after effective psychotherapy, even while symptoms resolved.

Cerebral blood flow changes during script-driven imagery in police officers with posttraumatic stress disorder.

BACKGROUND Functional brain imaging studies in posttraumatic stress disorder (PTSD) have focused mostly on war or sexual abuse victims, many of whom also had comorbid disorders. The aim of this study was to examine the neuronal circuitry underlying responses to script-driven imagery in traumatized police officers with and without PTSD and with low comorbidity rates. METHODS In a case-matched control study, 30 traumatized police officers with and without PTSD underwent clinical assessment and (99m)technetium-hexa-methyl-propylene-amine-oxime single photon emission computed tomography scanning with neutral and trauma scripts. Statistical parametric mapping was applied to analyze changes in regional cerebral blood flow. RESULTS The main findings were significantly less activation in the medial frontal gyrus and more activation in the right cuneus in the PTSD group relative to the trauma-exposed control group in reaction to trauma versus neutral scripts. Within the PTSD group, subjects showed less activation in the superior temporal gyrus, left lentiform nucleus, left middle frontal gyrus, and left inferior frontal gyrus in reaction to trauma scripts. CONCLUSIONS We confirmed previous findings of dysfunction of the medial frontal gyrus in PTSD in a new population with low comorbidity rates. Other alterations were found in certain brain structures involved in emotional, memory, linguistic, visuospatial, and motor processing.

White matter fibertracking in first-episode schizophrenia, schizoaffective patients and subjects at ultra-high risk of psychosis

There is increasing evidence of white matter pathology in schizophrenia. The aim of this study was to examine whether white matter abnormalities found with diffusion tensor imaging (DTI) in previous schizophrenia studies are present in the early phase of the illness. DTI was performed at 3 T on 10 male patients with a first (n = 8) or second (n = 2) psychotic episode of schizophrenia or schizoaffective disorder, 10 male patients at ultra-high risk of psychosis with (pre)psychotic symptoms and 10 healthy controls. Fibertracts found to be abnormal in other DTI studies (uncinate and arcuate fasciculus, anterior and dorsal cingulum, subdivisions of the corpus callosum) were calculated and visualized; tract-specific measurements (fractional anisotropy and trace) were performed. No differences were found between the healthy subjects and the 2 patient groups. These preliminary findings suggest that there is no white matter pathology of these association tracts detectable with DTI in the early stages of schizophrenic illness in males. Our findings are in contrast with DTI abnormalities found in some other first-episode studies. This discrepancy in findings may be related to differences in subject characteristics and DTI methodology. Possible effects of age, gender, level of education and illicit substance use on DTI findings in schizophrenia are discussed.

Comparison of Digital Screening Mammography and Screen-Film Mammography in the Early Detection of Clinically Relevant Cancers: A Multicenter Study

PURPOSE To compare screen-film mammography with digital mammography in a breast cancer screening program, with a focus on the clinical relevance of detected cancers. MATERIALS AND METHODS The study was approved by the regional medical ethics review board. Informed consent was not required. Before the nationwide transition to digital mammography in the Dutch biennial screening program, the performance of digital mammography was studied in three screening regions. For initial screening examinations, mediolateral oblique and craniocaudal views were obtained of each breast. In subsequent examinations, the mediolateral oblique view was standard. A craniocaudal view was added if indicated. Screening outcomes obtained with screen-film mammography and digital mammography, including radiologic and pathologic characteristics, were compared for initial and subsequent examinations. RESULTS A total of 1,198,493 screening examinations were performed between 2003 and 2007. Recall was indicated in 18 896 cases (screen-film mammography: 2.6% at initial examinations, 1.3% at subsequent examinations; digital mammography: 4.4% at initial examinations, 2.1% at subsequent examinations; P < .001 for both). Breast cancer was diagnosed in 6410 women (detection rate per 1000 women with screen-film mammography: 5.6 at initial examinations, 5.2 at subsequent examinations; detection rate per 1000 women with digital mammography: 6.8 at initial examinations, 6.1 at subsequent examinations; P = .02 and P < .001, respectively). Digital mammography depicted significantly more ductal carcinoma in situ (DCIS) lesions, irrespective of screening round. Invasive carcinoma was detected significantly more often in subsequent examinations, particularly when associated with microcalcifications (P = .047). The distribution of the histopathologic differentiation grades for DCIS and invasive carcinoma were similar with both modalities. However, with digital mammography more high-grade DCIS lesions were detected at subsequent examinations (P = .013). CONCLUSION In a population-based breast screening program, the performance of digital mammography in the detection of DCIS and invasive carcinoma was substantially better than that of screen-film mammography. There is no sign of an increase in detection of low-grade DCIS lesions-indicative of possible overdiagnosis-with digital breast cancer screening. Rather, digital mammography appears to add to the detection of high-grade DCIS.

Mood disorders and serotonin transporter density in ecstasy users - the influence of long-term abstention, dose, and gender

RationaleNeurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) on the serotonin (5-HT) system have been described in animals and humans, but little is known about long-term effects of ecstasy use on mood.ObjectivesTo investigate short-term and long-term effects of ecstasy use on mood and its association with 5-HT neurotoxicity, dose, and gender in humans.MethodsFifteen moderate ecstasy users, 23 heavy ecstasy users, 16 former heavy ecstasy users and 15 drug-using, but ecstasy-naive controls were included. Mood was assessed using the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory (BDI). Outcomes were correlated with 5-HT transporter (SERT) density, assessed with [123I]β-CIT single photon emission computed tomography (SPECT).ResultsThe prevalence of mood disorders assessed by CIDI did not differ between all groups. The overall test for differences in BDI scores between groups was near significance (P=0.056), with BDI scores higher in former heavy ecstasy users than in ecstasy-naive controls (P=0.045). BDI scores were correlated with the total number of ecstasy tablets used (r=0.310; P=0.021). No associations between CIDI or BDI outcomes and SERT density or gender were observed.ConclusionsThese results suggest that ecstasy use is not associated with clinical depression (CIDI). However, the number of ecstasy tablets taken lifetime was associated with higher BDI scores for depressive mood, and this relationship seemed to persist after ecstasy use had stopped. We did not find that depressed mood in ecstasy users was associated with decrease in SERT density. Prospective studies are needed to establish the causal relationship between ecstasy use and depressed mood.

Neuroimaging findings with MDMA/ecstasy: technical aspects, conceptual issues and future prospects.

Users of ecstasy (3,4-methylenedioxymethamphetamine; MDMA) may be at risk of developing MDMA-induced injury to the serotonin (5-HT) system. Previously, there were no methods available for directly evaluating the neurotoxic effects of MDMA in the living human brain. However, development of in vivoneuroimaging tools have begun to provide insights into the effects of ecstasy on the human brain. Single photon emission computed tomography (SPECT), positron emission computed tomography (PET) and proton magnetic resonance spectroscopy (1H-MRS) studies which have evaluated ecstasys neurotoxic potential will be reviewed and discussed in terms of technical aspects, conceptual issues and future prospects. Although PET and SPECT may be limited by several factors such as the low cortical uptake and the use of a non-optimal reference region (cerebellum) the few studies conducted so far provide suggestive evidence that people who heavily use ecstasy are at risk of developing subcortical, and probably also cortical reductions in serotonin transporter (SERT) densities, a marker of 5-HT neurotoxicity. There seem to be dose-dependent and transient reductions in SERT for which females may be more vulnerable than males. 1H-MRS appears to be a less sensitive technique for studying ecstasys neurotoxic potential. Whether individuals with a relatively low ecstasy exposure also demonstrate loss of SERT needs to be determined. Because most studies have had a retrospective design, in which evidence is indirect and differs in the degree to which any causal links can be implied, longitudinal studies in human ecstasy users are needed to draw de.nite conclusions.

Sustained effects of ecstasy on the human brain : a prospective neuroimaging study in novel users

Previous studies have suggested toxic effects of recreational ecstasy use on the serotonin system of the brain. However, it cannot be excluded that observed differences between users and non-users are the cause rather than the consequence of ecstasy use. As part of the Netherlands XTC Toxicity (NeXT) study, we prospectively assessed sustained effects of ecstasy use on the brain in novel ecstasy users using repeated measurements with a combination of different neuroimaging parameters of neurotoxicity. At baseline, 188 ecstasy-naive volunteers with high probability of first ecstasy use were examined. After a mean period of 17 months follow-up, neuroimaging was repeated in 59 incident ecstasy users and 56 matched persistent ecstasy-naives and their outcomes were compared. Neuroimaging included [(123)I]beta-carbomethoxy-3beta-(4-iodophenyl)tropane (CIT) SPECT to measure serotonin transporter densities as indicators of serotonergic function; (1)H-MR spectroscopy ((1)H-MRS) to measure brain metabolites as indicators of neuronal damage; diffusion tensor imaging (DTI) to measure the apparent diffusion coefficient and fractional anisotropy (FA) of the diffusional motion of water molecules in the brain as indicators of axonal integrity; and perfusion weighted imaging (PWI) to measure regional relative cerebral blood volume (rrCBV) which indicates brain perfusion. With this approach, both structural ((1)H-MRS and DTI) and functional ([(123)I]beta-CIT SPECT and PWI) aspects of neurotoxicity were combined. Compared to persistent ecstasy-naives, novel low-dose ecstasy users (mean 6.0, median 2.0 tablets) showed decreased rrCBV in the globus pallidus and putamen; decreased FA in thalamus and frontoparietal white matter; increased FA in globus pallidus; and increased apparent diffusion coefficient in the thalamus. No changes in serotonin transporter densities and brain metabolites were observed. These findings suggest sustained effects of ecstasy on brain microvasculature, white matter maturation and possibly axonal damage due to low dosages of ecstasy. Although we do not know yet whether these effects are reversible or not, we cannot exclude that ecstasy even in low doses is neurotoxic to the brain.

Use of amphetamine by recreational users of ecstasy (MDMA) is associated with reduced striatal dopamine transporter densities: a [123I]β-CIT SPECT study – preliminary report

Abstract.Rationale: Tablets sold as ecstasy often contain not only 3,4-methylenedioxymethamphetamine (MDMA) but other compounds well known to cause dopaminergic neurotoxicity, such as (meth)amphetamine. Furthermore, the use of ecstasy in the Netherlands is often combined with the use of amphetamine. However, little is known about the effects of ecstasy use or the combination of ecstasy and amphetamine use on dopamine (DA) neurones in the human brain. Objectives: This study was designed to investigate the effects of ecstasy as well as the combined use of ecstasy and amphetamine on the density of nigrostriatal DA neurones. Methods: [123I]β-CIT SPECT was used to quantify striatal DA transporters. Striatal [123I]β-CIT binding ratios of control subjects (n=15) were compared with binding ratios of ecstasy users (n=29) and individuals with a history of combined ecstasy and amphetamine use (n=9) after adjustment for age. Results: Striatal [123I]β-CIT binding ratios were significantly lower in combined ecstasy and amphetamine users compared to sole ecstasy users (6.75 versus 8.46, respectively: –20.2%, P=0.007). Binding ratios were significantly higher in ecstasy users when compared to controls (8.46 versus 7.47, respectively: +13.2%, P=0.045). Conclusions: These initial observations suggest that the sole use of ecstasy is not related to dopaminergic neurotoxicity in humans. In contrast, the reported use of amphetamine by regular users of ecstasy seems to be associated with a reduction in nigrostriatal DA neurones.

A Prospective Cohort Study on Sustained Effects of Low-Dose Ecstasy Use on the Brain in New Ecstasy Users

It is debated whether ecstasy use has neurotoxic effects on the human brain and what the effects are of a low dose of ecstasy use. We prospectively studied sustained effects (>2 weeks abstinence) of a low dose of ecstasy on the brain in ecstasy-naive volunteers using a combination of advanced MR techniques and self-report questionnaires on psychopathology as part of the NeXT (Netherlands XTC Toxicity) study. Outcomes of proton magnetic resonance spectroscopy (1H-MRS), diffusion tensor imaging (DTI), perfusion-weighted imaging (PWI), and questionnaires on depression, impulsivity, and sensation seeking were compared in 30 subjects (12M, 21.8±3.1 years) in two sessions before and after first ecstasy use (1.8±1.3 tablets). Interval between baseline and follow-up was on average 8.1±6.5 months and time between last ecstasy use and follow-up was 7.7±4.4 weeks. Using 1H-MRS, no significant changes were observed in metabolite concentrations of N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), and creatine (Cr), nor in ratios of NAA, Cho, and mI relative to Cr. However, ecstasy use was followed by a sustained 0.9% increase in fractional anisotropy (FA) in frontoparietal white matter, a 3.4% decrease in apparent diffusion (ADC) in the thalamus and a sustained decrease in relative regional cerebral blood volume (rrCBV) in the thalamus (−6.2%), dorsolateral frontal cortex (−4.0%), and superior parietal cortex (−3.0%) (all significant at p<0.05, paired t-tests). After correction for multiple comparisons, only the rrCBV decrease in the dorsolateral frontal cortex remained significant. We also observed increased impulsivity (+3.7% on the Barratt Impulsiveness Scale) and decreased depression (−28.0% on the Beck Depression Inventory) in novel ecstasy users, although effect sizes were limited and clinical relevance questionable. As no indications were found for structural neuronal damage with the currently used techniques, our data do not support the concern that incidental ecstasy use leads to extensive axonal damage. However, sustained decreases in rrCBV and ADC values may indicate that even low ecstasy doses can induce prolonged vasoconstriction in some brain areas, although it is not known whether this effect is permanent. Additional studies are needed to replicate these findings.