Thomas Zetzsche

Use of Neuroanatomical Pattern Classification to Identify Subjects in At-Risk Mental States of Psychosis and Predict Disease Transition

CONTEXT Identification of individuals at high risk of developing psychosis has relied on prodromal symptomatology. Recently, machine learning algorithms have been successfully used for magnetic resonance imaging-based diagnostic classification of neuropsychiatric patient populations. OBJECTIVE To determine whether multivariate neuroanatomical pattern classification facilitates identification of individuals in different at-risk mental states (ARMS) of psychosis and enables the prediction of disease transition at the individual level. DESIGN Multivariate neuroanatomical pattern classification was performed on the structural magnetic resonance imaging data of individuals in early or late ARMS vs healthy controls (HCs). The predictive power of the method was then evaluated by categorizing the baseline imaging data of individuals with transition to psychosis vs those without transition vs HCs after 4 years of clinical follow-up. Classification generalizability was estimated by cross-validation and by categorizing an independent cohort of 45 new HCs. SETTING Departments of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany. PARTICIPANTS The first classification analysis included 20 early and 25 late at-risk individuals and 25 matched HCs. The second analysis consisted of 15 individuals with transition, 18 without transition, and 17 matched HCs. MAIN OUTCOME MEASURES Specificity, sensitivity, and accuracy of classification. RESULTS The 3-group, cross-validated classification accuracies of the first analysis were 86% (HCs vs the rest), 91% (early at-risk individuals vs the rest), and 86% (late at-risk individuals vs the rest). The accuracies in the second analysis were 90% (HCs vs the rest), 88% (individuals with transition vs the rest), and 86% (individuals without transition vs the rest). Independent HCs were correctly classified in 96% (first analysis) and 93% (second analysis) of cases. CONCLUSIONS Different ARMSs and their clinical outcomes may be reliably identified on an individual basis by assessing patterns of whole-brain neuroanatomical abnormalities. These patterns may serve as valuable biomarkers for the clinician to guide early detection in the prodromal phase of psychosis.

Enlargement of the amygdala in patients with a first episode of major depression

BACKGROUND The amygdala plays a crucial role in the mediation of affective behavior in humans and is implemented in the limbic-thalamic-cortical network that is supposed to modulate human mood. The aim of the present study was to measure the amygdala volumes in patients with a first episode of major depression. METHODS Thirty inpatients with a first episode of depression were compared with 30 healthy volunteers matched for age, gender, handedness, and education by performing structural magnetic resonance imaging (MRI) measures of the amygdala. RESULTS Patients showed increased amygdala volumes in both hemispheres as compared to healthy control subjects. No significant correlations were found between amygdala volumes and age, age of onset, illness duration, or severity of depression in the patient group. CONCLUSIONS Enlarged amygdala volumes in patients with a first episode of major depression might be due to enhanced blood flow in the amygdala rather than to a neurodevelopmental structural predisposition to major depression.

Larger amygdala volumes in first depressive episode as compared to recurrent major depression and healthy control subjects.

BACKGROUND The aim of our study was to test the hypothesis that amygdala volumes are reduced in patients with recurrent major depression compared with first episode patients. METHODS Using structural magnetic resonance imaging, we compared 30 inpatients with first-episode depression and 27 inpatients with recurrent major depression (DSM-IV) with healthy volunteer subjects from the local community matched for age, gender, and handedness. RESULTS Patients with first-episode depression showed enlarged amygdala volumes compared with patients with recurrent major depression and healthy control subjects. No significant differences were found between patients with recurrent depression and healthy control subjects. No significant correlations were found between amygdala volumes and age of onset, illness duration, or severity of depression. CONCLUSIONS Larger amygdala volumes in patients with first-episode depression may result from higher amygdala metabolism and blood flow. Additionally, disease progression with stress-related excitotoxic processes during recurrent depressive episodes might result in decreased amygdala volumes. Prospective investigations to investigate amygdala changes during the course of depression are needed.

Structural correlates of psychopathological symptom dimensions in schizophrenia: A voxel-based morphometric study

Structural neuroimaging has substantially advanced the neurobiological research of schizophrenia by describing a range of focal brain alterations as possible neuroanatomical underpinnings of the disease. Despite this progress, a considerable heterogeneity of structural findings persists that may reflect the phenomenological diversity of schizophrenia. It is unclear whether the range of possible clinical disease manifestations relates to a core structural brain deficit or to distinct structural correlates. Therefore, gray matter density (GMD) differences between 175 schizophrenic patients (SZ) and 177 matched healthy control subjects (HC) were examined in a three-step approach using cross-sectional and conjunctional voxel-based morphometry (VBM): (1) analysis of structural alterations irrespective of symptomatology; (2) subdivision of the patient sample according to a three-dimensional factor model of the PANSS and investigation of structural differences between these subsamples and healthy controls; (3) analysis of a common pattern of structural alterations present in all patient subsamples compared to healthy controls. Significant GMD reductions in patients compared to controls were identified within the prefrontal, limbic, paralimbic, temporal and thalamic regions. The disorganized symptom dimension was associated with bilateral alterations in temporal, insular and medial prefrontal cortices. Positive symptoms were associated with left-pronounced alterations in perisylvian regions and extended thalamic GMD losses. Negative symptoms were linked to the most extended alterations within orbitofrontal, medial prefrontal, lateral prefrontal and temporal cortices as well as limbic and subcortical structures. Thus, structural heterogeneity in schizophrenia may relate to specific patterns of GMD reductions that possibly share a common prefrontal-perisylvian pattern of structural brain alterations.

Psychometrische Evaluation der deutschsprachigen Version der Barratt-Impulsiveness-Skala

BACKGROUND Impulsive behavior is an important characteristic in a range of psychiatric disorders. A unanimous definition of impulsivity is still under discussion, but a questionnaire to measure it has been available for quite some time, i.e. the Barratt Impulsiveness Scale Version 11 (BIS11). However, it lacks adequate psychometric characterization for German speakers. MATERIALS AND METHODS Control persons were recruited from the Munich city population. Patients with alcohol dependence, suicide attempts, and borderline personality disorders treated as inpatients at the Munich University Psychiatric Clinic were recruited. RESULTS Confirmatory analysis of the originally suggested factor structure did not adequately represent the data in our sample. The BIS11 sum score, which showed adequate internal consistencies in all subgroups, significantly differentiated the extent of impulsivity between patients and control persons. CONCLUSIONS Use of the BIS11 sum score in German-speaking regions can be recommended. This sum score shows adequate internal consistency and well differentiated the extent of impulsivity between different groups of patients with psychiatric diagnoses and control persons.

Cerebral differences in explicit and implicit emotional processing - An fMRI study

The processing of emotional facial expression is a major part of social communication and understanding. In addition to explicit processing, facial expressions are also processed rapidly and automatically in the absence of explicit awareness. We investigated 12 healthy subjects by presenting them with an implicit and explicit emotional paradigm. The subjects reacted significantly faster in implicit than in explicit trials but did not differ in their error ratio. For the implicit condition increased signals were observed in particular in the thalami, the hippocampi, the frontal inferior gyri and the right middle temporal region. The analysis of the explicit condition showed increased blood-oxygen-level-dependent signals especially in the caudate nucleus, the cingulum and the right prefrontal cortex. The direct comparison of these 2 different processes revealed increased activity for explicit trials in the inferior, superior and middle frontal gyri, the middle cingulum and left parietal regions. Additional signal increases were detected in occipital regions, the cerebellum, and the right angular and lingual gyrus. Our data partially confirm the hypothesis of different neural substrates for the processing of implicit and explicit emotional stimuli.

Advances and perspectives from genetic research: development of biological markers in Alzheimer’s disease

Despite important recent advances, a full understanding of the (genetic) etiology of Alzheimer’s disease (AD) is still a long way off. Large collaborative efforts are ongoing, as well as the exploration of various sources of genetic variation. Evidence supports the view that Mendelian early-onset familial forms of AD are caused by rare and usually highly penetrant mutations in three genes (APP, PSEN1 and PSEN2). Considering sporadic late-onset AD (LOAD), the APOE ε4 allele is by far the best-established risk gene. Recently published large-scale genome-wide analyses point to additionally relevant genetically associated loci, particularly CLU, PICALM and CR1. These susceptibility loci support existing hypotheses about the amyloid, lipid, chaperone and chronic inflammatory mechanisms in AD pathogenesis, and are therefore likely to provide the basis for the development of hypothesis-driven novel biomarker candidates. Additional genes, listed online in AlzGene (e.g., GAB2 or SORL1) have repeatedly shown risk effects in LOAD, and may be true risk genes, but this is much less certain. New epigenetic research provided some evidence that DNA modifications maybe involved in LOAD (e.g., post-mortem studies described both hypo- and hyper-methylation in AD-related susceptibility genes). With respect to biomarkers, elderly nondemented APOE ε4 carriers demonstrated distinct cerebrospinal fluid biomarker signatures and alterations of brain glucose metabolism similar to those observed in AD. Future research should evaluate the usefulness of newly detected AD risk genes and epigenetic changes as potential biomarkers towards genetic profiling of AD or for correlation with endophenotypes and therapeutic outcome.

Reduced hippocampal volumes associated with the long variant of the tri- and diallelic serotonin transporter polymorphism in major depression†

Substantial evidence supports a role for dysfunction of the serotonin transporter (5‐HTT) in the pathogenesis of major depression. The polymorphism of the serotonin transporter gene (5‐HTTLPR) was found to be associated with reduced hippocampal volume in major depression. However, the original diallelic polymorphism was criticized, because the L‐allele can be subtyped into La and Lg alleles, the latter of which is thought to be similar to the S‐allele. Therefore, the study aim was to examine the influences of the triallelic (La‐Lg‐S system) and diallelic 5‐HTTLPR on hippocampal volumes in patients with major depression and healthy controls. Using high‐resolution MRI hippocampal volumes and polymorphisms (5‐HTTLPR) were measured in 60 in‐patients with major depression and 60 healthy controls. Patients with the La/La genotype had significantly smaller hippocampal gray and white matter than La/La controls. No significant differences were found between patients and controls with La/(Lg + S) or (Lg + S)/(Lg + S) genotype. Moreover, within the patient group the La/La homozygous genotype had significantly smaller hippocampal white matter volumes than the La/(Lg + S) or (Lg + S)/(Lg + S) genotype. In conclusion, with the diallelic as well as the triallelic system the homozygosity for the long‐allele is associated with decreased hippocampal volumes in patients with major depression, but not in healthy controls, suggesting that disease or stress specific processes linked to the serotonergic system may enhance the vulnerability to morphological alterations.

Anterior cingulate cortex does not differ between patients with major depression and healthy controls, but relatively large anterior cingulate cortex predicts a good clinical course.

The anterior cingulate cortex (ACC) is involved in the regulation of emotion processing, and its volume has been found to be reduced in patients with major depression. Furthermore, larger ACC volumes have been associated with faster symptom improvement under therapy. The aims of the study were to examine whether volumes of the anterior cingulate cortex are altered and are related to the clinical course of major depression. Subjects comprised 78 inpatients with major depression and 78 age-, gender- and handedness- matched healthy volunteers, who were investigated with structural magnetic resonance imaging (MRI). The ACC was subdivided into the subgenual, pre-callosal, rostral-anterior and caudal-anterior ACC. No significant differences were observed for ACC volumes between patients and healthy controls. Left ACC volumes showed a significant negative correlation with the number of hospitalizations. These findings suggest that ACC volumes are not altered in patients with major depression, but that patients with larger ACC have a better clinical outcome than patients with smaller ACC.

Thalamic volume in first-episode and chronic schizophrenic subjects: a volumetric MRI study.

OBJECTIVE The thalamus, as a composite of several functionally very different nuclei, is a major relay and filter station in the CNS and is significantly involved in information processing and gating. The aim of our study is to investigate first-episode and chronic patients and controls to shed light on the potential pathogenetic role of the thalamus in schizophrenia and to assess the relationship between thalamic volumes and psychopathology ratings. METHODS Forty-three male right-handed chronic and 25 male right-handed first-episode schizophrenic patients treated at the psychiatric hospital of the Ludwig-Maximilians University in Munich and 50 male control subjects were enrolled into the study. Demographic information and current symptom profile of all schizophrenic subjects were assessed using a semistructured interview, including a variety of measures relevant to the study. Volumetry of the thalamic gray and white matter was obtained with 1.5 T MRI, using the BRAINS software application. RESULTS No significant differences regarding thalamic volumes were detected across groups. However, negative symptoms were significantly correlated with thalamic volumes in first-episode patients, whereas duration of illness and extrapyramidal symptoms were related to thalamic volumes in chronic patients. SUMMARY Our findings indicate that, while the thalamus might be involved in the pathogenesis of negative symptoms, thalamic volume reduction is not a required element in the pathophysiology of the schizophrenic phenotype.