Kognitive und neuronale Korrelate von Halluzinationen bei der Schizophrenie : Wahrnehmungsstörungen bei Patienten mit Schizophrenie im Vergleich zu erstgradigen Verwandten und Kontrollpersonen - untersucht mit psychometrischen Messungen und Magnetresonanz-Tomographie (MRT)

The present study consists of two parts: The first part is made up of questions concerning the cognitive underpinnings of auditory verbal hallucinations in schizophrenia. As this thesis framed schizophrenia as a multivariate problem, neural correlates to auditory verbal and visual hallucinations were investigated in the second part. The main finding is that vividness of mental imagery was increased in all putative high-risk groups as well as the patients themselves, compared with low-schizotypy controls. Therefore, it seems that vivid imagery is a trait rather than a state marker, and may be related to the genetic liability to develop schizophrenia. However, no evidence was found for a linear relationship between vividness of mental imagery and predisposition to hallucinate. Self-reported imagery vividness and predisposition to hallucinate did not depend on psychomotor speed or intelligence. In addition, individual psychopathology ratings did not correlate significantly with the mental imagery scores. Furthermore, the analysis of the control orientation and the degree of dysfunctional psychopathological status across the schizophrenia spectrum, showed an independence of control orientation and dysfunctional status from each other, as well as from other markers of schizophrenia or schizophrenic-like individuals. As a conclusion, external control orientation seems to be a symptom or a trait marker of schizophrenia. The results lead to the assumption that, beside schizophrenic individuals, first-degree relatives and schizotypy controls have some impairments and visible signs without suffering from the illness directly. This would lead to the further assumption that the illness schizophrenia is not only genetic but also dependent on environmental factors. In the second part of the study, we investigated anatomical and functional brain abnormalities in the schizophrenia patients compared with first-degree relatives and healthy controls. Here, the results followed the continuum of healthy controls, first-degree relatives and schizophrenic patients in the functional and anatomical data sets, and in the language lateralization. The decrease of lateralisation correlated with the severity of symptoms in the patient group. The investigation of visual hallucinations showed activity in higher visual areas during the experience of visual hallucinations in a schizophrenia patient and in a blindfolded subject. The activity in higher visual areas followed the boundaries of category-selective areas in both subjects. In contrast to the memory-related areas found in the schizophrenic patient experiencing visual hallucinations, we did not observe memory-related areas during visual hallucinations induced by blindfolding. This suggests that the neural mechanisms underlying hallucinations in schizophrenia are at least partly distinct from those operational in cortical deafferentation. It is proposed that individual differences in psychopathology, as well as neuropsychological and psychosocial functioning may provide further means to understand the complex and highly dynamic aspects of hallucinations specifically and schizophrenia in general. The enlargement of the subject sample to high-schizotypy controls and first-degree relatives of patients allowed new insights into the mental imagery debate and the dysfunctional connectivity pattern known to be responsible for psychotic symptoms. Further topics of research are discussed.Die hier präsentierte Arbeit untersucht die Erkrankung Schizophrenie, und speziell das Phänomen der Halluzinationen, unter multivariaten (kognitiv, neuronal) Gesichtspunkten. In der ersten Teiluntersuchung wurde geprüft, ob sich die mentale Vorstellungskraft bei den verschiedenen Versuchspersonengruppen, schizophrene Patienten, erstgradige Verwandte der Patienten, hoch-schizotype Kontrollpersonen und normale Kontrollpersonen, signifikant unterscheidet, und ob diese potentiellen Unterschiede eine Verbindung zu Halluzinationen, aufweisen. Das Hauptergebnis ist, dass die Lebhaftigkeit der mentalen Vorstellung in allen potentiellen Risikogruppen, also Verwandten, hoch-schizotypen Personen und schizophrenen Patienten selbst, erhöht ist, wenn man sie mit der Lebhaftigkeit der mentalen Vorstellungskraft bei normalen Kontrollprobanden vergleicht. Die Ergebnisse zeigen Hinweise auf eine genetische Disposition zu einer vermehrten Lebhaftigkeit visueller Vorstellungen im schizophrenen Spektrum. Jedoch zeigten die Ergebnisse nicht, wie von verschiedenen Autoren vermutet, einen direkten Zusammenhang zwischen der mentalen Vorstellungskraft und der Prädisposition zu halluzinieren. Beide Konstrukte scheinen darüber hinaus von psychomotorischer Verarbeitungsgeschwindigkeit und kristalliner Intelligenz unabhängig zu sein. Darüber hinaus besteht kein Zusammenhang zwischen der individuellen Ausprägung der psychopathologischen Symptome der schizophrenen Patienten und der subjektiven Einschätzung der mentalen Vorstellungskraft. Die Ergebnisse weisen darauf hin, dass die Lebhaftigkeit der Vorstellung eher etwas Überdauerndes (trait marker) als ein aktuell untersuchter Zustand (state marker) ist. Die Lebhaftigkeit der mentalen Vorstellungskraft scheint eine von Halluzinationen oder anderen psychopathologischen Symptomen unabhängige Auffälligkeit zu sein, die sich über das Schizophrenie-Spektrum erstreckt. Weiterhin konnten bei der Untersuchung weiterer möglicher Korrelate zu Halluzinationen andere kognitive Konstrukte mit den gleichen Probandengruppen untersucht werden: das Ausmaß an externaler Kontrollüberzeugung sowie an dysfunktionalen psychopathologischen Zustandsbild. Hier zeigte sich, dass schizophrene Patienten eher zu einer externalen Kontrollorientierung neigen, während Kontrollprobanden eine internal orientierte Kontrollüberzeugung hatten. Hoch-schizotype Personen sowie Verwandte der Patienten bildeten die Mitte zwischen den beiden anderen Probandengruppen. Auch bezüglich des dysfunktionalen Status konnte das eben beschriebene Kontinuum gezeigt werden. Beide Konstrukte zeigten sich unabhängig voneinander, wie auch von Halluzinationen. Jedoch zeigte sich ein Zusammenhang zwischen der externalen Kontrollüberzeugung und einem anderen psychopathologischen Symptom der Schizophrenie, den Wahnvorstellungen. Also scheint eine externale Kontrollüberzeugung ein Symptom oder ein Trait marker der des Schizophrenie-Spektrums zu sein. Diese Probandengruppen zeigen im Vergleich zu normalen Kontrollprobanden Auffälligkeiten, ohne dass sie an der Erkrankung direkt leiden. Dies könnte zu dem Schluss führen, dass gewisse Auffälligkeiten genetisch veranlagt sind, die Grenze zur Erkrankung Schizophrenie aber nur überschritten wird, wenn Umgebungs- oder andere Faktoren ungünstig dazu kommen. Im zweiten Teil der Studie untersuchten wir anatomische und funktionelle Auffälligkeiten des Gehirns. Die neurologischen Daten zeigen eine niedrigschwellige Aktivität im auditorischen Kortex außerdem eine reduzierte Sprachlateralisierung bei Schizophrenen und ihren Verwandten im Vergleich zu Normalpersonen. Sprache wird normalerweise stärker linksseitig im Gehirn verarbeitet, bei unseren Patienten scheint dieser Mechanismus jedoch gestört zu sein. Weitergehende Fragen zeigten, dass die Reduzierung der Sprach-Lateralisierung bei den Patienten in direkter Verbindung zu psychotischen Symptomen stehen. Je mehr psychotische Symptome die Patienten während des Zeitraums der Untersuchung aufwiesen, desto deutlicher gestaltete sich die Reduktion der Sprachlateralisierung. Diese Ergebnisse konnten auch für die Untersuchung des anatomischen Volumens des auditorischen Kortex gezeigt werden. Die hier vorliegenden Befunde sprechen für das schon zuvor beobachtete Kontinuum der Ergebnisse, von den Normalpersonen ohne Auffälligkeiten, zu den Verwandten mit leichten Auffälligkeiten, bis hin zu den Patienten mit deutlichen Auffälligkeiten in auditorischen und visuellen Verarbeitungsbereichen. Im weiteren Verlauf untersuchten wir das Phänomen der visuellen Halluzinationen bei einem schizophrenen Patienten sowie bei einer Probandin, die visuelle Halluzinationen durch sensorische Deprivation bewusst herbeigeführt hat. Wir konnten zeigen, dass höhere visuelle Areale während des Erlebens von visuellen Halluzinationen aktiviert sind, die direkt mit den Grenzen Kategorie-spezifischer Areale einhergingen. Während es gelungen ist, bei dem schizophrenen Patienten Gedächtnis-Areale zu finden, konnte dieser Befund für die Probandin mit den durch sensorische Deprivation herbeigeführten Halluzinationen nicht bestätigt werden. Dieser Befund bestätigt die Vermutung, dass die neuronalen Mechanismen, die den visuellen Halluzinationen bei schizophrenen Patienten zugrunde liegen, teilweise anders als bei operationaler kortikaler Deafferentation sind

Altered intrinsic functional connectivity in language-related brain regions in association with verbal memory performance in euthymic bipolar patients

Potential abnormalities in the structure and function of the temporal lobes have been studied much less in bipolar disorder than in schizophrenia. This may not be justified because language-related symptoms, such as pressured speech and flight of ideas, and cognitive deficits in the domain of verbal memory are amongst the hallmark of bipolar disorder (BD), and contribution of temporal lobe dysfunction is therefore likely. In the current study, we examined resting-state functional connectivity (FC) between the auditory cortex (Heschl’s gyrus [HG], planum temporale [PT]) and whole brain using seed correlation analysis in n = 21 BD euthymic patients and n = 20 matched healthy controls and associated it with verbal memory performance. In comparison to controls BD patients showed decreased functional connectivity between Heschl’s gyrus and planum temporale and the left superior and middle temporal gyrus. Additionally, fronto-temporal functional connectivity with the right inferior frontal/precentral gyrus and the insula was increased in patients. Verbal episodic memory deficits in the investigated sample of BD patients and language-related symptoms might therefore be associated with a diminished FC within the auditory/temporal gyrus and a compensatory fronto-temporal pathway

Reduced intrinsic visual cortical connectivity is associated with impaired perceptual closure in schizophrenia

Sensory perceptual processing deficits, such as impaired visual object identification and perceptual closure, have been reported in schizophrenia. These perceptual impairments may be associated with neural deficits in visual association areas, including lateral occipital cortex and inferior temporal areas. However, it remains unknown if such deficits can be found in the intrinsic architecture of the visual system. In the current study, we measured perceptual closure performance and resting-state functional connectivity using functional magnetic resonance imaging (FMRI) in 16 schizophrenia patients and 16 matched healthy controls. We estimated intrinsic functional connectivity using self-organized grouping spatial ICA, which clusters component maps in the subject space according to spatial similarity. Patients performed worse than controls in the perceptual closure task. This impaired closure performance of patients was correlated with increased severity of psychotic symptoms. We also found that intrinsic connectivity of the visual processing system was diminished in patients compared to controls. Lower perceptual closure performance was correlated to lower visual cortical intrinsic connectivity overall. We suggest that schizophrenia is associated with impaired intrinsic connectivity of the visual system, and that it is a potential mechanism leading to impaired visual object perception. These findings contribute to increasing evidence for impairments of higher visual functions in schizophrenia

Different patterns of white matter degeneration using multiple diffusion indices and volumetric data in mild cognitive impairment and Alzheimer patients

Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia

White matter abnormalities in the fornix are linked to cognitive performance in SZ but not in BD disorder: An exploratory analysis with DTI deterministic tractography

Background In psychosis, white matter (WM) microstructural changes have been detected previously; however, direct comparisons of findings between bipolar (BD) and schizophrenia (SZ) patients are scarce. In this study, we employed deterministic tractography to reconstruct WM tracts in BD and SZ patients. Methods Diffusion tensor imaging (DTI) data was carried out with n=32 euthymic BD type I patients, n=26 SZ patients and 30 matched healthy controls. Deterministic tractography using multiple indices of diffusion (fractional anisotropy (FA), tract volume (Vol), tract length (Le) and number of tracts (NofT)) were obtained from the fornix, the cingulum, the anterior thalamic radiation, and the corpus callosum bilaterally. Results We showed widespread WM microstructural changes in SZ, and changes in the corpus callosum, the left cingulum and the fornix in BD. Fornix fiber tracking scores were associated with cognitive performance in SZ, and with age and age at disease onset in the BD patient group. Limitations Although the influence of psychopharmacological drugs as biasing variables on morphological alterations has been discussed for SZ and BD, we did not observe a clear influence of drug exposure on our findings. Conclusions These results confirm the assumption that SZ patients have more severe WM changes than BD patients. The findings also suggest a major role of WM changes in the fornix as important fronto-limbic connections in the etiology of cognitive symptoms in SZ, but not in B

Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies

Background The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels. Methods We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder. Results Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = −0.57, P = 0.010) and depressive (Hedges' g = −0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one. Conclusions In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD

Associative memory impairments are associated with functional alterations within the memory network in schizophrenia patients and their unaffected first-degree relatives: an fMRI study

Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness

Associative Memory Impairments Are Associated With Functional Alterations Within the Memory Network in Schizophrenia Patients and Their Unaffected First-Degree Relatives: An fMRI Study

Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness