AGNP-Symposium 1999 - Workshop
Multimodal
neuroimaging in schizophrenia reasearch:
From pathophysiology to pharmacotherapeutic strategies
Organizers: R. Schlösser
(Mainz) and K. Maurer (Frankfurt)
| Program | Overview | Abstracts |
W.
K. Strik, T.J. Müller
Department of Psychiatry, University of Bern
Differential neurophysiologic mechanisms in endogenous psychoses
A.
Heinz
Central Institute of Mental Health (ZI), Mannheim
Psychopathological correlates of dopaminergic dysfunction in schizophrenia
and a primate model of neonatal mesolimbic lesions
T.
Dierks1, 2, M. Jandel2
Department of Psychiatry, University of Frankfurt1, University
of Bern2
Activation of Heschl`s gyrus during auditory hallucinations
U.
Habel, F. Schneider
Department of Psychiatry, University of Düsseldorf
Studying emotial experience of schizophrenic patients with fMRI
D.
F. Braus
Central Institute of Mental Health (ZI), Mannheim
Differentiel influence of typical and atypical neuroleptics on acoustic
and visual information processing of schizophrenic patients: Studies with
fMRI and 1H-MRS
R.
Schlösser
Department of Psychiatry, University of Mainz
Differential influence of typical and atypical neuroleptics on working
memory and executive functions of schizophrenic patients: Studies with
fMRI
Invited discussants
J. Schröder, Department
of Psychiatry, University of Heidelberg, Germany
H.P. Volz, Department of Psychiatry, University of Jena, Germany
F. Henn, Central Institute of Mental Health (ZI), Mannheim, Germany
The age of in vivo functional brain imaging has opened up new avenues for the study of pathophysiology and treatment strategies of schizophrenia. Currently, different methodological approaches in electrophysiology, nuclear medicine and radiology have been used for functional brain imaging studies. In the present workshop, results from electroencephalography (EEG), single photon emission tomography (SPECT), functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) will be presented. Furthermore, options for multimodal imaging in order to combine the information acquired by different imaging modalities will be evaluated. Finally, the use of multimodal imaging to develop and monitor treatment strategies in schizophrenia will be discussed.
Electrophysiological approaches to the study of psychotic disorders will be presented and discussed by W.K. Strik and T.J. Müller. The results indicate different neurophysiological mechanisms underlying the functional psychoses and provide a biological rationale for their clinical characterization.
Relationships between acquired prefrontal dysfunctions and increased dopaminergic responsivity to stress were described. A. Heinz discusses studies in primates where changes in striatal dopamine release subsequent to neonatal lesions of the temporo-limibic prefrontal network could be found. In schizophrenic patients, worsening of negative symtpoms was correlated with an increased availability of striatal dopamine D2 receptors.
Th. Dierks and M. Jandel elaborate the use of fMRI to directly investigate psychopathological symptoms. By this approach, evidence of the involvement of primary auditory areas in auditory verbal hallucinations was provided.
Aside from cognitive disturbances, pathology of emotional processes is involved in the schizophrenia. U. Habel and F. Schneider present the study of activation patterns with fMRI in response to emotional stimuli. Unlike controls, amygdala activation was not found in schizophrenic patients during sad mood induction despite matched ratings reflecting similar negative affect.
The possibilities of monitor influences of pharmacological treatment with fMRI will be explored. D. F. Braus focuses on early visual information processing networks in schizophrenia and discusses the possibility of fMRI to detect dysfunctions in prefronto-temporo-limbic networks.
R.
Schlösser discusses fMRI for the study of disturbances of neural
networks subserving working memory and executive functions in schizophrenia.
Atypical neuroleptics seem to have a favorable influence on functional
disturbances in these cognitive domains.
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Distinct neurophysiological mechanisms in functional psychoses
Strik WK, Müller
TJ
Department of Psychiatry, University of Bern, Switzerland
Amplitude reductions
of the auditory P300 component of evoked potentials have been repeatedly
found in schizophrenia as a non-specific finding. In more recent years,
methodological studies and diagnostic subgrouping allowed a better definition
of the characteristical P300 features in functional psychoses. In chronic
and subchronic schizophrenia a pathological asymmetry of the P300 field
was found (Strik et al., Psych Res 55:153-166, 1994) indicating a left
hemispheric deficit related to language functions (Heidrich and Strik,
Biol Psychiatry 41:327-335, 1997). In cycloid psychoses, the first time
in a psychotic disorder, increased amplitudes were reported indicating
a generalized cerebral hyperarousal (Strik et al, Acta Psychiat Scand
95:67-72, 1997). In a recent study, manic patients were studied as a control
for cycloid psychoses since both groups are bipolar with psychomotor excitation
and neuroleptic treatment. These patients differed significantly from
both, schizophrenia and cycloid psychosis: they had normal amplitudes
and a distinct topographical alteration indicating reduced inhibitory
frontal lobe activity (Strik et al, Acta Psychiat Scand, 98:459-466, 1998).
The results indicate different neurophysiological mechanisms at the basis
of functional psychoses and provide a biological rationale for their clinical
distinction.
Figure: P300 amplitudes
Figure: P300 topography,
Location of Maximal Positivity
Psychopathological correlates of dopaminergic dysfunction in schizophrenia and a primate model of neonatal mesolimbic lesions
1,2Heinz
A, 1Saunders R, 1Knable MB, D.R.2Weinberger
DR
1 Central Institute of Mental Health, Mannheim, Germany
2 National Institutes of Mental Health, Bethesda, MD, USA
It has been suggested
that early developmental disorganization of the mesial temporal lobe may
interfere with the prefrontal regulation of subcortical dopamine release
in schizophrenia. The resulting disinhibition of phasic dopamine release
may be associated with positive symptoms, while a reduction in tonic dopamine
release may be associated with negative symptoms in schizophrenia.
In thirteen drug-free schizophrenic patients, IBZM SPECT was applied twice
in the course of two weeks to assess striatal D2 receptor availability
and to compare it with positive and negative symptom severity. In a non-human
primate model of early developmental damage to the temporolimbic cortices,
tonic and phasic dopamine release were assessed with microdialysis and
IBZM and ß-CIT SPECT was used to measure striatal dopamine D2 receptors
and transporters. Four ten year old rhesus monkeys with neonatal temporolimbic
lesions were compared with four primates with adult temporolimbic lesions
and four age-matched control primates.
In drug-free schizophrenics we observed a positive correlation between
an increase in D2 receptor availability and the severity of negative symptoms.
In non-human primates with an adult temporolimbic lesion and in control
primates, prefrontal monoaminergic stimulation reduced subcortical dopamine
release. Primates with a neonatal limbic lesion displayed a significant
stimulus-dependent, phasic increase in subcortical dopamine release, which
was correlated with decreased availability of striatal dopamine D2 receptors.
A disinhibition of phasic, stimulus-dependent dopamine release can result
from early developmental lesions of the temporolimbic-prefrontal network.
In schizophrenic patients, worsening of negative symptoms was correlated
with an increased availability of striatal dopamine D2 receptors; this
finding may be due to reduced competition of the radioligand with basal
or "tonic" dopamine release. Supported in part by the DFG (He
2597/1-1).
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Activation of Heschl`s gyrus during auditory hallucinations
1,2Dierks,
T,2Jandl, M, 2Linden DEJ, 3Lanfermann
H., 2Maurer K.
1Dept. of Psychiatry, Univ. of Bern, Switzerland
2Dept. of Psychiatry, Univ. of Frankfurt, Germany
3Dept. of Neuroradiology, Univ. of Frankfurt, Germany
Apart from being a
common feature of mental illness, auditory hallucinations provide an intriguing
model for the study of internally generated sensory perceptions that are
attributed to external sources. Until now the knowledge about the cortical
network that supports such hallucinations has been restricted by methodological
limitations. Here we describe an experiment with paranoid schizophrenic
patients whose on- and offset of auditory hallucinations could be monitored
within one functional magnetic resonance imaging (fMRI) session. During
18 months, all patients admitted to the Department of Psychiatry of the
University of Frankfurt with a history of auditory hallucinations were
screened for a hallucination pattern compatible with a fMRI protocol.
Three patients could be included in the study. At the time of the investigation
their psychopathology consisted, beside negative symptoms like anhedonia,
predominantly in auditory verbal hallucinations, which were unresponsive
to neuroleptic treatment. We demonstrate an increase of the blood oxygen
level-dependent (BOLD) signal in Heschl`s gyrus during the patients’
hallucinations (Patient 1: Fig. 1a). During acoustic stimulation in the
same patients activation was observed in the transverse gyrus of Heschl,
at the same location as the focus of activation during hallucinations
(Patient 1: Fig. 1b). Our results provide the first direct evidence of
the involvement of primary auditory areas in auditory verbal hallucinations
and establish novel constraints for psychopathological models.
Emotional experiences in schizophrenic patients studied with fMRI
Habel U, Schneider
F
Department of Psychiatry, University of Düsseldorf, Germany
Several studies have
reported impaired emotion processing in schizophrenic patients. However,
the corresponding functional cerebral correlates of such impairment remain,
so far, elusive, leaving the neurobiological basis of their affective
symptoms unknown. 13 medicated male schizophrenic patients and 13 matched
healthy controls were investigated during a happy and sad mood induction
procedure, as well as an activating non-emotional (neutral) control task.
Functional magnetic resonance imaging (fMRI) was utilized to examine brain
activity in subcortical and cortical regions. Subjective ratings revealed
an expected mood induction effect for each experimental group. Analysis
of fMRI data shows brain activity in the amygdala of normal controls during
negative affect, thereby corresponding to previous neuroimaging findings.
Further investigation of gender effects in healthy controls revealed however,
that this effect was only present in the group of healthy males, which
is suggestive of a more focal and subcortical processing of sadness in
men. Correlations of subjective ratings with fMRI signal intensities were
significant for male controls: blood flow increases in the amygdala during
sadness were accompanied by stronger feelings of negative mood. Unlike
controls, amygdala activation was not found in schizophrenic patients
during sad mood induction despite matched ratings reflecting similar negative
affect. Recognizing that structural abnormalities exist in the amygdala
of schizophrenic patients, our results provide new evidence of functional
abnormalities in the limbic system. Furthermore, the results point to
probable different regional cerebral correlates of emotional states in
women and men.
Differential influence of typical and atypical neuroleptics on acoustic and visual information processing of schizophrenic patients: Studies with fMRI and 1H-MRS
Braus DF, Ende
G, Ruf M, Weber-Fahr W, Tost H, Severa L, Henn FA
Central Institute of Mental Health (ZI), Mannheim, Germany
The clinical picture
of patients with schizophrenic psychoses is characterized by disturbed
information processing. However, a high interindividual and intraindividual
variability of these deficits can be observed. Aside from genetic predispositions,
disturbances of complex intrauterine brain development processes may lead
to anatomic, functional and biochemical alterations of neuronal networks.
These effects are preferentially located in the prefrontal cortex and
thalamus. Current developments of functional and biochemical nuclear magnetic
resonance imaging (fMRI, MRSI) are opening up new avenues for non-invasive
studies of central nervous system dysfunctions. In the current study,
the phenotypic characterization of basic information processes in schizophrenic
patients was elaborated with fMRI and MRSI. A major focus was laid on
the modulation of brain function and biochemistry by antipsychotic therapy.
Functional and biochemical NMR was performed on a clinical 1.5 T Siemens
Magnetom Vision. Echo-planar imaging (EPI) technique and MR-spectroscopic
imaging (MRSI) were used. 12 neuroleptic naive first episode schizophrenic
patients (ICD 10 F20.x), 24 patients in remission with neuropsychological
deficits as measured by WCST and 20 matched controls were included
into the study. To characterize basic information processing, a passive
combined visual-acoustic stimulation paradigm was applied with simultaneous
presentation of drum noise and 6-hz-checkerboard patterns. Data analysis
was performed with BrainVoyager 3.0 and SPM96. For biochemical imaging
(MRSI), voxels-of-interest in the anterior cingulate and the thalamus
were selected.
fMRI demonstrated both in neuroleptic naive first episode and in chronically
ill schizophrenic patients in remission a dysfunction of the first relay
station of the thalamus, in area V5 and in the prefrontal cortex as compared
to normal controls. Furthermore, significant differences between patients
with typical and atypical antipsychotics could be observed. Consistent
with these functional results, significant biochemical differences as
measured by NAA/Cr ratios in relationship to medication status could be
found.
Clinical and biochemical results point towards a great heterogeneity of
schizophrenia spectrum disorders. Methods for non-invasive biological
characterization were rather limited so far. These pilot studies intended
to evaluate the possibility of current developments in NMR-technologies
(fMRI, MRS) to resolve this heterogeneity of schizophrenia spectrum disorders
and to investigated influences of neuroleptic treatment. In the present
study, both differences between patients and healthy subjects and differences
within the patient group could be found. The results support the hypothesis
of dysfunctions in prefronto-temporo-limbic and in early visual information
processing networks in schizophrenia. Atypical neuroleptics seem to have
a favorable influence on these functional disturbances. The results show
also that currently a number of methodological limitations are still present
which have to be taken into account with regard to possible clinical applications
of the available methods. However, it can be expected that in a near future
non-invasive functional and biochemical NMR-tomography will serve as a
rational basis for psychiatric treatment strategies and therapeutic monitoring.
Differential influence of typical and atypical neuroleptics on working memory and executive functions of schizophrenic patients: Studies with fMRI
1Schlösser
R, 1Gesierich Th, 1Rossbach W, 1Kaufmann
B, 1Estifan F, 2Hunsche S, 2Gawehn J,
2Vucurevic G, 1Hoffmann G, 1Gründer G
and 2Stoeter P
Department of 1Psychiatry and Department of 2Neuroradiology,
University of Mainz , Germany
Several lines of evidence
support the notion of schizophrenia as a neurodevelopmental disorder.
Functional impairments of cortical-subcortical neuronal circuits are associated
with psychopathological symptoms and deficits in a range of neurocognitive
functions. Particularly deficits of working memory and executive functions
were described in schizophrenic patients. Working memory is involved in
the short-term maintenance and transformation of information. Whereas
the major component of working memory has traditionally been related to
prefrontal functional brain areas, functional brain imaging approaches
provided information about widespread networks including frontal and parietal
association cortices involved in performance of working memory tasks.
The aim of the present study was to investigate whether schizophrenic
patients show defined changes in information processing networks while
performing a task involving working memory demands. Additionally, we intended
to elaborate differential influences of typical versus atypical neuroleptic
treatment on cognitive activation patterns in schizophrenia.
Data from 12 right-handed schizophrenic patients treated with typical
or atypical neuroleptics and 12 normal subjects were analyzed so far.
Patients were stabilized by neuroleptic treatment for at least 2-4 weeks.
All subjects performed a "2-back"-working memory task during
the functional scans. fMRI-scans were acquired on a Siemens Magnetom (Vision)
at 1.5 T with EPI capabilities (matrix size 128x128; 23 contiguous slices;
5 mm slice thickness). Data were analyzed with SPM96 including the random
effects kit.
In normal subjects, activation foci delineated the entire cortical-subcortical-cerebellar
circuit. Activations could be identified in the prefrontal and parietal
association cortices, thalamus, cerebellar vermis, and cerebellar hemispheres.
Schizophrenic patients revealed significantly diminished activation particularly
in subcortical and cerebellar areas. However, this difference in activation
was less pronounced in patients treated with atypical neuroleptics as
compared to those receiving conventional neuroleptic drugs.
The finding suggests that disruption of widespread neural networks in
schizophrenia can be favorably influenced by atypical neuroleptics.
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