Henning Witthaus

Smoking and structural brain deficits : a volumetric MR investigation

Growing evidence from animal studies indicates brain‐damaging properties of nicotine exposure. Investigations in humans found a wide range of functional cerebral effects of nicotine and cigarette smoking, but studies focusing on brain damage are sparse. In 22 smokers and 23 never‐smokers possible differences of the cerebral structures were investigated using magnetic resonance imaging and voxel‐based morphometry. Significantly smaller grey matter volume and lower grey matter density (Pu2003=u20030.05, corrected) were observed in the frontal regions (anterior cingulate, prefrontal and orbitofrontal cortex), the occipital lobe and the temporal lobe including parahippocampal gyrus, in smokers than in never‐smokers. Group differences of either grey matter volume or grey matter density were also found in the thalamus, cerebellum and substantia nigra, among other regions. Smokers did not show greater volumes than never‐smokers in any cerebral region. Magnitude of lifetime exposure to tobacco smoke (pack‐years) was inversely correlated with volume of frontal and temporal lobes and cerebellum (Pu2003=u20030.001, uncorrected). The data indicate structural deficits of several cortical and subcortical regions in smokers relative to never‐smokers. The topographic profile of the group differences show some similarities to brain networks known to mediate drug reinforcement, attention and working memory processing. The present findings may explain in part the frequently reported cognitive dysfunctions in chronic cigarette consumers.

Gray matter abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients compared to healthy controls

Neuroimaging studies have revealed gray matter abnormalities in schizophrenia in various regions of the brain. It is, however, still unclear whether such abnormalities are already present in individuals at ultra-high risk (UHR) for transition into psychosis. We investigated this issue using voxel-based morphometry of structural magnetic resonance images (MRI) and compared UHR patients with first-episode patients with schizophrenia and healthy controls. Gray matter volume maps from high-resolution MR T1-weighted whole brain images were analyzed in a cross-sectional study in 30 UHR patients, 23 first-episode schizophrenic patients and 29 controls. UHR patients showed significantly lower gray matter volume in the cingulate gyrus bilaterally, in the right inferior frontal and right superior temporal gyrus, as well as in the left and right hippocampus in comparison to healthy subjects. First-episode patients with schizophrenia showed smaller gray matter volume in the cingulate cortex bilaterally, in the left orbitofrontal gyrus, in the right inferior frontal and superior temporal gyrus, in the right temporal pole, in the left and right hippocampus, in the left parahippocampus, left amygdala, and in the left fusiform gyrus compared to the UHR patients. This study provides further evidence that gray matter brain volume, especially in the anterior cingulate cortex, is already reduced in the prodromal state of schizophrenia.

White matter abnormalities in subjects at ultra high-risk for schizophrenia and first-episode schizophrenic patients

Schizophrenia is associated with neuroanatomical abnormalities. Gray matter decrease seems to predate first schizophrenic episode. Whether white matter abnormalities predate the onset of psychotic symptoms is unclear. We investigated this issue using voxel-based morphometry (VBM) of structural magnetic resonance images to examine individuals with prodromal symptoms who were at ultra high-risk (UHR) of developing schizophrenia and compared them to first-episode schizophrenic patients and healthy controls. White matter volume maps from high-resolution magnetic resonance T1 weighted whole brain images were analyzed in a cross-sectional study using SPM2 in 30 UHR patients, 23 first-episode schizophrenic patients and 29 healthy controls. UHR patients showed significant lower white matter volume in the right superior temporal lobe compared to healthy controls. First-episode patients with schizophrenia showed widespread smaller white matter volume bilaterally compared to UHR patients. This study provides first evidence for smaller white matter volume in the right temporal lobe of UHR patients, one of the key structures in the pathophysiology of schizophrenia. Furthermore, white matter abnormalities seem to progress after transition into schizophrenia.

Reduction of auditory event-related P300 amplitude in subjects with at-risk mental state for schizophrenia

Neurophysiological methods allow the examination of cognitive-cortical functioning in patients with schizophrenia in its prodromal states. As revealed by previous studies, event-related potential components such as auditory evoked P300 associated with cognitive processes, such as attention and orientation, are known to be reduced in amplitude in acute and chronic as well as in medicated and unmedicated patients. It is, however, unclear whether a P300 amplitude reduction occurs before the schizophrenic psychosis is fully manifested. We studied patients in the prodromal phase of the schizophrenic disorder (i.e. subjects with an at-risk mental state showing attenuated psychotic symptoms or brief limited intermittent symptoms) as well as first-episode patients and chronic patients with schizophrenia and compared these groups to healthy subjects. The event-related P300 was recorded during an auditory oddball paradigm. Groups differed significantly from each other in the P300 amplitude at Pz (F(3/149)=2.532, p=0.02). Post-hoc tests revealed significantly lower P300 amplitudes of non-medicated prodromal (p=.03), first-episode (p=.01) and chronic patients (p=.001) compared to the healthy controls. The study revealed that there are neurophysiological changes as the reduction in P300 amplitudes begins early in schizophrenia at the prodromal phase, i.e. before a manifestation of full-blown psychosis, and that these changes seem to have a progressive course from prodromal to chronic state of schizophrenia as assumed in this cross-sectional study.

Validation of the Personal and Social Performance (PSP) Scale in a German sample of acutely ill patients with schizophrenia

In trying to more broadly define outcome in the efficient long-term treatment of patients with schizophrenia it is necessary to consider not only a reduction in psychopathological symptoms but also a successful psychosocial reintegration. Thus, a more exact assessment of psychosocial functioning is needed. Since the GAF (Global Assessment of Functioning) scale and the SOFAS (Social and Occupational Functioning Assessment Scale) are less operationalized and confuse psychosocial facts with psychopathological symptoms, the Personal and Social Performance (PSP) scale was developed [Morosini, P.L., Magliano, L., Brambilla, L., Ugolini, S., Pioli, R. (2000). Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatrica Scandinavica, 1001, 323-329.] containing the four main areas socially useful activities, personal and social relationships, self-care, as well as disturbing and aggressive behaviour. Validation of the PSP scale was conducted in a sample of 62 patients with acute schizophrenia. Rating instruments were PSP, GAF, SOFAS, PANSS, CGI, and Mini-ICF-P (Mini-ICF-Rating for Mental Disorders). The results showed good reliability with alpha=.64-.84, high test-retest reliability as well as good inter-rater reliability for the PSP scale. Furthermore, PSP proved good validity with high correlations to GAF (r=.91), SOFAS (r=.91), and Mini-ICF-P (r=-.69). The hypothesis that more critically ill patients would show lower scores on PSP than lesser ill patients was only confirmed for PANSS negative symptoms. Thus, the findings prove the PSP scale to be a reliable and valid instrument for assessing social functioning of patients with schizophrenia during the course of treatment as well as in the acute state.

Cooperation and deception recruit different subsets of the theory-of-mind network.

The term “theory of mind” (ToM) describes an evolved psychological mechanism that is necessary to represent intentions and expectations in social interaction. It is thus involved in determining the proclivity of others to cooperate or defect. While in cooperative settings between two parties the intentions and expectations of the protagonists match, they diverge in deceptive scenarios, in which one protagonist is intentionally manipulated to hold a false belief about the intention of the other. In a functional magnetic resonance imaging paradigm using cartoons showing social interactions (including the outcome of the interaction) between two or three story characters, respectively, we sought to determine those brain areas of the ToM network involved in reasoning about cooperative versus deceptive interactions. Healthy volunteers were asked to reflect upon the protagonists intentions and expectations in cartoons depicting cooperation, deception or a combination of both, where two characters cooperated to deceive a third. Reasoning about the mental states of the story characters yielded substantial differences in activation patterns: both deception and cooperation activated bilateral temporoparietal junction, parietal and cingulate regions, while deception alone additionally recruited orbitofrontal and medial prefrontal regions. These results indicate an important role for prefrontal cortex in processing a mismatch between a characters intention and anothers expectations as required in complex social interactions.

Serotonergic dysfunction in the prodromal, first-episode and chronic course of schizophrenia as assessed by the loudness dependence of auditory evoked activity

Recent studies revealing evidence of increased serotonergic neurotransmission in schizophrenia has generated substantial interest in the role of serotonin in its pathophysiology. None of these studies, however, have queried whether dysfunctional serotonergic activity might already have been present in subjects of at-risk mental state for schizophrenia before the onset of psychotic symptoms, and whether serotonergic activity further increases during the development of schizophrenia and the chronic course. Although no valid indicator for measuring the activity level of serotonergic neurotransmission has yet been found, a series of evidence from human and animal studies suggests that a weak loudness dependence of auditory evoked potentials (LDAEP) indicates high serotonergic activity and vice versa. We examined the LDAEP (N1/P2 component) in 60 patients with at-risk mental state for schizophrenia who showed characteristic prodromal symptoms, 34 first-episode patients, 28 patients with a chronic course of schizophrenia and 57 healthy controls. Prodromal patients showed significantly weaker LDAEP in comparison to healthy volunteers, but similarly to that in first-episode and chronic patients. None of the covariates such as age, gender, medication, age of onset, or psychopathology had an influence on this finding. In a subsample of prodromal patients, LDAEP values remain the same after retesting 10 months later. These results indicate that serotonergic neurotransmission had already increased before the onset of the full-blown psychosis of schizophrenia and remains enhanced in the further course of the disease. A weak LDAEP may therefore represent a vulnerability marker rather than an expression of illness progression.

“Theory of mind” is impaired in Huntington's disease†

Huntingtons disease (HD) is an autosomal dominant degenerative brain disorder that is characterized by motor, cognitive, and affective symptoms. There is, to some, degree, phenomenological overlap with schizophrenia. Schizophrenia patients are frequently impaired in “theory of mind” (ToM), that is, the ability to reflect on the mental states of self and others, with mixed evidence for a ToM deficit in HD.

Test-performance after cognitive training in persons at risk mental state of schizophrenia and patients with schizophrenia

This exploratory study aims to examine the differential effects of a computer-based cognitive training in prodromal patients (mean age 27.20 years, S.D. 5.31 years) compared with patients with full-blown schizophrenia (mean age 30.13 years, S.D. 7.77 years). Ten patients at risk for schizophrenia and 16 patients suffering from schizophrenia underwent a computerized cognitive training program (Cogpack). Cognitive functioning before and after a total of 10 training sessions was assessed by different tests controlling for memory, attention, and logical thinking. Prodromal patients turned out to be able to significantly improve their long-term memory functions and their attention after cognitive training with the Cogpack software package whereas in the group of patients with schizophrenia no improvement occurred (e.g. continuous performance test, identical pairs-subtest shapes: improvement from 0.73 to 0.88 in persons at risk of schizophrenia vs. no improvement in patients with schizophrenia (0.55 to 0.53). Cognitive training using Cogpack is helpful for the improvement of cognitive functioning in persons at risk of schizophrenia. Thus, the application of cognitive training should be provided as early as possible in the prodromal phases of schizophrenia in order to use the full rehabilitative potential of the patients. These results should be confirmed by further investigations including larger sample sizes.

Loudness dependence of the auditory evoked N1/P2 component as an indicator of serotonergic dysfunction in patients with schizophrenia — A replication study

Serotonergic dysfunction appears to be involved in the pathogenesis of schizophrenia. The loudness dependence of auditory evoked potentials (LDAEP) has been suggested to be a valid indicator of the brain serotonin systems activity in humans. Patients with schizophrenia showed weaker LDAEP, indicating high serotonergic activity, in comparison to healthy controls. Thus, we were able again to demonstrate electrophysiological evidence for an upregulated serotonergic system in schizophrenia.