Impact of cognitive performance on the reproducibility of fMRI activation in schizophrenia.

BACKGROUND: Longitudinal functional magnetic resonance imaging (fMRI) studies in patients with schizophrenia allow exploration of the course of the illness and brain activity after therapy. A crucial question, however, is whether fMRI findings are reliable, because they can be affected by performance deficits in patients with schizophrenia. Our aim was to evaluate the reproducibility of fMRI activations in highly integrated language areas in patients with schizophrenia, taking into account task performance. METHODS: Ten patients with schizophrenia and 10 matched healthy controls were scanned twice, 21 months apart, while performing a story comprehension task. The reproducibility of the activations in each participant was evaluated globally by the percentage of spatial overlap between the 2 sessions and locally by a voxel-wise computation of the between-session relative standard deviation. We performed between-group comparisons both with and without the inclusion of comprehension scores (measuring task performance) as a covariate. RESULTS: On average, patients with schizophrenia had significantly lower comprehension scores than controls (4.5/12 v. 7.8/12, p = 0.002). The mean spatial overlap between fMRI sessions was 30.6% in the patient group and 47.0% in the control group (p = 0.017). Locally, the lower reproducibility in patients was most prominent in the left posterior middle temporal gyrus, inferior frontal gyrus and medial prefrontal cortex (p < 0.001 uncorrected for multiple comparisons). Comprehension scores were positively correlated with both reproducibility measures in patients (overlap: r = 0.82, p = 0.004; relative standard deviation: several significant clusters at p < 0.001). When we included the comprehension scores as a covariate, most of the local between-group differences in reproducibility were removed, and the difference in overlap was not significant. LIMITATIONS: Owing to the small sample size, we could not investigate the impact of clinical subtypes and different types of medications on reproducibility. CONCLUSION: Our findings suggest that the greater variability in activation in patients with schizophrenia compared with controls concerns high-level areas and is mainly attributable to deficient task performance. Consequently, cognitive performance must be carefully controlled when longitudinal fMRI studies are undertaken.

Functional deficit in the medial prefrontal cortex during a language comprehension task in patients with schizophrenia.

OBJECTIVE: We and others have observed that patients with schizophrenia commonly presented a reduced left recruitment in language semantic brain regions. However, most studies include patients with leftward and rightward lateralizations for language. We investigated whether a cohort comprised purely of patients with typical lateralization (leftward) presented a reduced left recruitment in semantic regions during a language comprehension task. The goal was to reduce the inter-subject variability and thus improve the resolution for studying functional abnormalities in the language network. METHODS: Twenty-three patients with schizophrenia (DSM-IV) were matched with healthy subjects in age, sex, level of education and handedness. All patients exhibited leftward lateralization for language. Functional MRI was performed as subjects listened to a story comprising characters and social interactions. Functional MRI signal variations were analyzed individually and compared among groups. RESULTS: Although no differences were observed in the recruitment of the semantic language network, patients with schizophrenia presented significantly lower signal variations compared to controls in the medial part of the left superior frontal gyrus (MF1) (x=-6, y=58, z=20; Z(score)=5.6; p<0.001 uncorrected). This region corresponded to the Theory of Mind (ToM) network. Only 5 of the 23 patients (21.7%) and 21 of the 23 (91.3%) control subjects demonstrated a positive signal variation in this area. CONCLUSIONS: A left functional deficit was observed in a core region of the ToM network in patients with schizophrenia and typical lateralizations for language. This functional defect could represent a neural basis for impaired social interaction and communication in patients with schizophrenia.

Stability of functional language lateralization over time in schizophrenia patients.

BACKGROUND: Cross-sectional functional imaging studies have shown a reduced leftward language lateralization in schizophrenic patients. An unanswered question is whether this reduced leftward lateralization is stable over time or is modified over the course of the illness. METHODS: Ten right-handed (RH) patients (DSM-IV) and 10 RH controls were matched one-to-one for sex, age, and level of education. The subjects underwent two separate fMRI sessions while engaged in a story listening task, 21 months apart. After each session, story comprehension (task performance) was assessed through a 12-item questionnaire. The stability of the decreased asymmetry indices in the semantic region of interest (LANG) was investigated with an ANOVA to compare groups and sessions. In order to test the evolution of functional asymmetry indices at an individual level, a linear correlation between both fMRI session asymmetry indices was calculated in all subjects. Correlations between asymmetry indices and the severity of psychotic symptoms or task performances were computed. RESULTS: The asymmetry indices of the LANG were significantly reduced in patients as compared to controls and strongly correlated between sessions. Values of asymmetry indices were unrelated to either psychotic symptoms or task performances. CONCLUSIONS: This reduced leftward lateralization for language did not vary over time and was not influenced by the psychosis severity or the task performances. This result reinforces the hypothesis that schizophrenia is characterized by a particular organization of language.

Impact of Repetitive Transcranial Magnetic Stimulation (rTMS) on Brain Functional Marker of Auditory Hallucinations in Schizophrenia Patients.

UNLABELLED: Several cross-sectional functional Magnetic Resonance Imaging (fMRI) studies reported a negative correlation between auditory verbal hallucination (AVH) severity and amplitude of the activations during language tasks. The present study assessed the time course of this correlation and its possible structural underpinnings by combining structural, functional MRI and repetitive Transcranial Magnetic Stimulation (rTMS). METHODS: Nine schizophrenia patients with AVH (evaluated with the Auditory Hallucination Rating scale; AHRS) and nine healthy participants underwent two sessions of an fMRI speech listening paradigm. Meanwhile, patients received high frequency (20 Hz) rTMS. RESULTS: Before rTMS, activations were negatively correlated with AHRS in a left posterior superior temporal sulcus (pSTS) cluster, considered henceforward as a functional region of interest (fROI). After rTMS, activations in this fROI no longer correlated with AHRS. This decoupling was explained by a significant decrease of AHRS scores after rTMS that contrasted with a relative stability of cerebral activations. A voxel-based-morphometry analysis evidenced a cluster of the left pSTS where grey matter volume negatively correlated with AHRS before rTMS and positively correlated with activations in the fROI at both sessions. CONCLUSION: rTMS decreases the severity of AVH leading to modify the functional correlate of AVH underlain by grey matter abnormalities.

Repetitive transcranial magnetic stimulation in the treatment of auditory hallucinations in schizophrenic patients.

PURPOSE OF REVIEW: Since 1999, most studies have confirmed the initial positive results in the treatment of auditory verbal hallucination (AVH) with repetitive transcranial magnetic stimulation (rTMS) targeted to the classical site in the left temporo-parietal region. However, recent literature has tempered the initial interest in this treatment, requiring a new review on this topic. RECENT FINDINGS: From the four meta-analyses, the latest reported a moderate effect size of 0.54. Two recent controlled studies, not included in the meta-analyses, failed to observe a significant improvement of AVH after 1 Hz rTMS. While almost all trials have studied the effects of low-frequency rTMS (1Hz), two recent procedures using high-frequency (20 Hz) or continuous theta burst stimulation showed promising results. The interest in using cerebral imaging to increase the efficacy of rTMS in the treatment of AVH has not been clearly demonstrated. SUMMARY: Using rTMS to treat auditory hallucinations now seems less promising than it did 10 years ago because of the variable clinical effects and the high level of placebo responders. Evidence is still lacking concerning the maintenance treatment and the neurobiological underpinnings of rTMS efficacy, underscoring the need for further studies.

Language lateralization in left-handed patients with schizophrenia.

We evaluated hemispheric lateralization of language production in non-right-handed (NRH) patients with schizophrenia compared with matched right-handed (RH) patients, NRH control, and RH control subjects. First, the ability to generate verbs during overt training trials was checked in 78 subjects. They were then evaluated with functional magnetic resonance imaging (fMRI) while performing a covert verb generation task. No significant interactions between illness and handedness and no illness effect were observed in functional asymmetry. There was significantly less leftward asymmetry of the inferior frontal, precentral, and supramarginal gyri as well as the intra-parietal sulcus in non-right-handers compared to right-handers taking into account the task performances. Our findings suggested that decreased lateralization for language production was more closely related to handedness than to schizophrenia.

Reproducibility of fMRI activations during a story listening task in patients with schizophrenia.

A prerequisite to longitudinal fMRI studies in schizophrenia is the knowledge on fMRI signal reliability in schizophrenia patients. We assessed the reproducibility of activations elicited by two fMRI sessions, which were 21 months apart, of a story listening paradigm in 10 schizophrenia patients and 10 healthy subjects. In both groups, we observed a high degree of spatial overlap of activation maps as well as a good reproducibility of signal variations assessed on a voxel-wise basis in temporal areas underlying early stages of language processing. Task performance, assessed through a comprehension questionnaire, had no impact on the activation reproducibility.