Francesco Musso

ErbB4 Genotype Predicts Left Frontotemporal Structural Connectivity in Human Brain

Diminished left frontotemporal connectivity is among the most frequently reported findings in schizophrenia and there is evidence that altered neuronal myelination may in part account for this deficit. Several investigations have suggested that variations of the genes that encode the Neuregulin 1 (NRG1)–ErbB4 receptor complex are associated with schizophrenia illness. As NRG1-–ErbB4 has been implicated in neuronal myelination, we investigated with diffusion tensor imaging (DTI) whether fractional anisotropy (FA)—a putative measure of neuronal myelination—is predicted by a risk haplotype of the ErbB4 gene. The effects of the ErbB4 genotype were investigated in healthy subjects (N=59; mean age: 22.6±1.8 years). We also measured reaction time (RT) during a selective attention/working memory paradigm (visual oddball). In the schizophrenia risk genotype group, we found lower FA in the temporal lobe white matter (WM) including frontotemporal fiber tracts, predominantly in the left hemisphere. RT was increased in the risk genotype group and correlated with FA in the affected brain region. As FA is considered to index structural integrity of WM, to which neuronal fiber myelination is contributing, our results suggest that variations of the ErbB4 genotype may confer risk for schizophrenia illness via its impact on left frontotemporal connectivity in human brain. Reliability and validity of the result is suggested by our observation that (1) the FA–genotype association was not only obtained in the entire sample but also in both the split halves and (2) a statistical relationship was found among RT, genotype and FA.

Complex relationship between BOLD signal and synchronization/desynchronization of human brain MEG oscillations

Functional magnetic resonance imaging (fMRI) depends on the coupling of cerebral blood flow, energy demand, and neural activity. The precise nature of this interaction, however, is poorly understood. A positive correlation between BOLD‐response and cortically generated local field potentials, which reflect the weighted average of synchronized dentrosomatic components of pyramidal synaptic signals, has been demonstrated. Likewise, positive BOLD‐responses have been reported in conjunction with scalp‐recorded synchronized electromagnetic activity by a number of groups. However, it is not yet clear how the opposite electromagnetic pattern, i.e. cortical desynchronization, is related to the BOLD signal. To address this question, we conducted a combined event‐related fMRI and 275 sensor whole‐head MEG study during identical visual two‐choice reaction time task conditions in 10 human subjects. We found complex sequences of MEG‐synchronization and desynchronization across a wide frequency range in the visual and motor area in close correspondence with “locales” of positive BOLD‐responses. These results indicate that a correspondence of positive BOLD‐responses is not exclusively found for cortical synchronization but also for desynchronization, suggesting that the relationship between BOLD signals and electromagnetic activity might be more complex than previously thought. Hum Brain Mapp 2006.

Hippocampal subfields predict positive symptoms in schizophrenia : First evidence from brain morphometry

Alterations of hippocampal anatomy have been reported consistently in schizophrenia. Within the present study, we used FreeSurfer to determine hippocampal subfield volumes in 21 schizophrenic patients. A negative correlation between PANSS-positive symptom score and bilateral hippocampal subfield CA2/3 as well as CA1 volume was found on high-resolution magnetic resonance images. Our observation opens the gate for advanced investigation of the commonly reported hippocampal abnormalities in schizophrenia in terms of specific subfields.

Ketamine effects on brain function--simultaneous fMRI/EEG during a visual oddball task.

BACKGROUND Behavioral and electrophysiological human ketamine models of schizophrenia are used for testing compounds that target the glutamatergic system. However, corresponding functional neuroimaging models are difficult to reconcile with functional imaging and electrophysiological findings in schizophrenia. Resolving the discrepancies between different observational levels is critical to understand the complex pharmacological ketamine action and its usefulness for modeling schizophrenia pathophysiology. METHODS We conducted a within-subject, randomized, placebo-controlled pharmacoimaging study in twenty-four male volunteers. Subjects were given low-dose S-ketamine (bolus prior to functional imaging: 0.1mg/kg during 5min, thereafter continuous infusion: 0.015625mg/kg/min reduced by 10% every ten minutes) or placebo while performing a visual oddball task during simultaneous functional magnetic resonance imaging (fMRI) with continuous recording of event-related potentials (P300) and electrodermal activity (EDA). Before and after intervention, psychopathological status was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale. RESULTS P300 amplitude and corresponding BOLD responses were diminished in the ketamine condition in cortical regions being involved in sensory processing/selective attention. In both measurement modalities separation of drug conditions was achieved with area under the curve (AUC) values of up to 0.8-0.9. Ketamine effects were also observed in the clinical, behavioral and peripheral physiological domains (Positive and Negative Syndrome Scale, reaction hit and false alarm rate, electrodermal activity and heart rate) which were in part related to the P300/fMRI measures. CONCLUSION The findings from our ketamine experiment are consistent across modalities and directly related to observations in schizophrenia supporting the validity of the model. Our investigation provides the first prototypic example of a pharmacoimaging study using simultaneously acquired fMRI/EEG.

Laser-evoked potential P2 single-trial amplitudes covary with the fMRI BOLD response in the medial pain system and interconnected subcortical structures

Pain is a complex experience with sensory, emotional and cognitive aspects. The cortical representation of pain - the pain matrix - consists of a network of regions including the primary (S1) and secondary (S2) sensory cortex, insula, and anterior cingulate cortex (ACC). These structures interact with brain regions such as the prefrontal cortex and the amygdalae. Simultaneous EEG/fMRI (electroencephalography/functional magnetic resonance imaging) has recently been introduced as a method to study the spatiotemporal characteristics of cognitive processes with high spatial and high temporal resolution at the same time. The present study was conducted to clarify if single trial EEG-informed BOLD modeling supports the definition of functional compartments within the pain matrix and interconnected regions. Twenty healthy subjects received painful laser stimulation while EEG and the fMRI blood oxygen level dependent (BOLD) signal were recorded simultaneously. While the laser-evoked N2 potential provided no additional information for BOLD modeling, the regressor obtained from the single trial laser-evoked P2 potential explained additional variance in a network of cortical and subcortical structures that largely overlapped with the pain matrix. This modeling strategy yielded pronounced activation in the ACC, right amygdala and thalamus. Our results suggest that laser-evoked potential (LEP) informed fMRI can be used to visualize BOLD activation in the pain matrix with an emphasis on functional compartments (as defined by the temporal dynamics of the LEP) such as the medial pain system. Furthermore, our findings suggest a concerted effort of the ACC and the amygdala in the cognitive-emotional evaluation of pain.

Fluctuations in electrodermal activity reveal variations in single trial brain responses to painful laser stimuli--a fMRI/EEG study.

Pain is a complex experience with sensory, emotional and cognitive aspects. It also includes a sympathetic response that can be captured by measuring the electrodermal activity (EDA). The present study was performed to investigate which brain areas are associated with sympathetic activation in experimental pain; an issue that has not been addressed with fMRI (functional magnetic resonance imaging) thus far. Twelve healthy subjects received painful laser stimulation to the left hand. The event-related fMRI BOLD (blood oxygen level dependent) response was measured together with simultaneous EEG (electroencephalography) and EDA recordings. Laser stimuli induced the expected EDA response, evoked EEG potentials and BOLD responses. Single trial EDA amplitudes were used to guide further analysis of fMRI and EEG data. We found significantly higher BOLD responses in trials with high EDA vs. low EDA trials, predominantly in the insula and somatosensory cortex (S1/S2). Likewise, in the EEG we found the N2 laser evoked potentials to have significantly higher amplitudes in trials with high vs. low EDA. Furthermore EDA-informed BOLD modeling explained additional signal variance in sensory areas and yielded higher group level activation. We conclude that the sympathetic response to pain is associated with activation in pain-processing brain regions, predominantly in sensory areas and that single trial (EDA)-information can add to BOLD modeling by taking some of the response variability across trials and subjects into account. Thus, EDA is a useful additional, objective index when pain is studied with fMRI/EEG which might be of particular relevance in the context of genetic- and pharmacoimaging.

The precuneus and the insula in self-attributional processes

Attributions are constantly assigned in everyday life. A well-known phenomenon is the self-serving bias: that is, people’s tendency to attribute positive events to internal causes (themselves) and negative events to external causes (other persons/circumstances). Here, we investigated the neural correlates of the cognitive processes implicated in self-serving attributions using social situations that differed in their emotional saliences. We administered an attributional bias task during fMRI scanning in a large sample of healthy subjects (n = 71). Eighty sentences describing positive or negative social situations were presented, and subjects decided via buttonpress whether the situation had been caused by themselves or by the other person involved. Comparing positive with negative sentences revealed activations of the bilateral posterior cingulate cortex (PCC). Self-attribution correlated with activation of the posterior portion of the precuneus. However, self-attributed positive versus negative sentences showed activation of the anterior portion of the precuneus, and self-attributed negative versus positive sentences demonstrated activation of the bilateral insular cortex. All significant activations were reported with a statistical threshold of p ≤ .001, uncorrected. In addition, a comparison of our fMRI task with data from the Internal, Personal and Situational Attributions Questionnaire, Revised German Version, demonstrated convergent validity. Our findings suggest that the precuneus and the PCC are involved in the evaluation of social events with particular regional specificities: The PCC is activated during emotional evaluation, the posterior precuneus during attributional evaluation, and the anterior precuneus during self-serving processes. Furthermore, we assume that insula activation is a correlate of awareness of personal agency in negative situations.

Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating

Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition—an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerström Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 (P < 0.0002–0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ≥4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.

Single-trial P3 amplitude and latency informed event-related fMRI models yield different BOLD response patterns to a target detection task.

Using single-trial parameters as a regressor in the General Linear Model (GLM) is becoming an increasingly popular method for informing fMRI analysis. However, the parameter used to characterise or to differentiate brain regions involved in the response to a particular task varies across studies (e.g. ERP amplitude, ERP latency, reaction time). Furthermore, the way in which the single-trial information is used in the fMRI analysis is also important. For example, the single-trial parameters can be used as regressors in the GLM or to modify the duration of the events modelled in the GLM. The aim of this study was to investigate the BOLD response to a target detection task when including P3 amplitude, P3 latency and reaction time parameters in the GLM. Simultaneous EEG-fMRI was recorded from fifteen subjects in response to a visual choice reaction time task. Including P3 amplitude as a regressor in the GLM yielded activation in left central opercular cortex, left postcentral gyrus, left insula, left middle frontal gyrus, left insula and left parietal operculum. Using P3 latency and reaction time as an additional regressor yielded no additional activation in comparison with the conventional fMRI analysis. However, when P3 latency or reaction time was used to determine the duration of events at a single-trial level, additional activation was observed in the left postcentral gyrus, left precentral gyrus, anterior cingulate cortex and supramarginal gyrus. Our findings suggest that ERP amplitudes and latencies can yield different activation patterns when used to modify relevant aspects of the GLM.

Correlation of Brain White Matter Diffusion Anisotropy and Mean Diffusivity with Reaction Time in an Oddball Task

Background: Reaction time (RT) is a frequently used measure of information processing speed, but the underlying physiological and anatomical conditions are not yet fully understood. A correlation between measures of white matter (WM) ultrastructural properties and RT is expected – particularly for those WM tracts that are involved in the attentional system of the brain. Methods: Diffusion tensor imaging data were acquired in 43 unrelated healthy subjects (age: 22.7 ± 1.8 years), and RT was measured during an attention-requiring visual oddball task in the same scanning session. Voxel-by-voxel and region of interest analyses were performed for the large association tracts. A linear regression model was used to correlate fractional anisotropy (FA) and mean diffusivity (MD) values with mean RT. Results: Our analyses revealed significant positive correlations between RT and MD in several WM association tracts, predominantly in the right hemisphere. To a lesser extent, significant negative correlations were found between RT and FA in right temporal WM. Conclusion: These findings suggest that subcortical ultrastructural properties of the dorsal and ventral visual stream are relevant with regard to information processing speed. Furthermore, MD appears to be more sensitive than FA in detecting functionally relevant ultrastructural variations in WM tracts.