Francesco Di Salle

Metabolic and Hemodynamic Events after Changes in Neuronal Activity: Current Hypotheses, Theoretical Predictions and in vivo NMR Experimental Findings

Unraveling the energy metabolism and the hemodynamic outcomes of excitatory and inhibitory neuronal activity is critical not only for our basic understanding of overall brain function, but also for the understanding of many brain disorders. Methodologies of magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) are powerful tools for the noninvasive investigation of brain metabolism and physiology. However, the temporal and spatial resolution of in vivo MRS and MRI is not suitable to provide direct evidence for hypotheses that involve metabolic compartmentalization between different cell types, or to untangle the complex neuronal microcircuitry, which results in changes of electrical activity. This review aims at describing how the current models of brain metabolism, mainly built on the basis of in vitro evidence, relate to experimental findings recently obtained in vivo by 1H MRS, 13C MRS, and MRI. The hypotheses related to the role of different metabolic substrates, the metabolic neuron—glia interactions, along with the available theoretical predictions of the energy budget of neurotransmission will be discussed. In addition, the cellular and network mechanisms that characterize different types of increased and suppressed neuronal activity will be considered within the sensitivity-constraints of MRS and MRI.

Amygdala deactivation as a neural correlate of pain processing in patients with borderline personality disorder and co-occurrent posttraumatic stress disorder

BACKGROUND Previous studies have revealed altered affective pain processing in patients with borderline personality disorder (BPD) as well as in patients with posttraumatic stress disorder (PTSD). Reduced levels of activation in the amygdala might be related to antinociceptive mechanisms pertinent to both disorders. This study aimed at clarifying whether central antinoceptive mechanisms discriminate BPD patients with and without co-occurrent PTSD. METHODS We investigated 29 medication-free female outpatients with BPD, 12 with and 17 without co-occurrent PTSD. Psychophysical characteristics were assessed, and functional magnetic resonance imaging was performed during heat stimulation with stimuli adjusted for equal subjective painfulness. RESULTS No difference in pain sensitivity was found between both groups of patients. Amygdala deactivation, however, was more pronounced in BPD patients with co-occurrent PTSD compared with those without PTSD. Amygdala deactivation was independent of BPD symptom severity and dissociation. CONCLUSIONS Amygdala deactivation seems to differentiate patients who meet criteria for both BPD and PTSD from BPD patients without co-occurrent PTSD. On the basis of these preliminary findings it might be speculated that reduced pain sensitivity or at least the emotional component of it is associated with amygdala deactivation in patients with both disorders, whereas BPD patients without PTSD use different yet unknown antinociceptive mechanisms.

Functional magnetic resonance imaging in episodic cluster headache

We have investigated the cerebral activation centre in four patients with episodic cluster headache (CH) with functional magnetic resonance imaging (f-MRI). The patients underwent MRI scans for anatomical and functional data acquisition in the asymptomatic state, during a headache attack and after subcutaneous administration of sumatriptan. Anatomical images were acquired by means of 3D-MPRAGE sequences and f-MRI images were obtained by means of echo-planar imaging. Data was analysed using the BrainVoyager QX version 1.7.81 software package. In all patients, the data showed significant hypothalamic activation of the hypothalamus ipsilateral to the pain side, attributable to a headache attack. Overall, we have demonstrated the anatomical location of central nervous system activation by means the first f-MRI study in CH patients. f-MRI offers a good balance of spatial and temporal resolution, and this method of study appears appropriate for investigating the pathogenetic aspects of primary headaches. Positron emission tomography and f-MRI may be regarded as little or no importance in a clinical context, they do, however, offer great potential for the exploration of headache physiopathology and the effects of pharmacological treatment.

The default mode network and the working memory network are not anti-correlated during all phases of a working memory task

Introduction The default mode network and the working memory network are known to be anti-correlated during sustained cognitive processing, in a load-dependent manner. We hypothesized that functional connectivity among nodes of the two networks could be dynamically modulated by task phases across time. Methods To address the dynamic links between default mode network and the working memory network, we used a delayed visuo-spatial working memory paradigm, which allowed us to separate three different phases of working memory (encoding, maintenance, and retrieval), and analyzed the functional connectivity during each phase within and between the default mode network and the working memory network networks. Results We found that the two networks are anti-correlated only during the maintenance phase of working memory, i.e. when attention is focused on a memorized stimulus in the absence of external input. Conversely, during the encoding and retrieval phases, when the external stimulation is present, the default mode network is positively coupled with the working memory network, suggesting the existence of a dynamically switching of functional connectivity between “task-positive” and “task-negative” brain networks. Conclusions Our results demonstrate that the well-established dichotomy of the human brain (anti-correlated networks during rest and balanced activation-deactivation during cognition) has a more nuanced organization than previously thought and engages in different patterns of correlation and anti-correlation during specific sub-phases of a cognitive task. This nuanced organization reinforces the hypothesis of a direct involvement of the default mode network in cognitive functions, as represented by a dynamic rather than static interaction with specific task-positive networks, such as the working memory network.

Pain Processing in Medication Overuse Headache: A Functional Magnetic Resonance Imaging (fMRI) Study

OBJECTIVE The primary aim was to investigate functional differences between medication overuse headache (MOH) patients and controls with the purpose of evaluating the presence of a global alteration in the processing of noxious stimuli throughout the pain matrix. The secondary aim was to investigate whether activations in MOH patients normalize after medication withdrawal, which would suggest a possible role of the pain matrix in headache chronification. DESIGN Functional magnetic resonance imaging was performed during painful mechanical stimulation in nine female patients with MOH immediately and at 6 months after beginning medication withdrawal, and in nine control participants. RESULTS Compared with controls, immediately after beginning withdrawal, the MOH patients showed reduced pain-related activity across the primary somatosensory cortex, inferior parietal lobule, and supramarginal gyrus, as well as in regions of the lateral pathway of the pain matrix. At 6 months, these differences were no longer detectable. CONCLUSION Our findings suggest that significant functional changes occur in the lateral pain pathway in MOH patients. These could result from different processes: 1) cortical down-regulation aimed at reducing painful input to the cortex; 2) activity-dependent plasticity induced by excessive painful input during migraine attacks; and 3) direct effect of medication overuse. At 6 months after withdrawal, activity in these regions normalized, suggesting that no irreversible changes occur due to medication overuse.

The brain functional networks associated to human and animal suffering differ among omnivores, vegetarians and vegans.

Empathy and affective appraisals for conspecifics are among the hallmarks of social interaction. Using functional MRI, we hypothesized that vegetarians and vegans, who made their feeding choice for ethical reasons, might show brain responses to conditions of suffering involving humans or animals different from omnivores. We recruited 20 omnivore subjects, 19 vegetarians, and 21 vegans. The groups were matched for sex and age. Brain activation was investigated using fMRI and an event-related design during observation of negative affective pictures of human beings and animals (showing mutilations, murdered people, human/animal threat, tortures, wounds, etc.). Participants saw negative-valence scenes related to humans and animals, alternating with natural landscapes. During human negative valence scenes, compared with omnivores, vegetarians and vegans had an increased recruitment of the anterior cingulate cortex (ACC) and inferior frontal gyrus (IFG). More critically, during animal negative valence scenes, they had decreased amygdala activation and increased activation of the lingual gyri, the left cuneus, the posterior cingulate cortex and several areas mainly located in the frontal lobes, including the ACC, the IFG and the middle frontal gyrus. Nonetheless, also substantial differences between vegetarians and vegans have been found responding to negative scenes. Vegetarians showed a selective recruitment of the right inferior parietal lobule during human negative scenes, and a prevailing activation of the ACC during animal negative scenes. Conversely, during animal negative scenes an increased activation of the inferior prefrontal cortex was observed in vegans. These results suggest that empathy toward non conspecifics has different neural representation among individuals with different feeding habits, perhaps reflecting different motivational factors and beliefs.

Spatio-temporal pattern of vestibular information processing after brief caloric stimulation

Processing of vestibular information at the cortical and subcortical level is essential for head and body orientation in space and self-motion perception, but little is known about the neural dynamics of the brain regions of the vestibular system involved in this task. Neuroimaging studies using both galvanic and caloric stimulation have shown that several distinct cortical and subcortical structures can be activated during vestibular information processing. The insular cortex has been often targeted and presented as the central hub of the vestibular cortical system. Since very short pulses of cold water ear irrigation can generate a strong and prolonged vestibular response and a nystagmus, we explored the effects of this type of caloric stimulation for assessing the blood-oxygen-level-dependent (BOLD) dynamics of neural vestibular processing in a whole-brain event-related functional magnetic resonance imaging (fMRI) experiment. We evaluated the spatial layout and the temporal dynamics of the activated cortical and subcortical regions in time-locking with the instant of injection and were able to extract a robust pattern of neural activity involving the contra-lateral insular cortex, the thalamus, the brainstem and the cerebellum. No significant correlation with the temporal envelope of the nystagmus was found. The temporal analysis of the activation profiles highlighted a significantly longer duration of the evoked BOLD activity in the brainstem compared to the insular cortex suggesting a functional de-coupling between cortical and subcortical activity during the vestibular response.

Distributed analysis of simultaneous EEG-fMRI time-series: modeling and interpretation issues

Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) represent brain activity in terms of a reliable anatomical localization and a detailed temporal evolution of neural signals. Simultaneous EEG-fMRI recordings offer the possibility to greatly enrich the significance and the interpretation of the single modality results because the same neural processes are observed from the same brain at the same time. Nonetheless, the different physical nature of the measured signals by the two techniques renders the coupling not always straightforward, especially in cognitive experiments where spatially localized and distributed effects coexist and evolve temporally at different temporal scales. The purpose of this article is to illustrate the combination of simultaneously recorded EEG and fMRI signals exploiting the principles of EEG distributed source modeling. We define a common source space for fMRI and EEG signal projection and gather a conceptually unique framework for the spatial and temporal comparative analysis. We illustrate this framework in a graded-load working-memory simultaneous EEG-fMRI experiment based on the n-back task where sustained load-dependent changes in the blood-oxygenation-level-dependent (BOLD) signals during continuous item memorization co-occur with parametric changes in the EEG theta power induced at each single item. In line with previous studies, we demonstrate on two single-subject cases how the presented approach is capable of colocalizing in midline frontal regions two phenomena simultaneously observed at different temporal scales, such as the sustained negative changes in BOLD activity and the parametric EEG theta synchronization. We discuss the presented approach in relation to modeling and interpretation issues typically arising in simultaneous EEG-fMRI studies.

Catechol-O-methyltransferase genotype modifies executive functioning and prefrontal functional connectivity in women with anorexia nervosa

BACKGROUND Anorexia nervosa is characterized by high levels of perseveration and inflexibility, which interfere with successful treatments. Dopamine (DA) signalling seems to play a key role in modulating the prefrontal cortex, since both DA deficiency and excess nega tively influence the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene on the set-shifting abilities and prefrontal functional connectivity of patients with anorexia nervosa. METHODS All participants performed the Wisconsin Card Sorting Task, and a subsample underwent resting-state functional magnetic resonance imaging. RESULTS We included 166 patients with DSM-IV lifetime anorexia nervosa and 140 healthy women in our study. Both underweight and weight-recovered patients with anorexia nervosa showed high levels of perseveration, but only in the underweight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased DA signalling in the prefrontal cortex. Underweight patients with anorexia nervosa who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity than underweight patients in the other genotype groups, indicating abnormal regional cortical processing. LIMITATIONS Although our data show that grey matter reduction in starving patients with anorexia nervosa did not explain our findings, the cross-sectional design of the present study did not allow us to distinguish between the effects of starvation and those of low estrogen levels. CONCLUSION Starvation affects DA release in the prefrontal cortex of patients with anorexia nervosa with different effects on executive functioning and prefrontal functional connectivity according to the COMT genotype. This observation has several therapeutic implications that need to be addressed by future studies.

Neural correlates of pre‐attentive processing of pattern deviance in professional musicians

Pre‐attentive registration of aberrations in predictable sound patterns is attributed to the temporal cortex. However, electrophysiology suggests that frontal areas become more important when deviance complexity increases. To play an instrument in an ensemble, professional musicians have to rely on the ability to detect even slight deviances from expected musical patterns and therefore have highly trained aural skills. Here, we aimed to identify the neural correlates of experience‐driven plasticity related to the processing of complex sound features. We used functional magnetic resonance imaging in combination with an event‐related oddball paradigm and compared brain activity in professional musicians and non‐musicians during pre‐attentive processing of melodic contour variations. The melodic pattern consisted of a sequence of five tones each lasting 50 ms interrupted by silent interstimulus intervals of 50 ms. Compared to non‐musicians, the professional musicians showed enhanced activity in the left middle and superior temporal gyri, the left inferior frontal gyrus and in the right ventromedial prefrontal cortex in response to pattern deviation. This differential brain activity pattern was correlated with behaviorally tested musical aptitude. Our results thus support an experience‐related role of the left temporal cortex in fast melodic contour processing and suggest involvement of the prefrontal cortex. Hum Brain Mapp, 2009.