Rosa Hernández-Ribas

Consistency and functional specialization in the default mode brain network.

The notion of a “default mode of brain function” has taken on certain relevance in human neuroimaging studies and in relation to a network of lateral parietal and midline cortical regions that show prominent activity fluctuations during passive imaging states, such as rest. In this study, we perform three fMRI experiments that demonstrate consistency and specialization in the default mode network. Correlated activity fluctuations of default mode network regions are identified during (i) eyes-closed spontaneous rest, (ii) activation by moral dilemma, and (iii) deactivation by Stroop task performance. Across these imaging states, striking uniformity is shown in the basic anatomy of the default mode network, but with both tasks clearly and differentially modulating this activity compared with spontaneous fluctuations of the network at rest. Against rest, moral dilemma is further shown to evoke regionally specific activity increases of hypothesized functional relevance. Mapping spontaneous and task-related brain activity will help to constrain the meaning of the default mode network. These findings are discussed in relation to recent debate on the topic of default modes of brain function.

Cross-Sectional and Longitudinal Assessment of Structural Brain Alterations in Melancholic Depression

BACKGROUND Whole-brain imaging approaches may contribute to the characterization of neuroanatomic alterations in major depression, especially in clinically homogenous patient groups such as those with melancholic features. We assessed brain anatomic alterations, both cross-sectionally and longitudinally, in patients with melancholic depression using a whole-brain voxel-wise approach. METHODS Whole-brain magnetic resonance images were collected from a relatively aged sample of 70 consecutively recruited major depressive disorder inpatients with melancholic features and from a group of 40 healthy control subjects. All patients were clinically followed for at least 2 years, and a subset of 30 depressive patients and 20 control subjects were rescanned after a 7-year period. Imaging data were analyzed with voxel- and tensor-based morphometry techniques. RESULTS Melancholic patients showed gray matter reductions in the left insula and white matter increases in the upper brainstem tegmentum. Male patients showed gray matter decreases in the right thalamus, and periventricular white matter reductions were specifically observed in older patients. Volume decreases in the left insula, hippocampus, and lateral parietal cortex predicted a slower recovery after treatment initiation. In longitudinal assessment, white matter of the upper brainstem tegmentum showed a different temporal evolution between groups. Additionally, bilateral gray matter reductions in the insulae were associated with the number of relapses during follow-up. CONCLUSIONS Structural alterations were identified in regions potentially related to relevant aspects of melancholia pathophysiology. Longitudinal analyses indicated region-specific interactions of baseline alterations with age as well as a significant association of clinical severity with focal changes occurring over time.

Task-Induced Deactivation from Rest Extends beyond the Default Mode Brain Network

Activity decreases, or deactivations, of midline and parietal cortical brain regions are routinely observed in human functional neuroimaging studies that compare periods of task-based cognitive performance with passive states, such as rest. It is now widely held that such task-induced deactivations index a highly organized ‘default-mode network’ (DMN): a large-scale brain system whose discovery has had broad implications in the study of human brain function and behavior. In this work, we show that common task-induced deactivations from rest also occur outside of the DMN as a function of increased task demand. Fifty healthy adult subjects performed two distinct functional magnetic resonance imaging tasks that were designed to reliably map deactivations from a resting baseline. As primary findings, increases in task demand consistently modulated the regional anatomy of DMN deactivation. At high levels of task demand, robust deactivation was observed in non-DMN regions, most notably, the posterior insular cortex. Deactivation of this region was directly implicated in a performance-based analysis of experienced task difficulty. Together, these findings suggest that task-induced deactivations from rest are not limited to the DMN and extend to brain regions typically associated with integrative sensory and interoceptive processes.

Functional Connectivity Bias in the Prefrontal Cortex of Psychopaths.

BACKGROUND Psychopathy is characterized by a distinctive interpersonal style that combines callous-unemotional traits with inflexible and antisocial behavior. Traditional emotion-based perspectives link emotional impairment mostly to alterations in amygdala-ventromedial frontal circuits. However, these models alone cannot explain why individuals with psychopathy can regularly benefit from emotional information when placed on their focus of attention and why they are more resistant to interference from nonaffective contextual cues. The present study aimed to identify abnormal or distinctive functional links between and within emotional and cognitive brain systems in the psychopathic brain to characterize further the neural bases of psychopathy. METHODS High-resolution anatomic magnetic resonance imaging with a functional sequence acquired in the resting state was used to assess 22 subjects with psychopathy and 22 control subjects. Anatomic and functional connectivity alterations were investigated first using a whole-brain analysis. Brain regions showing overlapping anatomic and functional changes were examined further using seed-based functional connectivity mapping. RESULTS Subjects with psychopathy showed gray matter reduction involving prefrontal cortex, paralimbic, and limbic structures. Anatomic changes overlapped with areas showing increased degree of functional connectivity at the medial-dorsal frontal cortex. Subsequent functional seed-based connectivity mapping revealed a pattern of reduced functional connectivity of prefrontal areas with limbic-paralimbic structures and enhanced connectivity within the dorsal frontal lobe in subjects with psychopathy. CONCLUSIONS Our results suggest that a weakened link between emotional and cognitive domains in the psychopathic brain may combine with enhanced functional connections within frontal executive areas. The identified functional alterations are discussed in the context of potential contributors to the inflexible behavior displayed by individuals with psychopathy.

Effects of Duloxetine Treatment on Brain Response to Painful Stimulation in Major Depressive Disorder

Major depressive disorder (MDD) is characterized by a constellation of affective, cognitive, and somatic symptoms associated with functional abnormalities in relevant brain systems. Painful stimuli are primarily stressful and can trigger consistent responses in brain regions highly overlapping with the regions altered in MDD patients. Duloxetine has proven to be effective in treating both core emotional symptoms and somatic complaints in depression. This study aimed to assess the effects of duloxetine treatment on brain response to painful stimulation in MDD patients. A total of 13 patients and a reference group of 20 healthy subjects were assessed on three occasions (baseline, treatment week 1, and week 8) with functional magnetic resonance imaging (fMRI) during local application of painful heat stimulation. Treatment with duloxetine was associated with a significant reduction in brain responses to painful stimulation in MDD patients in regions generally showing abnormally enhanced activation at baseline. Clinical improvement was associated with pain-related activation reductions in the pregenual anterior cingulate cortex, right prefrontal cortex, and pons. Pontine changes were specifically related to clinical remission. Increased baseline activations in the right prefrontal cortex and reduced deactivations in the subgenual anterior cingulate cortex predicted treatment responders at week 8. This is the first fMRI study addressed to assess the effect of duloxetine in MDD. As a novel approach, the application of painful stimulation as a basic neural stressor proved to be effective in mapping brain response changes associated with antidepressant treatment and brain correlates of symptom improvement in regions of special relevance to MDD pathophysiology.

Brain structural correlates of depressive comorbidity in obsessive-compulsive disorder

The high comorbidity of obsessive-compulsive disorder (OCD) with major depressive disorder (MDD) suggests common neurobiological substrates. We assessed the contribution of lifetime MDD to brain structural alterations in OCD using magnetic resonance imaging. OCD patients with (n=33) or without (n=39) lifetime MDD, and 72 control subjects were assessed. Comparative region of interest (ROI) analyses assessed the contribution of lifetime MDD to gray matter volume alterations in OCD patients. Interregional correlations of gray matter volume were also examined and voxelwise analyses were performed to identify alterations in other brain regions. OCD patients with lifetime MDD showed a larger reduction of medial orbitofrontal cortex (mOFC) gray matter volume. Both OCD groups showed distinct correlations of mOFC gray matter volume with other relevant brain regions. For patients with MDD, this involved the medial frontal gyrus, and right insula and amygdala regions, whereas for those OCD patients without MDD, the rostral anterior cingulate cortex was involved. Our findings support existing evidence suggesting a non-specific involvement of mOFC alterations in a range of neuropsychiatric disorders. Nevertheless, volume reduction in this region, together with an abnormal pattern of interregional correlations with other emotion-relevant brain areas, may contribute to explain the diathesis for MDD comorbidity in OCD.

Enhanced brain responsiveness during active emotional face processing in obsessive compulsive disorder.

Abstract Objectives. The abnormal processing of emotional stimuli is common to a variety of psychiatric disorders. Specifically, patients with prominent anxiety symptoms generally overreact to emotional cues, which has been linked to increased amygdala activation. However, in OCD, enhanced responses are predominantly obtained using disease-specific stimuli and preferentially involve frontostriatal systems. Methods. We assessed 21 OCD patients and 21 healthy controls with fMRI during an emotional face-processing paradigm involving active response generation to test for alterations in both brain activation and task-induced functional connectivity of the frontal cortex, the amygdala and the fusiform face area. Results. OCD patients showed significantly greater activation of “face-processing” regions including the amygdala, fusiform gyrus and dorsolateral prefrontal cortex. The reciprocal connectivity between face-processing regions was enhanced in OCD. Importantly, we detected significant correlations between patients’ clinical symptom severity and both task-related region activation and network functional connectivity. Conclusions. The results suggest that OCD patients may show enhanced brain responsiveness during emotional face-processing when tasks involve active response generation. Our findings diverge from previously described alterations in anxiety disorders, as patients showed enhanced amygdala-prefrontal connectivity as opposed to negative reciprocal interaction. This pattern would appear to be disorder-specific and was significantly related to obsessive-compulsive symptom severity.

Dynamic functional connectivity reveals altered variability in functional connectivity among patients with major depressive disorder

Resting‐state fMRI (RS‐fMRI) has become a useful tool to investigate the connectivity structure of mental health disorders. In the case of major depressive disorder (MDD), recent studies regarding the RS‐fMRI have found abnormal connectivity in several regions of the brain, particularly in the default mode network (DMN). Thus, the relevance of the DMN to self‐referential thoughts and ruminations has made the use of the resting‐state approach particularly important for MDD. The majority of such research has relied on the grand averaged functional connectivity measures based on the temporal correlations between the BOLD time series of various brain regions. We, in our study, investigated the variations in the functional connectivity over time at global and local level using RS‐fMRI BOLD time series of 27 MDD patients and 27 healthy control subjects. We found that global synchronization and temporal stability were significantly increased in the MDD patients. Furthermore, the participants with MDD showed significantly increased overall average (static) functional connectivity (sFC) but decreased variability of functional connectivity (vFC) within specific networks. Static FC increased to predominance among the regions pertaining to the default mode network (DMN), while the decreased variability of FC was observed in the connections between the DMN and the frontoparietal network. Hum Brain Mapp 37:2918–2930, 2016.

Identifying brain imaging correlates of clinical response to repetitive transcranial magnetic stimulation (rTMS) in major depression.

BACKGROUND Partial response and non-response to treatments are common problems in major depression. The identification of biological markers of clinical response may be of special interest for some adjunctive treatments, such as repetitive transcranial magnetic stimulation (rTMS), as it may ultimately improve their cost-effectiveness. OBJECTIVE To identify pre-treatment functional imaging correlates of clinical response to rTMS in major depression. METHODS We evaluated 21 depressed patients. They were randomized to receive 15 sessions of active or sham rTMS on the left dorsolateral prefrontal cortex. Functional magnetic resonance imaging (fMRI) was used to assess pre-treatment regional brain activity evoked by a word generation task. These regional activations were correlated (voxel-wise) with the Hamilton Rating Scale for Depression (HAM-D) reduction between baseline and end of treatment. A group of 13 healthy controls was also assessed using the same fMRI protocol to obtain reference imaging measurements. RESULTS At the end of treatment, the percentage of patients with a HAM-D reduction greater than 50% was larger in the active than in the sham rTMS group (70% vs. 27.3%). In the active rTMS group, larger HAM-D reductions were significantly correlated with smaller deactivations during pre-treatment fMRI assessment in the anterior cingulate, the left medial orbitofrontal and the right middle frontal cortices, in addition to larger activations in the left ventral-caudal putamen. CONCLUSIONS These results suggest that brain activity in regions arguably relevant for major depression may predict clinical response to rTMS. This approach may help in identifying the most suitable candidates to undergo rTMS treatment.

Dynamic assessment of the right lateral frontal cortex response to painful stimulation.

The lateral surface of the right frontal lobe has a relevant role in modulating behavioral responses to aversive stimuli and may significantly influence pain experience. Imaging studies suggest that this modulatory role is multifaceted, but no studies have assessed the regional specialization of this cortex on the basis of its response dynamics during pain processing. We aimed to investigate functional specialization within the right lateral frontal cortex using a dynamic fMRI approach. Brain responses to a mechanical painful stimulus and a preceding anticipatory cue (auditory tone) were assessed in 25 healthy subjects. Functional data were decomposed into 15 sequential activation maps covering the full anticipation-painful stimulation cycle using a finite impulse response (FIR) analysis approach. Movie sequences showing the temporal evolution of brain activation illustrate the findings. A region involving premotor-prefrontal cortices was activated soon after the anticipatory cue and showed a significant correlation with both anterior cingulate cortex activation and subjective pain ratings. The frontal operculum also showed a significant anticipatory response, but the most robust activation followed painful stimulation onset and was strongly correlated with insula activation. The anterior prefrontal cortex showed full activation during late painful stimulation and was negatively correlated with pain unpleasantness. In conclusion, different elements within the right lateral frontal cortex showed distinct activation dynamics in response to painful stimulation, which would suggest relevant regional specialization during pain processing. These findings are congruent with the broad functional role of the right frontal cortex and its influence on crucial aspects of human behavior.