Filomeno Cortese

Reduced Intrinsic Connectivity of Amygdala in Adults with Major Depressive Disorder

Imaging studies of major depressive disorder (MDD) have demonstrated enhanced resting-state activity of the amygdala as well as exaggerated reactivity to negative emotional stimuli relative to healthy controls (HCs). However, the abnormalities in the intrinsic connectivity of the amygdala in MDD still remain unclear. As the resting-state activity and functional connectivity (RSFC) reflect fundamental brain processes, we compared the RSFC of the amygdala between unmedicated MDD patients and HCs. Seventy-four subjects, 55 adults meeting the DSM-IV criteria for MDD and 19 HCs, underwent a resting-state 3-T functional magnetic resonance imaging scan. An amygdala seed-based low frequency RSFC map for the whole brain was generated for each group. Compared with HCs, MDD patients showed a wide-spread reduction in the intrinsic connectivity of the amygdala with a variety of brain regions involved in emotional processing and regulation, including the ventrolateral prefrontal cortex, insula, caudate, middle and superior temporal regions, occipital cortex, and cerebellum, as well as increased connectivity with the bilateral temporal poles (p < 0.05 corrected). The increase in the intrinsic connectivity of amygdala with the temporal poles was inversely correlated with symptom severity and anxiety scores. Although the directionality of connections between regions cannot be inferred from temporal correlations, the reduced intrinsic connectivity of the amygdala predominantly with regions involved in emotional processing may reflect impaired bottom-up signaling for top-down cortical modulation of limbic regions leading to abnormal affect regulation in MDD.

Vigabatrin retinal toxicity in children with infantile spasms: An observational cohort study

Objectives: To determine time to vigabatrin (VGB, Sabril; Lundbeck, Deerfield, IL) induced retinal damage in children with infantile spasms (IS) and to identify risk factors for VGB-induced retinal damage (VGB-RD). Methods: Observational cohort study including 146 participants (68 female, 81 male) with IS, an age-specific epilepsy syndrome of early infancy, treated with VGB. Participants ranged from 3 to 34.9 months of age (median 7.6 months). The median duration of VGB treatment was 16 months (range 4.6–78.5 months). Electroretinograms (ERGs) were performed according to the Standards of the International Society for Clinical Electrophysiology of Vision. Inclusion required baseline (pre-VGB or within 4 weeks of starting VGB treatment) and at least 2 follow-up ERGs. Significant reduction from baseline of the 30-Hz ERG flicker amplitude on 2 consecutive visits identified VGB-RD. Kaplan-Meier survival analyses depicted the effect of duration of VGB on VGB-RD. Results: These data represent the largest survival analysis of children treated with VGB who did not succumb to retinal toxicity during the study. Thirty of the 146 participants (21%) showed VGB-RD. The ERG amplitude reduced with duration of VGB treatment (p = 0.0004) with no recovery after VGB cessation. With 6 and 12 months of VGB treatment, 5.3% and 13.3%, respectively, developed VGB-RD. There was neither effect of age of initiation of VGB treatment nor sex of the child on survival statistics and no significant effect of cumulative dosage on the occurrence of VGB-RD. Conclusions: Minimizing VGB treatment to 6 months will reduce the prevalence of VGB-RD in patients with IS.

The cholinergic forebrain arousal system acts directly on the circadian pacemaker

Significance Sleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state can influence the phase of the circadian clock. Here we demonstrate that the level of wakefulness is critical for arousal to reset circadian clock phase. We then show that treatments that produce arousal and reset the circadian clock activate the basal forebrain. Finally, we demonstrate that cholinergic input from the basal forebrain is both necessary and sufficient for eliciting this arousal-induced resetting of the circadian clock. These results establish a functional link between the major forebrain arousal center and the circadian system. Sleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state, such as sleep deprivation (SD) or arousal, can phase shift the circadian clock. Here we demonstrate that the level of wakefulness is critical for this arousal resetting of the circadian clock. Specifically, drowsy animals with significant power in the 7- to 9-Hz band of their EEGs do not exhibit phase shifts in response to a mild SD procedure. We then show that treatments that both produce arousal and reset the phase of circadian clock activate (i.e., induce Fos expression in) the basal forebrain. Many of the activated cells are cholinergic. Using retrograde tract tracing, we demonstrate that cholinergic cells activated by these arousal procedures project to the circadian clock in the suprachiasmatic nuclei (SCN). We then demonstrate that arousal-induced phase shifts are blocked when animals are pretreated with atropine injections to the SCN, demonstrating that cholinergic activity at the SCN is necessary for arousal-induced phase shifting. Finally, we demonstrate that electrical stimulation of the substantia innominata of the basal forebrain phase shifts the circadian clock in a manner similar to that of our arousal procedures and that these shifts are also blocked by infusions of atropine to the SCN. These results establish a functional link between the major forebrain arousal center and the circadian system.

Changes in cortical activity measured with EEG during a high intensity cycling exercise.

This study investigated the effects of a high-intensity cycling exercise on changes in spectral and temporal aspects of electroencephalography (EEG) measured from 10 experienced cyclists. Cyclists performed a maximum aerobic power test on the first testing day followed by a time-to-exhaustion trial at 85% of their maximum power output on 2 subsequent days that were separated by ∼48 h. EEG was recorded using a 64-channel system at 500 Hz. Independent component (IC) analysis parsed the EEG scalp data into maximal ICs. An equivalent current dipole model was calculated for each IC, and results were clustered across subjects. A time-frequency analysis of the identified electrocortical clusters was performed to investigate the magnitude and timing of event-related spectral perturbations. Significant changes (P < 0.05) in electrocortical activity were found in frontal, supplementary motor and parietal areas of the cortex. Overall, there was a significant increase in EEG power as fatigue developed throughout the exercise. The strongest increase was found in the frontal area of the cortex. The timing of event-related desynchronization within the supplementary motor area corresponds with the onset of force production and the transition from flexion to extension in the pedaling cycle. The results indicate an involvement of the cerebral cortex during the pedaling task that most likely involves executive control function, as well as motor planning and execution.

Influence of age of onset on limbic and paralimbic structures in depression

Major depressive disorder (MDD) onset during childhood/adolescence is associated with a greater illness burden and distinct clinical profile. However, limited research exists on the effect of age of MDD onset on volumetric abnormalities in para/limbic structures during adulthood.

A Preliminary Study of the Influence of Age of Onset and Childhood Trauma on Cortical Thickness in Major Depressive Disorder

Background. Major depressive disorder (MDD) neural underpinnings may differ based on onset age and childhood trauma. We assessed cortical thickness in patients who differed in age of MDD onset and examined trauma history influence. Methods. Adults with MDD (N = 36) and controls (HC; N = 18) underwent magnetic resonance imaging. Twenty patients had MDD onset <24 years of age (pediatric onset) and 16 had onset >25 years of age (adult onset). The MDD group was also subdivided into those with (N = 12) and without (N = 19) physical and/or sexual abuse as assessed by the Childhood Trauma Questionnaire (CTQ). Cortical thickness was analyzed with FreeSurfer software. Results. Thicker frontal pole and a tendency for thinner transverse temporal cortices existed in MDD. The former was driven by the pediatric onset group and abuse history (independently), particularly in the right frontal pole. Inverse correlations existed between CTQ scores and frontal pole cortex thickness. A similar inverse relation existed with left inferior and right superior parietal cortex thickness. The superior temporal cortex tended to be thinner in pediatric versus adult onset groups with childhood abuse. Conclusions. This preliminary work suggests neural differences between pediatric and adult MDD onset. Trauma history also contributes to cytoarchitectural modulation. Thickened frontal pole cortices as a compensatory mechanism in MDD warrant evaluation.

The temporal interaction of modality specific and process specific neural networks supporting simple working memory tasks

Several theories of brain function emphasize distinctions between sensory and cognitive systems. We hypothesized, instead, that sensory and cognitive systems interact to instantiate the task at the neural level. We tested whether input modality interacts with working memory operations in that, despite similar cognitive demands, differences in the anatomical locations or temporal dynamics of activations following auditory or visual input would not be limited to the sensory cortices. We recorded event-related brain potentials (ERPs) while participants performed simple short-term memory tasks involving visually or auditorily presented bandpass-filtered noise stimuli. Our analyses suggested that working memory operations in each modality had a very similar spatial distribution of current sources outside the sensory cortices, but differed in terms of time course. Specifically, information for visual processing was updated and held online in a manner that was different from auditory processing, which was done mostly after the offset of the final stimulus. Our results suggest that the neural networks that support working memory operations have different temporal dynamics for auditory and visual material, even when the stimuli are matched in term of discriminability, and are designed to undergo very similar transformations when they are encoded and retrieved from memory.

Analysis of multifocal electroretinograms from a population with type 1 diabetes using partial least squares reveals spatial and temporal distribution of changes to retinal function

Spatial–temporal partial least squares (ST-PLS) is a multivariate statistical analysis that has improved the analysis of modern imaging techniques. Multifocal electroretinograms (mfERGs) contain a large amount of data, and averaging and grouping have been used to reduce the amount of data to levels that can be handled using traditional statistical methods. In contrast, using all acquired data points, ST-PLS enables statistically rigorous testing of changes in waveform shape and in the distributed signal related to retinal function. We hypothesise that ST-PLS will improve analysis of the mfERG. Two mfERG protocols, a 103 hexagon clinical protocol and a slow-flash mfERG (sf-mfERG) protocol, were recorded from an adolescent population with type 1 diabetes and an age similar control population. The standard mfERGs were analysed using a template-fitting algorithm and the sf-mfERG using a signal-to-noise measure. The results of these traditional analysis techniques are compared with those of the ST-PLS analysis. Traditional analysis of the mfERG recordings revealed changes between groups for implicit time but not amplitude; however, the spatial location of these changes could not be identified. In contrast, ST-PLS detected significant changes between groups and displayed the spatial location of these changes on the retinal map and the temporal location within the mfERG waveforms. ST-PLS confirmed that changes to diabetic retinal function occur before the onset of clinical pathology. In addition, it revealed two distinct patterns of change depending on whether the multifocal paradigm was optimised to target outer retinal function (photoreceptors) or middle/inner retinal function (collector cells).

Amygdala responses to quetiapine XR and citalopram treatment in major depression: The role of 5-HTTLPR-S/Lg polymorphisms

Genotype and drug pharmacology may contribute to variations in brain response to antidepressants. We examined the impact of two antidepressants with differential actions on serotonin transporter and the 5‐HHTLPR‐S/Lg polymorphisms on amygdala responses in major depressive disorder (MDD).

The modulation of EEG variability between internally- and externally-driven cognitive states varies with maturation and task performance

Increasing evidence suggests that brain signal variability is an important measure of brain function reflecting information processing capacity and functional integrity. In this study, we examined how maturation from childhood to adulthood affects the magnitude and spatial extent of state-to-state transitions in brain signal variability, and how this relates to cognitive performance. We looked at variability changes between resting-state and task (a symbol-matching task with three levels of difficulty), and within trial (fixation, post-stimulus, and post-response). We calculated variability with multiscale entropy (MSE), and additionally examined spectral power density (SPD) from electroencephalography (EEG) in children aged 8–14, and in adults aged 18–33. Our results suggest that maturation is characterized by increased local information processing (higher MSE at fine temporal scales) and decreased long-range interactions with other neural populations (lower MSE at coarse temporal scales). Children show MSE changes that are similar in magnitude, but greater in spatial extent when transitioning between internally- and externally-driven brain states. Additionally, we found that in children, greater changes in task difficulty were associated with greater magnitude of modulation in MSE. Our results suggest that the interplay between maturational and state-to-state changes in brain signal variability manifest across different spatial and temporal scales, and influence information processing capacity in the brain.