Pierfilippo De Sanctis

Are Auditory-Evoked Frequency and Duration Mismatch Negativity Deficits Endophenotypic for Schizophrenia? High-Density Electrical Mapping in Clinically Unaffected First-Degree Relatives and First-Episode and Chronic Schizophrenia

BACKGROUND Mismatch negativity (MMN) is a negative-going event-related potential (ERP) component that occurs in response to intermittent changes in constant auditory backgrounds. A consistent finding across a large number of studies has been impaired MMN generation in schizophrenia, which has been interpreted as evidence for fundamental deficits in automatic auditory sensory processing. The aim of this study was to investigate the extent to which dysfunction in MMN generation might represent an endophenotypic marker for schizophrenia. METHODS We measured MMN to deviants in duration (25 msec, 1000 Hz) and deviants in pitch (50 msec, 1200 Hz) relative to standard tones (50 msec, 1000 Hz) in 45 chronic schizophrenia patients, 25 of their first-degree unaffected biological relatives, 12 first-episode patients, and 27 healthy control subjects. RESULTS In line with previous work, MMN amplitudes to duration deviants (but not to pitch deviants) were significantly reduced in patients with chronic schizophrenia compared with control subjects. However, both duration and pitch MMNs were completely unaffected in the first-degree biological relatives and this was also the case for the first-episode patients. Furthermore, length of illness did not predict the extent of MMN deficit. CONCLUSIONS These findings suggest that the MMN deficit seen in schizophrenia patients is most likely a consequence of the disease and that MMN, at least to basic auditory feature deviants, is at best only weakly endophenotypic for schizophrenia.

Early Visual Processing Deficits in Dysbindin-Associated Schizophrenia

BACKGROUND Variation at the dysbindin gene (DTNBP1) has been associated with increased risk for schizophrenia in numerous independent samples and recently with deficits in general and domain-specific cognitive processing. The relationship between dysbindin risk variants and sensory-level deficits in schizophrenia remains to be explored. We investigated P1 performance, a component of early visual processing on which both patients and their relatives show deficits, in carriers and noncarriers of a known dysbindin risk haplotype. METHODS Event-related potential responses to simple visual isolated-check stimuli were measured using high-density electrical scalp recordings in 26 individuals meeting DSM-IV criteria for schizophrenia, comprising 14 patients who were carriers of the dysbindin risk haplotype and 12 patients who were nonrisk haplotype carriers. RESULTS Carriers of the dysbindin risk haplotype demonstrated significantly reduced P1 amplitudes compared with noncarriers. A large effect size of d = .89 was calculated for the difference in P1 amplitude over scalp sites where the deficit was maximal. CONCLUSIONS The P1 deficits associated with a dysbindin risk haplotype previously identified in our sample presents functional confirmation of its deleterious effect on brain activity. Building on evidence of dysbindins role in higher cognitive function, these early visual processing deficits suggest a generalized role for dysbindin in brain function and is likely to be part of the mechanism by which illness susceptibility is mediated.

Enhanced and bilateralized visual sensory processing in the ventral stream may be a feature of normal aging

Evidence has emerged for age-related amplification of basic sensory processing indexed by early components of the visual evoked potential (VEP). However, since these age-related effects have been incidental to the main focus of these studies, it is unclear whether they are performance dependent or alternately, represent intrinsic sensory processing changes. High-density VEPs were acquired from 19 healthy elderly and 15 young control participants who viewed alphanumeric stimuli in the absence of any active task. The data show both enhanced and delayed neural responses within structures of the ventral visual stream, with reduced hemispheric asymmetry in the elderly that may be indicative of a decline in hemispheric specialization. Additionally, considerably enhanced early frontal cortical activation was observed in the elderly, suggesting frontal hyper-activation. These age-related differences in early sensory processing are discussed in terms of recent proposals that normal aging involves large-scale compensatory reorganization. Our results suggest that such compensatory mechanisms are not restricted to later higher-order cognitive processes but may also be a feature of early sensory-perceptual processes.

Intact inhibitory control processes in abstinent drug abusers (II): A high-density electrical mapping study in former cocaine and heroin addicts

Response inhibition deficits are well-documented in drug users, and are related to the impulsive tendencies characteristic of the addictive phenotype. Addicts also show significant motivational issues that may accentuate these inhibitory deficits. We investigated the extent to which these inhibitory deficits are present in abstinence. Salience of the task stimuli was also manipulated on the premise that emotionally-valenced inputs might impact inhibitory efficacy by overcoming the blunted responses to everyday environmental inputs characteristic of this population. Participants performed response inhibition tasks consisting of both neutral and emotionally valenced stimuli while high-density event-related potentials (ERPs) were recorded. Electrophysiological responses (N2/P3 components) to successful inhibitions in abstinent abusers (N = 20) and non-using participants (N = 21) were compared. In contrast to previous work in current users, our abstinent cohort showed no detectable behavioral or electrophysiological differences in their inhibitory responses, and no differences on self-reports of impulsivity, despite their long histories of chronic use (mean = 10.3 years). The current findings are consistent with a recovery of inhibitory control processes as a function of abstinence. Abstinent former users, however, did show a reduced modulation, relative to controls, of their ERPs to valenced input while performing successful inhibitions, although contrary to our hypothesis, the use of valenced inputs had no impact on inhibitory performance. Reduced ERP modulation to emotionally valenced inputs may have implications for relapse in emotional contexts outside the treatment center.

Recalibration of inhibitory control systems during walking-related dual-task interference: A Mobile Brain-Body Imaging (MOBI) Study ☆

Walking while simultaneously performing cognitively demanding tasks such as talking or texting are typical complex behaviors in our daily routines. Little is known about neural mechanisms underlying cortical resource allocation during such mobile actions, largely due to portability limitations of conventional neuroimaging technologies. We applied an EEG-based Mobile Brain-Body Imaging (MOBI) system that integrates high-density event-related potential (ERP) recordings with simultaneously acquired foot-force sensor data to monitor gait patterns and brain activity. We compared behavioral and ERP measures associated with performing a Go/NoGo response-inhibition task under conditions where participants (N=18) sat in a stationary way, walked deliberately or walked briskly. This allowed for assessment of effects of increasing dual-task load (i.e. walking speed) on neural indices of inhibitory control. Stride time and variability were also measured during inhibitory task performance and compared to stride parameters without task performance, thereby assessing reciprocal dual-task effects on gait parameters. There were no task performance differences between sitting and either walking condition, indicating that participants could perform both tasks simultaneously without suffering dual-task costs. However, participants took longer strides under dual-task load, likely indicating an adaptive mechanism to reduce inter-task competition for cortical resources. We found robust differences in amplitude, latency and topography of ERP components (N2 and P3) associated with inhibitory control between the sitting and walking conditions. Considering that participants showed no dual-task performance costs, we suggest that observed neural alterations under increasing task-load represent adaptive recalibration of the inhibitory network towards a more controlled and effortful processing mode, thereby optimizing performance under dual-task situations.

Executive dysfunction and reward dysregulation: a high-density electrical mapping study in cocaine abusers.

Executive function deficits and reward dysregulation, which mainly manifests as anhedonia, are well documented in drug abusers. We investigated specific aspects of executive function (inhibitory control and cognitive control), as well as anhedonia, in a cohort of current cocaine abusers in order to ascertain to what extent these factors are associated with more severe drug dependence. Participants filled out questionnaires relating to anhedonia and their addiction history. Participants also performed a response inhibition task while high-density event-related potentials (ERPs) were recorded. Electrophysiological responses to successful inhibitions (N2/P3 components) and to commission errors (ERN/Pe components) were compared between 23 current users of cocaine and 27 non-using controls. A regression model was performed to determine the association of our measures of reward dysregulation and executive function with addiction severity. As expected, cocaine users performed more poorly than controls on the inhibitory control task and showed significant electrophysiological differences. They were also generally more anhedonic than controls. Higher levels of anhedonia were associated with more severe substance use, whereas the level of executive dysfunction was not associated with more severe substance use. However, N2 amplitude was associated with duration of drug use. Further, inhibitory control and anhedonia were correlated, but only in controls. These data suggest that while executive dysfunction characterizes drug abuse, it is anhedonia, independent of executive dysfunction, that is most strongly associated with more severe use.

Preserved executive function in high-performing elderly is driven by large-scale recruitment of prefrontal cortical mechanisms

High‐density electrical mapping of event‐related potentials was used to investigate the neural processes that permit some elderly subjects to preserve high levels of executive functioning. Two possibilities pertain: (1) high‐performance in elderly subjects is underpinned by similar processing mechanisms to those seen in young adults; that is, these individuals display minimal functional decay across the lifespan, or (2) preserved function relies on successfully recruiting and amplifying control processes to compensate for normal sensory‐perceptual decline with age. Fifteen young and nineteen elderly participants, the latter split into groups of high and low performers, regularly alternated between a letter and a number categorization task, switching between tasks every third trial (AAA‐BBB‐AAA…). This allowed for interrogation of performance during switch, repeat, and preparatory pre‐switch trials. Robust effects of age were observed in both frontal and parietal components of the task‐switching network. Greatest differences originated over prefrontal regions, with elderly subjects generating amplified, earlier, and more differentiated patterns of activity. This prefrontal amplification was evident only in high‐performing (HP) elderly, and was strongest on pre‐switch trials when participants prepared for an upcoming task‐switch. Analysis of the early transient and late sustained activity using topographic analyses and source localization collectively supported a unique and elaborated pattern of activity across frontal and parietal scalp in HP‐elderly, wholly different to that seen in both young and low‐performing elderly. On this basis, we propose that preserved executive function in HP‐elderly is driven by large‐scale recruitment and enhancement of prefrontal cortical mechanisms. Hum Brain Mapp, 2009.

Visual sensory processing deficits in schizophrenia: Is there anything to the magnocellular account?

Visual processing studies have repeatedly shown impairment in patients with schizophrenia compared to healthy controls. Electroencephalography (EEG) and, specifically, visual evoked potential (VEP) studies have identified an early marker of this impairment in the form of a decrement in the P1 component of the VEP in patients and their clinically unaffected first-degree relatives. Much behavioral and neuroimaging research has implicated specific dysfunction of either the subcortical magnocellular pathway or the cortical visual dorsal stream in this impairment. In this study, EEG responses were obtained to the contrast modulation of checkerboard stimuli using the VESPA (Visual Evoked Spread Spectrum Analysis) method. This was done for a high contrast condition and, in order to bias the stimuli towards the magnocellular pathway, a low contrast condition. Standard VEPs were also obtained using high contrast pattern reversing checkerboards. Responses were measured using high-density electrical scalp recordings in 29 individuals meeting DSM-IV criteria for schizophrenia and in 18 control subjects. Replicating previous research, a large (Cohens d=1.11) reduction in the P1 component of the VEP was seen in patients when compared with controls with no corresponding difference in the VESPA response to high contrast stimuli. In addition, the low-contrast VESPA displayed no difference between patients and controls. Furthermore, no differences were seen between patients and controls for the C1 components of either the VEP or the high-contrast VESPA. Based on the differing acquisition methods between VEP and VESPA, we discuss these results in terms of contrast gain control and the possibility of dysfunction at the cortical level with initial afferent activity into V1 along the magnocellular pathway being intact when processing is biased towards that pathway using low contrast stimuli.

Throwing out the rules: anticipatory alpha-band oscillatory attention mechanisms during task-set reconfigurations.

We assessed the role of alpha‐band oscillatory activity during a task‐switching design that required participants to switch between an auditory and a visual task, while task‐relevant audiovisual inputs were simultaneously presented. Instructional cues informed participants which task to perform on a given trial and we assessed alpha‐band power in the short 1.35‐s period intervening between the cue and the task‐imperative stimuli, on the premise that attentional biasing mechanisms would be deployed to resolve competition between the auditory and visual inputs. Prior work had shown that alpha‐band activity was differentially deployed depending on the modality of the cued task. Here, we asked whether this activity would, in turn, be differentially deployed depending on whether participants had just made a switch of task or were being asked to simply repeat the task. It is well established that performance speed and accuracy are poorer on switch than on repeat trials. Here, however, the use of instructional cues completely mitigated these classic switch‐costs. Measures of alpha‐band synchronisation and desynchronisation showed that there was indeed greater and earlier differential deployment of alpha‐band activity on switch vs. repeat trials. Contrary to our hypothesis, this differential effect was entirely due to changes in the amount of desynchronisation observed during switch and repeat trials of the visual task, with more desynchronisation over both posterior and frontal scalp regions during switch‐visual trials. These data imply that particularly vigorous, and essentially fully effective, anticipatory biasing mechanisms resolved the competition between competing auditory and visual inputs when a rapid switch of task was required.

Early sensory–perceptual processing deficits for affectively valenced inputs are more pronounced in schizophrenia patients with a history of violence than in their non-violent peers

Individuals with schizophrenia are more prone to violent behaviors than the general population. It is increasingly recognized that processing of emotionally valenced stimuli is impaired in schizophrenia, a deficit that may play a role in aggressive behavior. Our goal was to establish whether patients with a history of violence would show more severe deficits in processing emotionally valenced inputs than non-violent patients. Using event-related potentials, we measured how early during processing of emotional valence, evidence of aberrant function was observed. A total of 42 schizophrenia patients (21 with history of violence; 21 without) and 28 healthy controls were tested. Participants performed an inhibitory control task, making speeded responses to pictorial stimuli. Pictures occasionally repeated twice and participants withheld responses to these repeats. Valenced pictures from the International Affective Picture System were presented. Results in controls showed modulations during the earliest phases of sensory processing (<100 ms) for negatively valenced pictures. A cascade of modulations ensued, involving sensory and perceptual processing stages. In contrast, neither schizophrenia group showed early differentiation. Non-violent patients showed earliest modulations beginning ∼150 ms. For violent patients, however, earliest modulations were further delayed and highly attenuated. The current study reveals sensory-perceptual processing dysfunction for negatively valenced inputs, which is particularly pronounced in aggressive patients.