Casey S. Gilmore

Abnormalities of Neuronal Oscillations and Temporal Integration to Low- and High-Frequency Auditory Stimulation in Schizophrenia

BACKGROUND Electroencephalography and magnetoencephalography studies indicate among schizophrenia patients (SZ) abnormal, often reduced, entrained steady-state (aSSR) and transient (N100/M100) neural responses to auditory stimuli. We complement this literature by focusing analyses on auditory cortices, assessing a wide range of stimulation frequencies with long driving periods and evaluating relationships between aSSR and M100 reductions in SZ. METHODS Seventeen SZ and 17 healthy subjects (H) participated. Stimuli were 1500 msec binaural broadband noise sequences modulated at 5, 20, 40, 80, or 160 Hz. Magnetoencephalography data were collected and co-registered with structural magnetic resonance images. The aSSRs and M100s projected into brain space were analyzed as a function of hemisphere, stimulus density, and time. RESULTS For aSSR, SZ displayed weaker entrainment bilaterally at low (5-Hz) and high (80-Hz) modulation frequencies. To 40-Hz stimuli, SZ showed weaker entrainment only in right auditory cortex. For M100, while responses for H increased linearly with stimulus density, this effect was weaker or absent in SZ. A principal components analysis of SZ deficits identified low (5-Hz entrainment and M100) and high (40- to 80-Hz entrainment) frequency components. Discriminant analysis indicated that the low-frequency component uniquely differentiated SZ from H. The high-frequency component correlated with negative symptoms among SZ. CONCLUSIONS The SZ auditory cortices were unable to 1) generate healthy levels of theta and high gamma band (80-Hz) entrainment (aSSR), and 2) augment transient responses (M100s) to rapidly presented auditory information (an index of temporal integration). Only the latter was most apparent in left hemisphere and may reflect a prominent neurophysiological deficit in schizophrenia.

Brain electrophysiological endophenotypes for externalizing psychopathology: a multivariate approach.

Abnormalities in electrophysiological measures of stimulus-evoked brain activity (including the P3 event-related potential (ERP) and its associated delta and theta time–frequency (TF) components), and intrinsic, resting state brain activity (including EEG in the beta frequency band) have each been associated with biological vulnerability to a variety of externalizing (EXT) spectrum disorders, such as substance use disorders, conduct disorder, and antisocial behavior. While each of these individual measures has shown promise as an endophenotype for one or more aspects of EXT, we proposed that the power to identify EXT-related genes may be enhanced by using these measures collectively. Thus, we sought to explore a multivariate approach to identifying electrophysiological endophenotypes related to EXT, using measures identified in the literature as promising individual endophenotypes for EXT. Using data from our large twin sample (634 MZ and 335 DZ, male and female same-sex pairs), and fitting multivariate biometric Cholesky models, we found that these measures (1) were heritable, (2) showed significant phenotypic and genetic correlation with a general vulnerability to EXT (which is itself highly heritable), (3) showed modest phenotypic and genetic correlation with each other, and (4) were sensitive to genetic effects that differed as a function of gender. These relationships suggest that these endophenotypes are likely tapping into neurophysiological processes and genes that are both common across them and unique to each—all of which are relevant to a biological vulnerability to EXT psychopathology.

Relationship between the P3 Event-Related Potential, Its Associated Time-Frequency Components, and Externalizing Psychopathology

P3 amplitude reduction (P3-AR) is associated with biological vulnerability to a spectrum of externalizing disorders, such as ADHD, conduct disorder, and substance use disorders. P3, however, is generally characterized as a broad activation involving multiple neurophysiological processes. One approach to separating P3-related processes is time-frequency (TF) analysis. The current study used a novel PCA-based TF analysis method to investigate relationships between P3, its associated TF components, and externalizing in a community-based sample of adolescent males. Results showed that 1) alone, P3 and each TF-PCA derived component could successfully discriminate diagnostic groups from controls, and 2) delta components in specific time ranges accounted for variance beyond that accounted for by P3. One delta component was associated with all diagnostic groups, suggesting it may represent a more parsimonious endophenotype for externalizing than P3-AR.

Augmented gamma band auditory steady-state responses: Support for NMDA hypofunction in schizophrenia

Individuals with schizophrenia (SZ) have deviations in auditory perception perhaps attributable to altered neural oscillatory response properties in thalamo-cortical and/or local cortico-cortical circuits. Previous EEG studies of auditory steady-state responses (aSSRs; a measure of sustained neuronal entrainment to repetitive stimulation) in SZ have indicated attenuated gamma range (≈40 Hz) neural entrainment. Stimuli in most such studies have been relatively brief (500-1000 ms) trains of 1 ms clicks or amplitude modulated pure tones (1000 Hz) with short, fixed interstimulus intervals (200-1000 ms). The current study used extended (1500 ms), more aurally dense broadband stimuli (500-4000 Hz noise; previously demonstrated to elicit larger aSSRs) with longer, variable interstimulus intervals (2700-3300 ms). Dense array EEG (256 sensor) was collected while 17 SZ and 16 healthy subjects passively listed to stimuli modulated at 15 different frequencies spanning beta and gamma ranges (16-44 Hz in 2 Hz steps). Results indicate that SZ have augmented aSSRs that were most extreme in the gamma range. Results also constructively replicate previous findings of attenuated low frequency auditory evoked responses (2-8 Hz) in SZ. These findings (i) highlight differential characteristics of low versus high frequency and induced versus entrained oscillatory auditory responses in both SZ and healthy stimulus processing, (ii) provide support for an NMDA-receptor hypofunction-based pharmacological model of SZ, and (iii) report a novel pattern of aSSR abnormalities suggesting that gamma band neural entrainment deviations among SZ may be more complex than previously supposed, including possibly being substantially influenced by physical stimulus properties.

Hemispheric differences in auditory oddball responses during monaural versus binaural stimulation

Hemispheric lateralization of early event-related potentials (ERPs; e.g. N1) is largely based on anatomy of the afferent pathway; lateralization of later auditory ERPs (P2/N2, P250, P3b) is less clear. Using 257-channel EEG, the present study examined hemispheric laterality of auditory ERPs by comparing binaural and monaural versions of an auditory oddball task. N1 showed a contralateral bias over auditory cortex in both hemispheres as a function of ear of stimulation, although right hemisphere sources were activated regardless of which ear received input. Beginning around N1 and continuing through the time of P3b, right hemisphere temporal-parietal and frontal areas were more activated than their left hemisphere counterparts for stimulus evaluation/comparison and target detection. P250 and P3b component amplitudes, topographies, and source estimations were significantly influenced by ear of stimulation, with right hemisphere activity being stronger. This was particularly true for anterior temporal and inferior frontal sources which were more strongly associated with the later, more cognitive components (P250, P3b). Results are consistent with theories of a right hemisphere network that is prominently involved in sustained attention, stimulus evaluation, target detection, and working memory/context updating.

Deficits in Visual System Functional Connectivity after Blast‐Related Mild TBI are Associated with Injury Severity and Executive Dysfunction

Approximately, 275,000 American service members deployed to Iraq or Afghanistan have sustained a mild traumatic brain injury (mTBI), with 75% of these incidents involving an explosive blast. Visual processing problems and cognitive dysfunction are common complaints following blast‐related mTBI.

Is the P3 amplitude reduction seen in externalizing psychopathology attributable to stimulus sequence effects

P3 amplitude reduction (P3-AR) is associated with biological vulnerability to a spectrum of externalizing (EXT) disorders, such as conduct disorder, antisocial behavior, and substance use disorders. P3 amplitude, however, can be affected by the context within which it is measured, for example, by the position of the target in the sequence of stimuli during an oddball task. We hypothesized that EXT-related P3-AR may be due to attention or working memory deficits in EXT that would weaken these stimulus sequence effects. Using a community-based sample of adolescent males, we examined the relationship between P3 and EXT as a function of the number of standards preceding the target. Higher EXT was associated with significantly smaller P3 amplitude, regardless of the number of standards preceding the target. These results suggest that P3-AR in EXT does not vary as a function of stimulus sequence, further supporting P3-AR as an endophenotype for EXT disorders.

Theta event‐related synchronization is a biomarker for a morbid effect of alcoholism on the brain that may partially resolve with extended abstinence

Analyzing the induced (non‐stimulus‐phase‐locked) EEG activity elicited by targets in a three‐condition visual oddball task, Fein and colleagues have shown increased theta band event‐related synchronization (ERS) in two different samples of long‐term abstinent alcoholics (LTAA) compared with age‐ and gender‐comparable controls. The theta ERS effect in alcoholics was also shown to be independent of, and opposite in direction to, the reduced amplitude evoked (stimulus‐phase‐locked) activity typically found in alcoholics and those at genetic risk of developing alcoholism. This study extends these findings by applying time‐frequency analysis to target stimulus event‐related EEG to compare evoked and induced theta activity in 43 LTAA and 72 nonalcoholic controls with a group of 31 alcoholics who just recently initiated abstinence from alcohol (between 6‐ and 15‐week abstinent; referred to as short‐term abstinent alcoholics, STAA). Results demonstrated that (1) evoked theta power was reduced to the same degree in STAA and LTAA compared with nonalcoholic control participants, while (2) induced theta activity, measured by theta ERS, was increased in both STAA and LTAA relative to controls, but was also increased in STAA relative to LTAA. The STAA and LTAA groups did not differ on measures of alcohol use severity or family history of alcohol problems. These results, coupled with previous findings that show a relationship between stronger theta ERS and increased memory load and attention allocation, suggest that increased theta ERS may be a biomarker for a detrimental effect of chronic alcohol abuse on the brain – a detriment that may recover, at least partially, with extended abstinence.

Reduced P3b brain response during sustained visual attention is associated with remote blast mTBI and current PTSD in U.S. military veterans

HighlightsNeural correlates of sustained visual attention in veterans with blast mTBI and/or PTSD were examined.P3b amplitude comparably reduced in veterans with blast mTBI and/or PTSD compared to controls.P3b amplitude reduction during a DS‐CPT may index generalized brain pathology in mTBI/PTSD. ABSTRACT Approximately 275,000 American service members deployed to Iraq or Afghanistan have sustained a mild traumatic brain injury (mTBI), with 75% of these incidents involving an explosive blast. Combat‐related mTBI is frequently associated with comorbid mental health disorders, especially posttraumatic stress disorder (PTSD). Attention problems, including sustained attention, are common cognitive complaints of veterans with TBI and PTSD. The present study sought to examine neural correlates of sustained attention in veterans with blast mTBI and/or current PTSD. In 124 veterans of Operations Enduring and Iraqi Freedom (OEF/OIF), we examined event‐related potentials (ERPs) elicited by targets and non‐targets during performance of a degraded‐stimulus continuous performance task (DS‐CPT). Four groups, consisting of veterans with blast‐related mTBI only, current PTSD only, both blast mTBI and PTSD, and a control group, were studied. Compared to all other groups, blast mTBI only participants were more likely to respond regardless of stimulus type during the DS‐CPT. During target detection, the three mTBI/PTSD groups showed reduced amplitude of the P3b (i.e., P300) ERP at Pz compared to the control group. P3b of the three affected groups did not differ from each other. These results suggest that parietal P3b amplitude reduction during target detection in the DS‐CPT task may be an index of brain pathology after combat trauma, yet the diminished brain response fails to differentiate independent effects of blast‐related mTBI or severity of PTSD symptomatology.