Brian A. Coffman

Mismatch Negativity in First-Episode Schizophrenia: A Meta-Analysis.

Mismatch negativity (MMN) to deviant stimuli is robustly smaller in individuals with chronic schizophrenia compared with healthy controls (Cohen’s d > 1.0 or more), leading to the possibility of MMN being used as a biomarker for schizophrenia. However, there is some debate in the literature as to whether MMN is reliably reduced in first-episode schizophrenia patients. For the biomarker to be used as a predictive marker for schizophrenia, it should be reduced in the majority of cases known to have the disease, particularly at disease onset. We conducted a meta-analysis on the fourteen studies that measured MMN to pitch or duration deviants in healthy controls and patients within 12 months of their first episode of schizophrenia. The overall effect size showed no MMN reduction in first-episode patients to pitch-deviants (Cohen’s d < 0.04), and a small-to-medium reduction to duration-deviants (Cohen’s d = 0.47). Together, this indicates that pitch-deviant MMN is not a candidate biomarker for schizophrenia prediction, while duration-deviant MMN may hold some promise, albeit nearly a third as large an effect as in chronic schizophrenia. Potential causes for discrepancies between studies are discussed.

Transcranial Direct Current Stimulation Modulates Neuronal Activity and Learning in Pilot Training

Skill acquisition requires distributed learning both within (online) and across (offline) days to consolidate experiences into newly learned abilities. In particular, piloting an aircraft requires skills developed from extensive training and practice. Here, we tested the hypothesis that transcranial direct current stimulation (tDCS) can modulate neuronal function to improve skill learning and performance during flight simulator training of aircraft landing procedures. Thirty-two right-handed participants consented to participate in four consecutive daily sessions of flight simulation training and received sham or anodal high-definition-tDCS to the right dorsolateral prefrontal cortex (DLPFC) or left motor cortex (M1) in a randomized, double-blind experiment. Continuous electroencephalography (EEG) and functional near infrared spectroscopy (fNIRS) were collected during flight simulation, n-back working memory, and resting-state assessments. tDCS of the right DLPFC increased midline-frontal theta-band activity in flight and n-back working memory training, confirming tDCS-related modulation of brain processes involved in executive function. This modulation corresponded to a significantly different online and offline learning rates for working memory accuracy and decreased inter-subject behavioral variability in flight and n-back tasks in the DLPFC stimulation group. Additionally, tDCS of left M1 increased parietal alpha power during flight tasks and tDCS to the right DLPFC increased midline frontal theta-band power during n-back and flight tasks. These results demonstrate a modulation of group variance in skill acquisition through an increasing in learned skill consistency in cognitive and real-world tasks with tDCS. Further, tDCS performance improvements corresponded to changes in electrophysiological and blood-oxygenation activity of the DLPFC and motor cortices, providing a stronger link between modulated neuronal function and behavior.

Abnormal auditory pattern perception in schizophrenia

Mismatch negativity (MMN) in response to deviation from physical sound parameters (e.g., pitch, duration) is reduced in individuals with long-term schizophrenia (Sz), suggesting deficits in deviance detection. However, MMN can appear at several time intervals as part of deviance detection. Understanding which part of the processing stream is abnormal in Sz is crucial for understanding MMN pathophysiology. We measured MMN to complex pattern deviants, which have been shown to produce multiple MMNs in healthy controls (HC). Both simple and complex MMNs were recorded from 27 Sz and 27 matched HC. For simple MMN, pitch- and duration-deviants were presented among frequent standard tones. For complex MMN, patterns of five single tones were repeatedly presented, with the occasional deviant group of tones containing an extra sixth tone. Sz showed smaller pitch MMN (p=0.009, ~110ms) and duration MMN (p=0.030, ~170ms) than healthy controls. For complex MMN, there were two deviance-related negativities. The first (~150ms) was not significantly different between HC and SZ. The second was significantly reduced in Sz (p=0.011, ~400ms). The topography of the late complex MMN was consistent with generators in anterior temporal cortex. Worse late MMN in Sz was associated with increased emotional withdrawal, poor attention, lack of spontaneity/conversation, and increased preoccupation. Late MMN blunting in schizophrenia suggests a deficit in later stages of deviance processing. Correlations with negative symptoms measures are preliminary, but suggest that abnormal complex auditory perceptual processes may compound higher-order cognitive and social deficits in the disorder.

Enhanced working memory performance via transcranial direct current stimulation: The possibility of near and far transfer

Although working memory (WM) training programs consistently result in improvement on the trained task, benefit is typically short-lived and extends only to tasks very similar to the trained task (i.e., near transfer). It is possible that pairing repeated performance of a WM task with brain stimulation encourages plasticity in brain networks involved in WM task performance, thereby improving the training benefit. In the current study, transcranial direct current stimulation (tDCS) was paired with performance of a WM task (n-back). In Experiment 1, participants performed a spatial location-monitoring n-back during stimulation, while Experiment 2 used a verbal identity-monitoring n-back. In each experiment, participants received either active (2.0mA) or sham (0.1mA) stimulation with the anode placed over either the right or the left dorsolateral prefrontal cortex (DLPFC) and the cathode placed extracephalically. In Experiment 1, only participants receiving active stimulation with the anode placed over the right DLPFC showed marginal improvement on the trained spatial n-back, which did not extend to a near transfer (verbal n-back) or far transfer task (a matrix-reasoning task designed to measure fluid intelligence). In Experiment 2, both left and right anode placements led to improvement, and right DLPFC stimulation resulted in numerical (though not sham-adjusted) improvement on the near transfer (spatial n-back) and far transfer (fluid intelligence) task. Results suggest that WM training paired with brain stimulation may result in cognitive enhancement that transfers to performance on other tasks, depending on the combination of training task and tDCS parameters used.

Complex mismatch negativity to tone pair deviants in long-term schizophrenia and in the first-episode schizophrenia spectrum

Mismatch negativity (MMN) is an event-related potential to stimulus change. MMN to infrequent deviant tones that differs in a simple physical parameter from repetitive standard tones is reduced in patients with long-term schizophrenia (Sz; d=~1). However, this simple MMN is not uniformly reduced at the first-episode of schizophrenia-spectrum psychosis (FESz; d<0.1 for pitch; <0.4 for duration). Deviant stimuli that violate pattern rules also evoke MMN. This complex MMN is evoked by deviations in the relation of sounds to each other. The simplest pattern involves tone pairs. Although the pitch of first tone in the pair varies, the second tones pitch always follows a rule (e.g., always 3 semitones higher). We measured complex MMN to deviant tone pairs that descended in pitch among standard tone pairs that ascended in pitch, never before examined in Sz or in FESz. Experiment 1 showed significant reductions in complex MMN in 20 Sz compared to 22 matched controls. Experiment 2 replicated smaller complex MMN in a shorter protocol in 24 Sz compared to 21 matched controls, but showed no significant complex MMN reduction in 21 FESz compared to 21 matched controls. Although reduced in Sz, indicating deficits in generation of a simple acoustic pattern rule, the tone pair complex MMN was within normal limits in FESz. This suggests that more complex perceptual pattern analysis processes are, at least partially, still intact at the first break. Future work will determine at what point of pattern complexity subtle auditory perception pathophysiology will be revealed in FESz.

Event-related potentials demonstrate deficits in acoustic segmentation in schizophrenia

Segmentation of the acoustic environment into discrete percepts is an important facet of auditory scene analysis (ASA). Segmentation of auditory stimuli into perceptually meaningful and localizable groups is central to ASA in everyday situations; for example, separation of discrete words from continuous sentences when processing language. This is particularly relevant to schizophrenia, where deficits in perceptual organization have been linked to symptoms and cognitive dysfunction. Here we examined event-related potentials in response to grouped tones to elucidate schizophrenia-related differences in acoustic segmentation. We report for the first time in healthy subjects a sustained potential that begins with group initiation and ends with the last tone of the group. These potentials were reduced in schizophrenia, with the greatest differences in responses to first and final tones. Importantly, reductions in sustained potentials in schizophrenia patients were associated with greater negative symptoms and deficits in IQ, working memory, learning, and social cognition. These results suggest deficits in auditory pattern segmentation in schizophrenia may compound deficits in many higher-order facets of the disorder.

Mismatch Negativity to Pitch Pattern Deviants in Schizophrenia

Simple mismatch negativity (MMN) to infrequent pitch deviants is impaired in individuals with long‐term schizophrenia (Sz). The complex MMN elicited by pattern deviance often manifes is cut from here]‐>ts later after deviant onset than simple MMN and can ascertain deficits in abstracting relationships between stimuli. Sz exhibit reduced complex MMN, but so far this has only been measured when deviance detection relies on a grouping rule. We measured MMN to deviants in pitch‐based rules to see whether MMN is also abnormal in Sz under these conditions. Three experiments were conducted. Twenty‐seven Sz and 28 healthy matched controls (HC) participated in Experiments 1 and 2, and 24 Sz and 26 HC participated in Experiment 3. Experiment 1 was a standard pitch MMN task, and Sz showed the expected MMN reduction (~ 115 ms) in the simple pitch deviant compared to HC. Experiment 2 comprised standard groups of six tones that ascended in pitch, and deviant groups where the last tone descended in pitch. Complex MMN was late (~ 510 ms) and significantly blunted in Sz. Experiment 3 comprised standard groups of 12 tones (six tones ascending in pitch followed by six tones descending in pitch, like a scale), and deviant groups containing two repetitions of six ascending tones (the scale restarted midstream). Complex MMN was also late (~ 460 ms) and significantly blunted in Sz. These results identify a late pitch pattern deviance‐related MMN that is deficient in schizophrenia. This suggests specific deficits in later more complex deviance detection in schizophrenia for abstract patterns.

Does Neurotechnology Produce a Better Brain

Neurotechnologies in clinical applications can image the brain noninvasively, but they typically require surgical insertion to stimulate it. Although an increasingly popular alternative is to use noninvasive stimulation to enhance nervous system functions, questions about its effectiveness and ethical use remain unanswered.

F173. PITCH AND DURATION MISMATCH NEGATIVITY, AUDITORY CORTEX GRAY MATTER, AND PRODROMAL ROLE FUNCTIONING IN THE FIRST EPISODE SCHIZOPHRENIA SPECTRUM

Abstract Background Primary auditory cortex, contained within Heschl’s gyrus, is implicated auditory processing deficits and auditory verbal hallucinations in schizophrenia. Previously we showed a pathological correlation between the magnitude of the pitch-deviant mismatch negativity (pMMN) response during a passive auditory task and reductions in gray matter volume in Heschl’s gyrus in subjects with first hospitalized for schizophrenia. The aim of this study was to replicate this finding, examine duration-deviant mismatch negativity (dMMN) and gray matter correlations, and to examine pre-psychosis role functioning, in a first episode psychosis sample within the schizophrenia-spectrum. Methods Participants included 40 first episode schizophrenia subjects (FESz) and 40 healthy controls (HC) matched for age, parental socioeconomic status, IQ, sex, and handedness. For MMN extracted from the EEG, standard tones were presented repeatedly (1 kHz, 75 dB, 50 ms pips, 5 ms rise/fall times, 330 ms SOA) with an occasional pitch deviant (1.2 kHz, 10% of trials) or duration deviant (100 ms, 10% of trials) interspersed. pMMN and dMMN were measured from subtraction waveforms as the average voltage within a 100-ms group averaged peak window at Fz. Role functioning was measured with the Cornblatt Global Functioning: Role scale. A subset of 28 FESz and 28 matched HC underwent structural MRI. High-resolution T1-weighted structural MRI data (3T) were acquired for each subject. Freesurfer was used to segment white matter, gray matter, and pial surfaces. Left and right Heschl’s gyri were manually edited regions of interest, and gray matter volumes determined. Results Despite a lack of pMMN or dMMN reduction at the group level in FESz, both measures were pathologically correlated with role functioning in the year prior to hospitalization. In FESz, smaller pMMN at Fz was associated with poorer role functioning in the year prior to psychosis (rho= -.35, p =.03). Similar associations were observed for dMMN (rho= -.41, p <.01). Furthermore, in the subset of FESz with sMRI, smaller pMMN at Fz was associated with less total gray matter volume in left Heschl’s gyrus (TGMV) (rho= -.40, p =.03) but not right. Similar associations were observed for dMMN (rho= -.47, p .01). As well, role functioning and auditory cortex gray matter volumes were not correlated in FESz. There were no significant correlations within HC. Discussion Although pMMN and dMMN are not reduced at the group level, the size of both are associated with impaired functioning prior to psychosis and reduced gray matter volume of left hemisphere Heschl’s gyrus, containing primary and secondary auditory cortices. Thus, pMMN and dMMN although not sufficient as biomarkers of disease presence, are suitable as reliable biomarkers of disease progression. Presumably, poorer role functioning and less gray matter reflect more of the pre-psychosis progressive pathological process thought to occur in the prodromal phase of psychosis. Hence, pMMN and dMMN are likely to serve as sensitive and robust outcome measures for therapeutic interventions and to guide treatment strategies in the prodrome and during early psychosis.

S168. AUDITORY TRANSCALLOSAL FIBERS AND AUDITORY HALLUCINATIONS

Abstract Background Auditory verbal hallucinations (AVH) are one of the most common symptoms in schizophrenia. Connectivity between left and right auditory cortex may be related to AVH. The aim of this study was to examine transcallosal auditory cortex connectivity in first-episode schizophrenia patients (FESz) who experience AVH. Methods Diffusion spectrum imaging (DSI) data were obtained from 29 FESz and 23 healthy controls (HCs). Of the 29 FESz participants, 15 were AVH-, with a score of 0 for auditory hallucinations, voices commenting, and voices conversing measured with the Scale for the Assessment of Positive Symptoms (SAPS), and 14 were AVH+, with a score of 2 or greater on at least one of these questions. The three groups (AVH+, AVH-, and healthy controls) were matched for age, parental socioeconomic status, years of education, IQ, gender, and handedness. A deterministic fiber tracking algorithm was used to identify the transcallosal auditory white matter tract, which was identified as the 1000 fibers passing through the posterior third of the corpus callosum and ending bilaterally in Brodmann’s area 22, Heschl’s gyrus, or planum temporale. Transcallosal auditory cortex connectivity was compared between groups for tract volume, generalized Fractional Anisotropy (gFA), and isotropy. Results MANOVA revealed a significant difference in connectivity between groups (F(6, 94) = 2.34, p = .038) that was driven by group differences in tract volume (F(2, 49) = 3.46, p =.039) and gFA (F(2, 49) = 4.77, p = .013)). Within FESz, AVH severity significantly correlated with auditory cortex transcallosal gFA (r =-.44, p =.013). Pairwise t-tests indicated lower gFA and greater tract volume for AVH+ vs AVH- (p’s < .05). HCs had a trend towards greater gFA (p = .068) vs AVH+ and tract volume (p = .063) vs AVH-. All other comparisons were nonsignificant (p >.1). Discussion These findings suggest that structural connectivity differences may underlie AVH in schizophrenia, even early in disease course. FESz participants with AVH have less efficient transcallosal auditory connectivity compared to those without AVH. The reduced gFA in FESz correlated with hallucination severity, suggesting that inefficient coordination of left and right hemisphere auditory processing, crucial for language, was impaired in the disorder. The transcallosal structural integrity and connectivity may indicate a subtype characterized by AVH. Current work is determining the extent to which this fiber deficit is common across Kraepelinian diagnostic categories of psychosis (e.g., bipolar disorder and depression with psychotic features).