Intensity-dependent modulation of the early auditory gamma-band response in first-episode schizophrenia and its association with disease symptoms.

BACKGROUND: Gamma-band activity has been the focus of considerable research in schizophrenia. Discrepancies exist regarding the integrity of the early auditory gamma-band response (EAGBR), a stimulus-evoked oscillation, and its relationship to symptoms in early disease. Variability in task design may play a role. This study examined sensitivity of the EAGBR to stimulus intensity and its relation to symptoms and functional impairments in the first-episode schizophrenia spectrum (FESz). METHOD: Magnetoencephalography was recorded from 35 FESz and 40 matched healthy controls (HC) during presentation of 3 tone intensities (75 dB, 80 dB, 85 dB). MRIs were collected to localize auditory cortex activity. Wavelet-transformed single trial epochs and trial averages were used to assess EAGBR intertrial phase coherence (ITPC) and evoked power, respectively. Symptoms were assessed using the Positive and Negative Syndrome Scale. RESULTS: Groups did not differ in overall EAGBR power or ITPC. While HC exhibited EAGBR enhancement to increasing intensity, FESz exhibited reduced power to the 80 dB tone and, relative to HC, increased power to the 75 dB tone. Larger power and ITPC were correlated with more severe negative, thought disorganization, and resistance symptoms. Stronger ITPC was associated with impaired social functioning. DISCUSSION: EAGBR showed no overall deficit at disease onset. Rather, FESz exhibited a differential response across tone intensity relative to HC, emphasizing the importance of stimulus characteristics in EAGBR studies. Associations between larger EAGBR and more severe symptoms suggest aberrant synchronization driving overinclusive perceptual binding that may relate to deficits in executive inhibition of initial sensory activity.

Functional and structural connectivity correlates of semantic verbal fluency deficits in first-episode psychosis.

INTRODUCTION: Semantic verbal fluency (SVF) impairments are debilitating and present early in the course of psychotic illness. Deficits within frontal, parietal, and temporal brain regions contribute to this deficit, as long-range communication across this functionally integrated network is critical to SVF. This study sought to isolate disruptions in functional and structural connectivity contributing to SVF deficits during first-episode psychosis in the schizophrenia spectrum (FESz). METHODS: Thirty-three FESz and 34 matched healthy controls (HC) completed the Animal Naming Task to assess SVF. Magnetoencephalography was recorded during an analogous covert SVF task, and phase-locking value (PLV) used to measure functional connectivity between inferior frontal and temporoparietal structures bilaterally. Diffusion imaging was collected to measure fractional anisotropy (FA) of the arcuate fasciculus, the major tract connecting frontal and temporoparietal language areas. RESULTS: SVF scores were lower among FESz compared to HC. While PLV and FA did not differ between groups overall, FESz exhibited an absence of the left-lateralized nature of both measures observed in HC. Among FESz, larger right-hemisphere PLV was associated with worse SVF performance (ρ = -0.51) and longer DUP (ρ = -0.50). DISCUSSION: In addition to worse SVF, FESz exhibited diminished leftward asymmetry of structural and functional connectivity in fronto-temporoparietal SVF network. The relationship between theta-band hyperconnectivity and poorer performance suggests a disorganized executive network and may reflect dysfunction of frontal cognitive control centers. These findings illustrate an aberrant pattern across the distributed SVF network at disease onset and merit further investigation into development of asymmetrical hemispheric connectivity and its failure among high-risk populations.

Longitudinal Investigation of Auditory Dynamic Range Deficits in Early Psychosis and its Relationship to Negative Symptoms.

BACKGROUND AND HYPOTHESIS: Despite accounting for significant disease morbidity in schizophrenia, the neuropathological basis of negative symptoms remains poorly understood and options for treatment limited. Our recent study identified robust associations between diminished auditory cortex (AC) dynamic range and social functioning impairments and negative symptoms in first episode psychosis (FESz). The current investigation examined the progression of these relationships 4-8 months from baseline testing. STUDY DESIGN: Twenty-six FESz and 38 healthy controls (HC) were tested at baseline and follow-up. Magnetoencephalography (MEG) was recorded during binaural presentation of tones (75, 80, and 85 dB). Assessments included the MATRICS cognitive consensus battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS) and the Positive and Negative Syndrome Scale. STUDY RESULTS: Overall, FESz exhibited a blunted response to increasing tone intensity relative to HC. While this deficit did not change over time at the group level, recovery of right hemisphere AC dynamic range (85-75 dB response) among FESz individuals was associated with reductions in negative symptoms (ρ = -0.50). Diminished dynamic range was also associated with impaired GFS (ρ = 0.65), GFR (ρ = 0.51), and MCCB (ρ = 0.49) at baseline and increased negative symptoms at baseline (ρ = -0.53) and follow-up (ρ = -0.51). CONCLUSION: Despite persistent dynamic range impairment in FESz as a group, individual recovery of this AC response property was associated with significant reduction in negative symptoms. Identification of a functional neural deficit that tracts progression of negative symptoms during a critical period for disease modification is essential to the management of these devastating and historically treatment refractory symptoms.

Functional connectivity and gray matter deficits within the auditory attention circuit in first-episode psychosis.

Background: Selective attention deficits in first episode of psychosis (FEP) can be indexed by impaired attentional modulation of auditory M100. It is unknown if the pathophysiology underlying this deficit is restricted to auditory cortex or involves a distributed attention network. We examined the auditory attention network in FEP. Methods: MEG was recorded from 27 FEP and 31 matched healthy controls (HC) while alternately ignoring or attending tones. A whole-brain analysis of MEG source activity during auditory M100 identified non-auditory areas with increased activity. Time-frequency activity and phase-amplitude coupling were examined in auditory cortex to identify the attentional executive carrier frequency. Attention networks were defined by phase-locking at the carrier frequency. Spectral and gray matter deficits in the identified circuits were examined in FEP. Results: Attention-related activity was identified in prefrontal and parietal regions, markedly in precuneus. Theta power and phase coupling to gamma amplitude increased with attention in left primary auditory cortex. Two unilateral attention networks were identified with precuneus seeds in HC. Network synchrony was impaired in FEP. Gray matter thickness was reduced within the left hemisphere network in FEP but did not correlate with synchrony. Conclusion: Several extra-auditory attention areas with attention-related activity were identified. Theta was the carrier frequency for attentional modulation in auditory cortex. Left and right hemisphere attention networks were identified, with bilateral functional deficits and left hemisphere structural deficits, though FEP showed intact auditory cortex theta phase-gamma amplitude coupling. These novel findings indicate attention-related circuitopathy early in psychosis potentially amenable to future non-invasive interventions.

Diminished Auditory Cortex Dynamic Range and its Clinical Correlates in First Episode Psychosis.

BACKGROUND AND HYPOTHESIS: There is growing appreciation for the contribution of sensory disruptions to disease morbidity in psychosis. The present study examined auditory cortex (AC) dynamic range: the scaling of neurophysiological responses to stimulus intensity, among individuals with a schizophrenia spectrum illness (FESz) and its relationship to clinical outcomes at disease onset. STUDY DESIGN: Magnetoencephalography (MEG) was recorded from 35 FESz and 40 healthy controls (HC) during binaural presentation of tones at three intensities (75 dB, 80 dB, and 85 dB). MRIs were obtained to enhance cortical localization of MEG sensor-level activity. All participants completed the MATRICS cognitive battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS). Patients were administered the Positive and Negative Syndrome Scale (PANSS). STUDY RESULTS: FESz exhibited reduced AC response relative to HC. Enhancement of AC activity to tones of increasing intensity was blunted in FESz relative to HC. Reduced dynamic range (85-75 dB AC response) was associated with lower GFS (r = .58) and GFR (r = .45) scores, worse MCCB performance (r = .45), and increased PANSS Negative symptom subscale scores (r = -.55) among FESz, relationships not observed with AC responses to individual tones. CONCLUSION: Beyond an impaired AC response to pure tones, FESz exhibit reduced dynamic range relative to HC. This impairment was correlated with markers of disease morbidity including poorer community functioning as well as cognitive and negative symptoms. The relationship with impaired social functioning may reflect the role of AC dynamic range in decoding the emotional content of language and highlights its importance to future therapeutic sensory remediation protocols.

Load-dependent functional connectivity deficits during visual working memory in first-episode psychosis.

INTRODUCTION: Aberrant network connectivity is a core deficit in schizophrenia and may underlie many of its associated cognitive deficits. Previous work in first-episode schizophrenia spectrum illness (FESz) suggests preservation of working memory network function during low-load conditions with dysfunction emerging as task complexity increases. This study assessed visual network connectivity and its contribution to load-dependent working memory impairments. METHODS: Magnetoencephalography was recorded from 35 FESz and 28 matched controls (HC) during a lateralized change detection task. Impaired alpha desynchronization was previously identified within bilateral dorsal occipital (Occ) regions. Here, whole-brain alpha-band connectivity was examined using phase-locking (PLV) and bilateral Occ as connectivity seeds. Load effects on connectivity were assessed across participants, and PLV modulation within networks was compared between groups. RESULTS: Occ exhibited significant load modulated connectivity with six regions (FDR-corrected). HC exhibited PLV enhancement with load in all connections. FESz failed to show PLV modulation between right Occ and left inferior frontal gyrus, lateral occipito-temporal sulcus, and anterior intermediate parietal sulcus. Smaller PLVs in all three network connections during both memory load conditions were associated with increased reality distortion in FESz (FDR-corrected.) CONCLUSION: Examination of functional connectivity across the visual working memory network in FESz revealed an inability to enhance communication between perceptual and executive networks in response to increasing cognitive demands. Furthermore, the degree of network communication impairment was associated with positive symptoms. These findings provide insights into the nature of brain dysconnectivity and its contribution to symptoms in early psychosis and identify potential targets for future interventions.

Fronto-parietal network function during cued visual search in the first-episode schizophrenia spectrum.

Cognitive impairments account for significant morbidity in schizophrenia and are present at disease onset. Controlled processes are particularly susceptible and may contribute to pervasive selective attention deficits. The present study assessed fronto-parietal attention network (FPAN) functioning during cue presentation on a visual search task in first-episode schizophrenia spectrum patients (FE) and its relation to symptom burden and community functioning. Brain activity was recorded with magnetoencephalography from 38 FE and 38 healthy controls (HC) during blocks of pop-out and serial search target detection. Activity during cue presentation was compared between groups across bilateral FPAN regions (frontal eye fields (FEF), inferior frontal gyrus (IFG), midcingulate cortex (MCC), and intraparietal sulcus (IPS)). FE exhibited greater right hemisphere IFG activity despite worse performance relative to HC. Performance and FPAN activity were not correlated in HC. Among FE, however, stronger activity within right hemisphere FEF and IFG was associated with faster responses. Stronger right IPS and left IFG activity in patients was also associated with reduced negative symptoms and improved community functioning, respectively. Increased reliance on the FPAN for task completion suggests an inefficient cognitive control network and might reflect a compensation for impaired attentional deployment during target detection, a strategy employed by those with less severe illness. These findings represent a critical step towards identifying the neural substrates of negative symptoms and impaired neurocognition at disease onset.

Inefficient visual search strategies in the first-episode schizophrenia spectrum.

BACKGROUND: Knowledge is lacking regarding deficits in selective attention and their underlying biological mechanisms during early stages of schizophrenia. The present study examined the N2pc, a neurophysiological index of covert spatial attention, and its cortical sources at first psychotic episode in the schizophrenia spectrum (FESz). METHODS: Neurophysiological responses measured simultaneously with magnetoencephalography (MEG) and electroencephalography (EEG) during pop-out and serial search tasks were compared between 32 FESz and 32 matched healthy controls (HC). Mean scalp-recorded N2pc was measured from a cluster of posterior-lateral EEG electrodes. Cortical source-resolved MEG activity contributing to the N2pc signal was derived for the intraparietal sulcus (IPS) and lateral occipital complex (LOC). RESULTS: Group differences in EEG N2pc varied by task demand. FESz exhibited reduced N2pc amplitude during pop-out (p < .01), but not serial search (p = .11). Furthermore, group differences in N2pc-related MEG cortical activity varied by task demand and cortical region. Compared to HC, FESz exhibited greater IPS during serial search (p < .01). DISCUSSION: Reductions in EEG N2pc amplitude indicate an impairment of visuo-spatial attention evident at an individual's first psychotic episode, specifically during conditions emphasizing bottom-up processing. Examination of its cortical sources with MEG revealed that, compared to HC, FESz engaged parietal structures to a greater extent during the serial search condition. This pattern suggests a less efficient, more resource intensive strategy employed by FESz in response to a minimal demand on attention. The greater reliance on this controlled attentional network may negatively impact real-world functions with much greater complexity and attentional demands.

Localization of Early-Stage Visual Processing Deficits at Schizophrenia Spectrum Illness Onset Using Magnetoencephalography.

Impairments in early-stage visual processing are observed in chronic psychosis. However, their presence, localization within the brain, and contribution to cognitive symptoms remain less well established early in disease course. The present study utilized magnetoencephalography (MEG) to examine sensory responses within primary visual cortex (V1). MEG was recorded from 38 individuals diagnosed with a schizophrenia spectrum illness at first psychotic episode (FESz) and 38 matched healthy controls (HC) during visual search tasks. The inverse solution for cortical activity contributing to the M100 visual evoked field was derived. Task performance and V1 activation were compared between groups. FESz exhibited a reduced V1 response relative to HC. This group deficit, however, was selective for the left hemisphere (LH). A similar interaction was observed for response time with FESz exhibiting slower responses to right visual field targets, a difference not observed among HC. Among FESz, larger LH V1 activity was associated with larger hallucination subscale scores on the Scale for the Assessment of Positive Symptoms. Early-stage visual processing deficits localized to V1 are present at disease onset in the schizophrenia spectrum. This impairment appears to be restricted to the LH, consistent with previous reports detailing a predominantly LH disease process in early psychosis, and activity within this region was associated with an increased experience of hallucinations. These findings detail the cortical responses contributing to visual processing impairments and their relationship with symptoms at disease onset, advancing our understanding of their developmental trajectory over the course of psychotic illness.

The effects of acute alcohol on psychomotor, set-shifting, and working memory performance in older men and women.

A limited number of publications have documented the effects of acute alcohol administration among older adults. Among these, only a few have investigated sex differences within this population. The current project examined the behavioral effects of acute low- and moderate-dose alcohol on 62 older (ages 55-70) male and female, healthy, light to moderate drinkers. Participants were randomly assigned to one of three dose conditions: placebo (peak breath alcohol concentration [BrAC] of 0 mg/dL), low (peak BrAC of 40 mg/dL), and moderate (peak BrAC of 65 mg/dL). Tasks assessed psychomotor, set-shifting, and working memory performance. Better set-shifting abilities were observed among women, whereas men demonstrated more efficient working memory, regardless of dose. The moderate-dose group did not significantly differ from the placebo group on any task. However, the low-dose group performed better than the moderate-dose group across measures of set shifting and working memory. Relative to the placebo group, the low-dose group exhibited better working memory, specifically for faces. Interestingly, there were no sex by dose interactions. These data suggest that, at least for our study's task demands, low and moderate doses of alcohol do not significantly hinder psychomotor, set-shifting, or working memory performance among older adults. In fact, low-dose alcohol may facilitate certain cognitive abilities. Furthermore, although sex differences in cognitive abilities were observed, these alcohol doses did not differentially affect men and women. Further investigation is necessary to better characterize the effects of sex and alcohol dose on cognition in older adults.

Disruption of sensory gating by moderate alcohol doses.

RATIONALE: Evidence from a growing body of literature suggests that alcohol, even at moderate-dose levels, disrupts the ability to ignore distractors. However, little work has been done to elucidate the neural processes underlying this deficit. OBJECTIVE: The present study was conducted to determine if low-to-moderate alcohol doses affect sensory gating, an electrophysiological phenomenon believed to reflect the pre-attentive filtering of irrelevant sensory information. METHODS: Sixty social drinkers were administered one of three doses intended to produce breath alcohol concentrations of 0.0% (placebo), 0.04% (i.e., low dose), and 0.065% (i.e., moderate dose). A paired-click paradigm consisting of 100 pairs of identical tones (S1 and S2) was used to assess sensory gating. Amplitudes of P50, N100, and P200 auditory evoked potentials (AEPs) were used to calculate gating difference (S1-S2) and ratio (S2/S1) scores. RESULTS: The moderate alcohol dose significantly decreased P50 and N100 gating relative to placebo. Comparisons between the difference and ratio scores helped characterize the gating mechanisms affected at these stages of information processing. Alcohol did not alter P200 sensory gating. CONCLUSIONS: These data suggest that alcohol disrupts pre-attentional sensory-filtering processes at breath alcohol concentrations (BrACs) below the current 0.08% legal limit. Future studies should perform a combined assessment of sensory gating and selective attention to better understand the relationship between these two alcohol-induced deficits.

Interactions between age and moderate alcohol effects on simulated driving performance.

RATIONALE: There is a substantial body of literature documenting the deleterious effects of both alcohol consumption and age on driving performance. There is, however, limited work examining the interaction of age and acute alcohol consumption. OBJECTIVES: The current study was conducted to determine if moderate alcohol doses differentially affect the driving performance of older and younger adults. METHODS: Healthy older (55-70) and younger (25-35) adults were tested during a baseline session and again following consumption of one of three beverages [0.0 % (placebo), 0.04 % or 0.065 % target breath alcohol concentration]. Measures of driving precision and average speed were recorded. RESULTS: Older adults performed more poorly on precision driving measures and drove more slowly than younger adults at baseline. After controlling for baseline performance, interactions between alcohol and age were observed following beverage consumption on two measures of driving precision with older adults exhibiting greater impairment as a result of alcohol consumption. CONCLUSIONS: These data provide evidence that older adults may be more susceptible to the effects of alcohol on certain measures of driving performance. An investigation of mechanisms accounting for alcohol's effects on driving in older and younger adults is required. Further evaluation using more complex driving environments is needed to assess the real-world implication of this interaction.

Differential effects of moderate alcohol consumption on performance among older and younger adults.

BACKGROUND: Studies exploring differential effects of acute alcohol consumption on younger and older adults are lacking within the field of alcohol research, especially those using moderate doses. Previous studies addressing this question have tended to use complex behavioral tasks too broad to isolate specific neurocognitive processes affected by both alcohol and aging. Compromises in cognitive efficiency (i.e., the ability to respond both quickly and accurately) have previously been identified in both elderly and acutely intoxicated individuals. METHODS: The present study employed a visual-spatial, 2-choice reaction time (RT) task to evaluate the interactive effects of aging and alcohol on cognitive efficiency. Our primary outcome measure was an efficiency ratio derived from each participant's response accuracy (ACC) and mean RT (%correct/RT). Younger (25 to 35; n = 22) and older (55 to 74; n = 37) participants were randomly assigned to receive either a placebo or moderate alcohol dose intended to produce a peak breath alcohol concentration of 0.04%. Participants performed the task at peak alcohol levels. RESULTS: A significant interaction between age group and dose assignment was observed, F(3, 55) = 4.86, p = 0.03, for the efficiency ratio. Younger participants who received alcohol performed significantly better than did their older counterparts regardless of alcohol condition and despite no differences in performance between the 2 age groups in the placebo condition. Additional correlation analyses between ACC and RT suggested that moderately intoxicated older adults become more accurate as response times increase. This relationship was not observed in older adults in the placebo condition. CONCLUSIONS: These data suggest that healthy individuals exhibit a differential susceptibility to the effects of alcohol depending on their age. Unfortunately, because of the presumed safety of moderate alcohol doses and a lack of studies investigating the interactive effects of acute alcohol consumption and aging, most individuals are unlikely to be aware of this relationship between alcohol consumption and age.

Comprehensive gene expression profiling and functional analysis of matrix metalloproteinases and TIMPs, and identification of ADAM-10 gene expression, in a corneal model of epithelial resurfacing.

This study provides a comprehensive expression analysis for the entire matrix metalloproteinase (MMP) gene family during the process of epithelial resurfacing following corneal abrasion injury in the mouse. The mRNA levels for all known MMP genes expressed in mouse, the related enzyme ADAM-10, and the known tissue inhibitors of metalloproteinases (TIMPs) were determined semi-quantitatively by reverse transcriptase-polymerase chain reaction (RT-PCR) in the uninjured epithelium, and in the epithelial tissue resurfacing the abraded area or residing in its periphery at two time points: during the epithelial migration phase and immediately following wound closure. The mRNA levels for MMP-1a, -1b, -9, -10, -12, and -13 as well as TIMP-1 were significantly up-regulated in the migrating corneal epithelium. After wound resurfacing, the mRNA levels for all of these MMPs were down-regulated, although MMP-1a, -1b, and -13 remained significantly elevated in comparison to the uninjured epithelium. The only gene found to be down-regulated was TIMP-3, which occurred throughout the wound-healing process. During resurfacing, MMP-9 was localized to the front of the migrating epithelium, MMP-10 and -13 were localized throughout the migrating epithelium, and MMP-13 could also be found in the periphery. Following epithelial closure, immunoreactive MMPs-9 and -10 became undetectable, but MMP-13 continued to be found throughout the epithelium. Functional analysis of MMP-10 revealed no effects on epithelial migration or cell proliferation. In conclusion, distinct MMP temporal-spatial profiles define the uninjured corneal epithelium and the corneal epithelium at different stages of regeneration. An extensive review of the literature is also provided in the discussion.