Sarah M Haigh
I am an Assistant Professor at the University of Nevada, Reno. My main research interests focus on neurological responses to basic sensory stimuli, specifically what drives the system to over-respond (hyper-excitable) or to under-respond (hypo-excitable), and how this impacts sensory-related cognition. I am interested in what this can reveal 1) about early sensory processing in neurotypical individuals, and 2) about the underlying pathophysiology in certain clinical conditions, for example, schizophrenia, autism, migraine or traumatic brain injury. My aim is to establish if methods for improving sensory processing would then have cascading improvements on complex cognitive processing.
Supervisors: Arnold Wilkins, Marlene Behrmann, and Dean Salisbury
Address: Clinical Neurophysiology Research Laboratory,
University of Pittsburgh Medical Center,
Oxford Building, Suite 420,
3501 Forbes Ave,
Pittsburgh, PA 15213, USA.
Supervisors: Arnold Wilkins, Marlene Behrmann, and Dean Salisbury
Address: Clinical Neurophysiology Research Laboratory,
University of Pittsburgh Medical Center,
Oxford Building, Suite 420,
3501 Forbes Ave,
Pittsburgh, PA 15213, USA.
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Background: Individuals with long-term schizophrenia (SZ) show reductions in simple mismatch negativity (MMN) to infrequent stimulus parameter deviance, and in complex MMN to infrequent pattern deviance. First episode schizophrenia-spectrum individuals (FE) show less reduction of simple MMN. Complex pattern deviance may be more suitable for elucidating subtle deficits in auditory perception at first-episode, and may be a useful biomarker for the presence of schizophrenia. Methods: We measured simple MMN to pitch and duration deviants, and complex MMN to an extra fourth tone amongst standard groups of three tones (1 kHz, 50 ms duration, 5 ms rise/fall, 80 dB, 330 ms SOA, 800 ms ITI) in 24 SZ), and 23 matched healthy controls (HCSZ), and in 24 FE (within 6 months of first-episode), and 23 matched healthy controls (HCFE). Results: For simple MMN, SZ showed reductions in pitch (p <.001) and duration (p <.008), and for complex MMN (p=.043). Simple MMN was not significantly reduced in FE (pitch p =.215, duration (p =.705), but complex MMN was (p=.003). Conclusions: Both simple MMN and complex MMN are impaired in long-term schizophrenia, whilst only complex MMN was impaired in FE; simple MMN was not impaired at first break. Thus, complex MMN may be a more sensitive biomarker of the presence of schizophrenia early in disease course. To assess whether complex MMN has greater sensitivity to detect incipient psychosis, both simple MMN and complex MMN will be measured in prodromal individuals.
Complex pattern deviance may be more suitable for elucidating subtle deficits in auditory perception at first-episode compared to single-tones deviance detection, and may be a useful biomarker for presence of schizophrenia. We measured MMN to an extra tone amongst standard groups of three tones (1 kHz, 50 ms duration, 5 ms rise/fall, 80 dB, 330 ms SOA, 800 ms ITI) in 24 individuals at their first-episode of schizophrenia (within 6 months of first-episode; FE), 23 healthy controls matched to the FE group (HCFE), 24 individuals with long-term schizophrenia (minimum 5 years of diagnosis; SZ), and 23 healthy controls matched to the SZ group (HCSZ). For the complex extra tone MMN, all groups produced an early MMN (more sensory-driven; ~140 ms after deviant-onset), but the late MMN (more cognitively driven, ~400 ms after deviant onset) was significantly blunted in SZ (p=.043) and in FE (p=.003) compared to their matched controls. Together, this suggests deficits in top-down deviance-detection in FE, and relatively intact sensory-driven deviance-detection, by contrast with SZ, where sensory and cognitive MMN are impaired. Complex late MMN may be a more powerful biomarker for indicating disease presence. To verify this, the next step will be to measure complex MMN in prodromal individuals.
Previous research has suggested that autism is associated with abnormalities in sensory and attentional processing. Here, we assessed these processes independently in the visual and auditory domains using a visual contrast-discrimination task and an auditory modulation-depth discrimination task. To evaluate changes in sensory function by attention, we measured behavioral performance (discrimination accuracy) when subjects were cued to attend and respond to the same stimulus (frequent valid cue) or cued to attend to one stimulus and respond to the non-cued stimulus (infrequent invalid cue). The stimuli were presented at threshold to ensure equal difficulty across participants and groups. Results from fifteen high-functioning adult individuals with autism and fifteen matched controls revealed no significant differences in visual or auditory discrimination thresholds across groups. Furthermore, attention robustly modulated performance accuracy (performance was better for valid than invalid cues) in both sensory modalities and to an equivalent extent in both groups. In conclusion, when using this well-controlled method, we found no evidence of atypical sensory function or attentional modulation in a group of high functioning individuals with clear autism symptomatology.
Mismatch negativity (MMN) is a negative deflection in response to a deviant stimulus measured in the EEG. The mechanisms driving the MMN are heavily debated: MMN is either echoic sense memory, or is a release from stimulus-specific adaptation. Individuals with chronic schizophrenia (SZ) exhibit reduced MMN responses compared to healthy controls (HC), suggesting that one of these mechanisms is abnormal in schizophrenia. Deviance in complex patterns also elicits and MMN which is not contaminated by stimulus-specific adaptation. We measured MMN to three pattern-deviants in HC and SZ. (1) Deviant trials of six identical tones amongst standard trials of five tones (HC N = 25, SZ N = 15); (2) deviant trials of six tones ascending in pitch repeated twice, amongst standard trials of six tones ascending in pitch followed by six tones descending in pitch (HC N = 24, SZ N = 24); (3) standard trials of eight tones that increased in pitch by 1 kHz then decreased by 0.5 kHz, and deviant trials where the eighth tone was either repeated, or increased in pitch by 1.5 kHz (HC N = 23, SZ N = 23). All three paradigms evoked an MMN in healthy controls that was much later than expected (300-500 ms after deviant-tone onset), whereas individuals with schizophrenia exhibited a blunted MMN. Together this shows that SZ exhibit deficits in novelty detection, and that deviants in complex patterns may be more suitable for detecting subtle deficits in auditory perception. The timing of the MMN may be a function of the complexity of the pattern: the more complex the pattern, the longer it takes for the deviant to be detected.
Individuals with autism produce greater trial-to-trial variability in fMRI responses in sensory cortices compared to neuro-typical controls, despite producing similar fMRI response amplitudes. Here, we aimed to test the specificity of this unreliable sensory-evoked activity in autism compared to another clinical condition, namely schizophrenia. Autism and schizophrenia share similar genetic markers, most of which are associated with neural and glial activity, particularly through development. Therefore, identifying the differences in unreliable sensory-evoked activity between autism and schizophrenia can help understand the underlying pathophysiology associated with each disorder. Participants completed a letter detection one-back task whilst being shown visual (moving white dots), somatosensory (air-puffs to the back of the left hand) and auditory stimuli (pure tone beeps). Compared to age-matched controls and ASD individuals, individuals with schizophrenia produced smaller fMRI response amplitudes, and the amount of trial-to-trial variability lay in between autistics and controls, but was not clearly distinguishable from either. Behavioral responses were indistinguishable across the three groups. The sensory-evoked activity appears to differ between individuals with autism and individuals with schizophrenia: autism is associated with greater trial-to-trial variability, whereas schizophrenia is associated with smaller response amplitudes. These dissociations might help understand the neural mechanisms behind each condition.
Individuals with autism were tested on their perception of tactile roughness over multiple repetitions compared to a non-autistic control group. Participants were asked to rate a series of surfaces on how rough they felt (a total of 12 surfaces) on a scale of 1 (not rough) to 10 (very rough). The surfaces contained 1mm high dots that varied in their inter-spacing interval. Participants used their right index finger to lightly rub the surface. During the study, participants wore headphone playing white noise and an eye mask, to avoid other sensory information indicating roughness.
The autism group were more variable in their ratings compared to controls, but there was no difference in overall roughness judgments, or which surface was judged to be the roughest. This suggests that there is a behavioural correlate of the variability in the cortical response.
Variable sensory input could have neurological and behavioural consequences, which may, in part, contribute to the higher cognitive abnormalities that are characteristic of autism. However, at present it is unclear if the variability in the sensory-evoked response is specific to autism, or if it is also present in other neurological and psychiatric conditions."
Large colour differences are uncommon in the natural environment and are uncomfortable to view. Over five separate studies, we found a linear increase in aversion with larger colour differences in chromatic grating patterns. We investigated the physiological responses to these patterns by 1) looking at how the ocular accommodative system reacts to such images, and 2) looking at the metabolic response in the visual cortex using near infrared spectroscopy. There appears to be no effect of the colour difference on the accommodative response, but there was a significant linear increase in metabolic response. The aversion appears to be cortical in origin.
It has been suggested that disturbance of accommodation could cause the discomfort. We measured the accommodative response to drifting, vibrating and stationary gratings. We found no differences in accommodative response to the gratings, and no difference between migraineurs and controls that could account for the aversion. Therefore the finding is consistent with the assumption that the aversion is due to a cortical response."
Background: Schizophrenia is associated with deficits in language processing, thought to reflect left frontal and temporal cortex abnormalities. Positive symptoms tend to be associated with temporal cortex gray matter loss, and negative symptoms with prefrontal gray matter loss. The degree to which language deficits are due to impaired memory-based categorical perception, and whether such abnormalities are present at first psychotic break are unknown. Methods: We investigated categorical perception of syllables in 19 long-term schizophrenia individuals (Sz; min 5 years illness duration) and 20 matched controls (HCSz), and 21 individuals at their first-episode of schizophrenia (FE; within 2 months) and 19 matched controls (HCFE). Participants were presented with nine artificial syllables varying in 5ms increments of voice-onset time (VOT) along the Ba-Pa continuum. VOT ranged from 0ms (strong Ba) to 40ms (strong Pa). Participants decided whether the syllable was “Ba” or “Pa”. Results: Linear regression tested whether Sz and FE utilized more linear (and less categorical) perception. There were no significant differences in regression coefficients for Sz compared to HCSz (effect size d=0.01), or for FE compared to HCFE (d=0.12). However, FE individuals who showed more linear perception were more symptomatic on PANSS positive symptoms, thought disturbance, and paranoid-belligerence factors (.49 .92). Conclusions: The behavioral data suggest no significant group-level deficits in the categorical perception of syllables in schizophrenia. However, the ability to categorically perceive syllables at first-episode is related to positive symptoms, suggesting subtle deficits in linguistic processing early in disease course, likely related to pathophysiology of left temporal cortex.
Background: The P3 is biphasic, with P3a reflecting automatic orienting and P3b cognitive processing. Reductions in P3b in first episode schizophrenia-spectrum individuals (FE) are present on target detection “oddball” tasks, although P3a reductions are equivocal. P3 can also be “emitted” by an expected but missing stimulus. Surprisingly, the emitted P3 has been little studied in long-term schizophrenia (Sz) and not at all in FE. Methods: Twenty-seven Sz (minimum 5 years diagnosis) were compared to 20 matched controls (HCSz), and 27 FE (within 6 months of their first psychotic episode) were compared to 26 matched controls (HCFE). Participants were presented with standard sets of four identical tones (1kHz, 50ms, 330ms SOA, 750ms ITI). For one in seven sets, the fourth tone was missing. Participants counted the number of tones within each set, with no instruction to detect missing tones. Results: The P3b emitted by missing tones was significantly reduced in both Sz and FE (p=.039 and p=.017, respectively). Conclusions: Sz and FE displayed impaired emitted P3b on a missing tone task. Presumably, HC implicitly developed an expectation for groups of 4 tones, with the P3b emitted when the 4th tone was missing. By contrast, Sz and FE did not. The emitted P3b may be useful to understand cognitive neuropathophysiology early in psychosis. Its reduction in FE suggests it may show promise as a biomarker of schizophrenia presence. Future work will assess its sensitivity to the schizophrenia prodrome prior to conversion to frank psychosis among clinical high risk individuals.
Oxidative stress and neuroinflammation may contribute to decreased neuronal activity in schizophrenia by affecting the high metabolic demand parvalbumin-containing fast-spiking cortical interneurons. We measured the effects of the anti-oxidant and anti-inflammatory Ashwagandha (Withania Somnifera; WSE) on event-related potentials (ERPs). Eleven patients with long-term schizophrenia participated in a pilot double-blind adjunctive medication study: 6 took WSE, 5 placebo. Participants heard pitch (10%) and duration deviants (10%) among standard tones (80%) in a mismatch negativity (MMN) task while watching a silent movie. They also performed two auditory oddball tasks, either counting rare pitch deviants (15%) or ignoring sounds. For the oddball tasks, a 500 ms duration 40 Hz click train was presented between tones. ERPs were measured before administration of WSE or placebo (T1) and 3 months later (T2). Preliminary analyses indicated improvements in duration MMN with WSE (d=1.28) but not with placebo (d=0.27). In the oddball task, the WSE group showed a larger P3 from T1 to T2 (attend d=0.47; ignore d=0.69) compared to placebo (attend d=0.24; ignore d=0.29). Gamma-band steady-state potentials in the WSE group displayed greater attention-related amplitude increase at T2 (d=0.59) than the placebo group (d=0.07). WSE intake appears to recover some of the impaired early sensory/cognitive potentials in schizophrenia, possibly by reversing oxidative stress and neuroinflammation. These pilot data indicate further investigation into such adjunctive target pharmacotherapy is warranted.
Biomarkers are needed to help identify individuals who are likely to develop schizophrenia before their first-episode. Simple mismatch negativity (negative ERP to a deviant stimulus; MMN) to tones that differ in pitch or duration is reduced in individuals with long-term schizophrenia (LTSZ; N=50) compared to their matched controls (LTHC; N=50; pitch p<.001; duration p<.001), but are not consistently reduced in individuals at their first-episode of schizophrenia (FESZ; N=30) compared to their matched controls (FEHC; N=30; pitch p=.124; duration p=.699). Complex pattern deviance may be more suitable for elucidating subtle deficits in auditory perception at first-episode. Therefore, we measured MMN to an extra tone amongst standard groups of three tones in 20 FESZ (within 6 months of first-episode), 20 age-matched healthy controls (FEHC), 20 LTSZ (minimum 5 years of disease), and 17 age-matched controls (LTHC). For the complex extra tone MMN, all groups produced an early MMN (more sensory-driven; ~140 ms after deviant-onset), but the late MMN (more cognitively driven, ~400 ms after deviant onset) was significantly blunted in FESZ (p=.010) and marginally so in LTSZ (p=.070) compared to their matched controls. Together, this suggests deficits in top-down deviance-detection in FESZ, and relatively intact sensory-driven deviance-detection, by contrast with LTSZ, where sensory and cognitive MMN are impaired. Complex late MMN may be a more powerful biomarker for indicating disease presence. To verify this, the next step will be to measure complex MMN in prodromal individuals.
Grouping of auditory percepts is necessary for interpretation of patterns. Long-term schizophrenia patients (Sz) have blunted responses to deviance from an established pattern, such as reduced mismatch negativity (MMN). Sz also show impairments segmenting groups of acoustic stimuli into discrete percepts, indexed by reduced N2 and sustained potential amplitudes in response to auditory patterns. Recent meta-analysis suggests that standard MMN is not much affected at first-episode of schizophrenia, but it is unknown whether acoustic segmentation is intact at early stage of illness. Nineteen FESz (within 6 months of first-episode), 20 age-matched healthy controls (FEHC), 20 Sz (minimum 5 years of disease), and 17 age-matched controls (SzHC) ignored tone groups while watching a silent video. Stimuli comprised 300 groups of three identical tones (1 kHz; 80 dB; 50 ms duration; SOA = 330 ms). Groups were separated by 750 ms ITI. Sustained potentials were measured from data filtered between 0.5-1.5Hz, from 300ms to 900 ms after onset of the first tone. Sustained potentials and N2 to initial and final tones were reduced in both Sz and FESz compared to matched controls (p<0.05), and sustained potentials were correlated with negative symptoms as measured with the PANSS in FESz (r=0.3). Individual item correlations were strongest for emotional withdrawal, poor rapport, and social withdrawal. These results suggest that deficits in auditory pattern segmentation in schizophrenia occur early in the disease course, and may compound deficits in higher-order cognitive functions.
Grouping of auditory percepts is necessary for making sense of the auditory scene. Schizophrenia patients have blunted responses to auditory change, such as reduced mismatch negativity (MMN), which may reflect deficits in forming perceptual groupings. Here we examined event-related potentials in response to groups of tones to measure schizophrenia-related differences in acoustic segmentation. In two separate experiments, we identified a sustained potential in HC that begins with group initiation and ends with the last tone of the group. In experiment 1, ERPs were measured in an auditory pattern in which 6 tones increased in pitch in 500 Hz steps, from 1.5 – 4 kHz. In experiment 2, the first 6 tones increased in pitch in from 1.5 – 4 kHz, and the last 6 tones decreased in pitch (4 – 1.5 kHz). All other stimulus parameters were identical between experiments (50 ms duration; SOA = 330 ms; ITI = 800 ms). Sustained potentials were reduced in schizophrenia patients compared to matched controls. We additionally found that N2 response was greater for initial and final tones in the group for healthy controls, but not schizophrenia patients, and that this correlated with sustained potential amplitude. Importantly, reductions in sustained potentials in schizophrenia patients were associated with greater negative symptoms, and impaired IQ, working memory, learning, and social cognition. These results suggest that deficits in auditory pattern segmentation occurs in schizophrenia early in sensory perception, and may compound deficits in many higher-order facets of the disorder.
Cognitive impairments are a hallmark of schizophrenia. Biomarkers of these impairments may be useful for identifying those at-risk for developing schizophrenia. For example, the P3 ERP to an oddball stimulus is reduced in individuals with schizophrenia. The P3 is biphasic, with the earlier peak (P3a) reflecting automatic orienting and processing and the later peak (P3b) reflecting cognitive and memory processing. Here we examined the “emitted” P3 to absent stimuli on a counting task. Seventeen individuals with long-term schizophrenia (minimum 5 years diagnosis; Sz), 20 individuals within 6 months of their first psychotic episode within the schizophrenia-spectrum (FESz), and 26 healthy controls (HC) were presented with standard sets of four identical tones (1 kHz, 50 ms long, presented 330 ms apart with a 750 ms interval between sets). For one in seven sets, the fourth tone was missing. Participants counted the number of tones within each set. Sz showed reduced emitted P3a and P3b compared to HC (p<.05). FESz showed a healthy P3a (p=.133) but significant reduction in P3b (p=.013) compared to HC. Sz were impaired in both automatic and controlled aspects of deviance detection within the focus of selective attention. By contrast, FESz showed intact automatic but impaired controlled detection of deviance during selective attention to stimuli. The emitted P3 shows promise as a biomarker to (1) help diagnose schizophrenia before first episode by identifying an impaired P3b and (2) to track disease progression of schizophrenia by observing a diminishing P3a with disease course.
Previous studies have identified specific event-related potentials (ERPs) in response to feedback in gambling tasks, including N1, P2, and feedback-related negativity (FRN). Here we compared these ERPs at different levels of risk/reward expectation and outcome uncertainty in healthy participants. Twenty participants (age range = 18-25; 11 female) predicted whether a single-digit number would be greater or less than 5. After a variable interval, one of 4 outcome scenarios was indicated: Win scenarios, where correct choices were awarded $0.10 and incorrect choices broke even; Lose scenarios, where correct choices broke even and incorrect choices lost $0.08; Win/Lose scenarios that awarded $0.10 or lost $0.08, and Neutral scenarios that broke even regardless of guess accuracy. After a variable interval (1.5, 2, or 3s), feedback was presented. We compared ERPs in response to win feedback in Win scenarios vs Win/Loss scenarios and ERPs to loss feedback in Loss scenarios vs Win/Loss scenarios. There were 75 trials for each feedback and scenario pair per subject. Our results indicate significantly larger N1 (t(19)=-4.84; p<0.05) and P2 (t(19)=6.07; p<0.05) when outcomes were more ambiguous (i.e. Win/Lose scenarios). These results demonstrate that the feedback-evoked ERP is sensitive to risk/reward expectation, where greater uncertainty evoked larger ERP amplitudes. This is similar to recent work showing a relationship between N1 and learning from prediction errors, and may be related to greater information content in ambiguous outcome scenarios.
Patients with long-term schizophrenia (Sz) typically have reduced mismatch negativity (MMN) to deviant syllables. It is unclear whether this deficit is present early in the disease course. Twenty-four first psychotic episode schizophrenia-spectrum participants (FESz), 19 SZ, and 37 healthy controls (HC; 19 age-matched to FESz, 18 age-matched to Sz) watched a silent film while passively hearing auditory stimuli through headphones. Subjects were presented with four artificial syllables varying in voice-onset time (VOT) along the Ba-Pa continuum. A standard syllable sounding strongly like a “Ba” (VOT=0ms) comprised 70% of the stimuli and deviant syllables with VOT at either 15ms (weak “Ba”), 25ms (weak “Pa”), or 40ms (strong “Pa”) each comprised 10% of the remaining stimuli. No MMN at FCz was apparent for the 15ms or 25ms VOT syllables in any group. There was a significant reduction in MMN for the 40ms VOT in Sz compared to matched HC (p=.034), but no significant difference between FESz and matched HC (p=.447). These findings suggest that the mechanisms for syllable processing may be intact at first schizophrenic episode, and that MMN amplitude reduction at FCz reflecting the automatic detection of syllable change may not be a useful biomarker of the presence of schizophrenia early in disease course. Currently we are analyzing MMN topography to determine if more subtle deficits may exist at first break.
Mismatch negativity is a negative event-related potential evoked by a deviant stimulus outside the focus of attention. MMN to infrequent pitch deviants amongst repeated standard tones is reduced in long-term schizophrenia (Sz, illness duration over 5 years), but not as robustly, if at all, in the first episode schizophrenia spectrum (FESz). Because more neural processing resources are likely needed for detection of pattern deviants, complex pattern MMN may reveal abnormalities earlier in disease course by taxing a less impaired system. Here, tone pairs were used to measure complex MMN. Twenty-one FESz, 23 Sz, and 37 healthy controls (19 age-matched to FE, HCFE; 18 age-matched to Sz, HCSz) watched a silent movie while ignoring a stream of paired tones (50 ms duration, 200 ms SOA, 1000 ms ITI). The standard tone pair was played 87.5% of the time, with the second tone three semitones higher than the first. The deviant tone pair was played 12.5% of the time, with the second tone three semitones lower than the first. All deviant second tones were also used as standard second tones. Complex tone-pair MMN was significantly reduced in Sz (p=.026), but not in FESz (p=.808). These preliminary results suggest that FESz, unlike Sz, do not show deficits in tone-pair complex MMN. It is unclear if tone-pair complex MMN deficits develop with disease duration. The two-tone pattern is relatively simple; further research with more complex patterns is underway to examine whether complex MMN may detect deviance-related processing abnormalities at first episode.
Large effect size (d ≥1) reductions of mismatch negativity (MMN) amplitude are seen in long term schizophrenia (Sz). However, the effect sizes for MMN reductions at the first psychotic episode within the schizophrenia-spectrum (FESz) are much smaller. Our recent meta-analysis showed no evidence for pitch MMN reduction (d <0.1) and a medium effect size for duration MMN reduction (d ~0.5). To explore factors that might explain the variable findings of MMN reductions in FESz, we recorded MMN from 50 Sz (WASI =104, sd 14) and 50 age-, gender-, and IQ-matched controls (WASI =104, sd 11), and 30 FESz (WASI =113, sd 14) and 30 matched controls (WASI =110, sd 10). Participants watched a silent video while ignoring randomly presented tones (330ms SOA; standards: 1 kHz, 50ms, 80%; pitch-deviants: 1.2 kHz, 50ms, 10%; duration-deviants: 1 kHz, 100ms, 10%). Sz exhibited robust MMN reductions at FCz to pitch (p<.001) and duration (p<.001) deviants. FESz did not show MMN amplitude reductions to pitch (p=.12) or duration (p=.70) deviants. However, within FESz the duration of the prodromal phase was associated with duration MMN (r= -.573, p=.003), such that a more rapid transition to full psychosis was reflected in a more impaired duration MMN within the context of a “within normal limits” group mean MMN. Rapid conversion may reflect greater underlying cortical pathology, and these defective mechanisms appear to be reflected in duration MMN pathophysiology. Differences in prodrome duration may explain some of the discrepant findings in duration MMN in FESz.
Schizophrenia is associated with smaller auditory evoked potentials, reduced detection of auditory novelty (smaller mismatch negativity), and poor click pair sensory-gating (reduced P50 suppression). Here we examined repetition suppression (the reduction of sensory responses with repeated presentations) to repeated tones in 15 individuals with chronic schizophrenia (Sz), 23 individuals at their first psychotic episode within the schizophrenia-spectrum (FESz), and 32 healthy controls (HC, 15 age matched to Sz and 23 age matched to FESz). Participants heard sets of 4 identical tones (1.0 kHz, 80 dB, 50 ms) while watching a silent movie. Tones were separated by 330 ms with an inter-set interval of 750 ms. Deviant sets of 3 identical tones were also presented, but only responses to standard sets are discussed here. For Sz and matched HC, P1, N1 and P2 amplitudes were reduced with repeated presentations (p<0.05) Of primary importance, this repetition suppression did not differ between groups. Similarly, for FESz and matched HC, P1, N1 and P2 amplitudes were reduced with repeated presentations (p<0.05), and repetition suppression was unimpaired in FESz. These data suggest that local inhibition of sensory responses may be intact in schizophrenia, and does not contribute to other deficits in early auditory processing such as MMN deficits.
Oxidative stress and neuroinflammation may contribute to decreased neuronal activity in schizophrenia by affecting the high metabolic demand parvalbumin-containing fast-spiking cortical interneurons. We measured the effects of the anti-oxidant and anti-inflammatory Ashwagandha (Withania Somnifera; WSE) on event-related potentials (ERPs). Eleven patients with long-term schizophrenia participated in a pilot double-blind adjunctive medication study: 6 took WSE, 5 placebo. Participants heard pitch (10%) and duration deviants (10%) among standard tones (80%) in a mismatch negativity (MMN) task while watching a silent movie. They also performed two auditory oddball tasks, either counting rare pitch deviants (15%) or ignoring sounds. For the oddball tasks, a 500 ms duration 40 Hz click train was presented between tones. ERPs were measured before administration of WSE or placebo (T1) and 3 months later (T2). Preliminary analyses indicated improvements in duration MMN with WSE (d=1.28) but not with placebo (d=0.27). In the oddball task, the WSE group showed a larger P3 from T1 to T2 (attend d=0.47; ignore d=0.69) compared to placebo (attend d=0.24; ignore d=0.29). Gamma-band steady-state potentials in the WSE group displayed greater attention-related amplitude increase at T2 (d=0.59) than the placebo group (d=0.07). WSE intake appears to recover some of the impaired early sensory/cognitive potentials in schizophrenia, possibly by reversing oxidative stress and neuroinflammation. These pilot data indicate further investigation into such adjunctive target pharmacotherapy is warranted.
Background: Individuals with schizophrenia (Sz) show deficits in auditory deviance detection. This could be due to poor neural sensitivity to changes in auditory stimuli, or stimulus-independent sensory dysfunction. We measured the effects of multiple repetitions of the same tone on mismatch negativity (MMN). Three differently pitched tones were used to measure MMN as a function of frequency change (Δƒ).
Methods: Twelve healthy controls (HC) and six Sz watched a silent movie while tones were presented. A roving standard paradigm was used, with tones repeated either three or nine times (standard tones) followed by the deviant tone. The deviant tone became standard tones for the next trial, repeated either three or nine times. Tones were C6 (1046.5 Hz), C6# (1108.7 Hz), or D6# (1244.5 Hz), resulting in tones that were either one (C6-C6#), two (C6#-D6#), or three (C6-D6#) semi-tones apart.
Results: For HC, greater Δf produced larger MMN than mid and small Δf when preceded by three standard tones (p<0.01), but MMN amplitudes were statistically similar across all Δf when preceded by nine standard tones. Sz, however, showed a trend effect for Δf only after nine standard tones (p=0.09).
Conclusions: Multiple stimulus repetitions may improve MMN in Sz, as shown by sensitivity to Δf. with nine tones but not three. This suggests that poor deviance detection is (at least partially) affected by poor auditory representation. This could be due to sharpened tuning curves or improved sensory-memory traces. Distinguishing the mechanism has implications for circuit dysfunction underlying auditory deficits in Sz.
Background: Schizophrenia is associated with reduced auditory evoked potentials (AEPs). Reduced mismatch negativity (MMN) along with dampened sensory-gating (reduced P1 suppression) to repeated, paired clicks have also been observed in schizophrenia. Here we examined repetition suppression, a reduced sensory response to repeated stimuli, to a series of identical tones.
Methods: AEPs were recorded from 15 chronic schizophrenic participants (Sz), 15 first episode schizophrenia participants (FESz), and overlapping groups of age-matched controls (HC1, HC2: N’s=15). Participants heard groups of 4 tones played at the same pitch, intensity, and duration (1 kHz, 80 dB, 50 ms, SOA=330 ms, ITI=750 ms). Infrequent deviant groups of 3 tones were also presented, but only responses to the standard groups are discussed here. Tones were presented while participants watched a silent movie. Repetition suppression was assessed by comparing responses to the first vs. second tone using paired t-tests at each time point, separately for each group.
Results: Both HC1 and HC2 showed repetition suppression for P1 (p’s<0.001), N1 (p’s<0.05), and P2 (p’s<0.001). Conversely, SZ and FESz showed repetition suppression for P1 (p’s<0.001) and P2 (p’s<0.001), but not N1 (p’s>0.1).
Conclusions: The reduction of P1 and P2 AEPs to repeated stimuli can be seen in all groups; however, N1 repetition suppression was only seen for healthy controls. These data suggests that the neural underpinnings of N1 repetition suppression may differ from those of P1 and P2 repetition suppression, that repetition suppression deficits in schizophrenia maybe specific to N1, present even early in the disease course.
Background: Working memory is impaired in schizophrenia. Superior parietal lobule (SPL) is implicated in visual working memory maintenance. We measured neurophysiological indices of working memory maintenance in first-episode psychosis participants (FEP) and healthy controls (HC) using concurrent electroencephalography (EEG) and magnetoencephalography (MEG).
Methods: Twelve HC and 19 FEP performed a working memory task. Participants were cued to covertly attend one visual hemifield, then viewed an array of 1 (low-load) or 3 (high-load) colored circles in each hemifield for 200 ms. One second later, another array was presented and participants indicated whether any circles in the attended hemifield had changed color. Sustained posterior contralateral negativity (SPCN) was measured at EEG sensors, and source-level evoked activity was extracted from combined EEG and MEG data for primary visual cortex (V1) and SPL. Scalp and source activity was compared between groups, cerebral hemispheres, and conditions (hemifield/load).
Results: No significant differences in SPCN were detected, although SPCN was greater for high-load than low-load in controls. In V1, a loadXgroup interaction (p=0.04) indicated greater activity for controls than FEP at high-load (p=0.01) but not low-load. In SPL, a hemifieldXhemisphereXgroup interaction (p=0.02) indicated greater response to contralateral than ipsilateral hemifield within the right hemisphere for controls (p=0.01), but not FEP.
Conclusions: These preliminary data suggest FEP were unable to modulate V1 activity by working memory load to the same degree as controls, and did not show lateralized activity in SPL. This cortical pathophysiology early in the disease course may relate to emerging visual working memory deficits.
Background: Mismatch negativity is a negative event-related potential evoked by a deviant stimulus. MMN to a single pitch deviant amongst repeated standard tones is reduced in long-term schizophrenia (Sz, illness duration over 5 years), but not as robustly in the first-hospitalized schizophrenia-spectrum (FHSz) or the first episode schizophrenia spectrum (FESz). Because more neural processing resources are likely recruited for complex pattern deviant detection, it may reveal abnormalities earlier in disease course. Here tone pairs were used as the complex MMN paradigm.
Methods: Fifteen FESz, 18 Sz, and 25 healthy control (HC) participants watched a silent movie while pairs of tones were presented. The standard tone pair was played 87.5% of the time, with the second tone three semitones higher than the first. The deviant tone pair was played 12.5% of the time, with the second tone three semitones lower than the first. All tones were 50 ms. long with 200 ms. SOA, and an inter-pair interval of 1000 ms. All deviant second tones were also used as standard second tones.
Results: HC MMN was nominally larger than in Sz (p=0.09), but did not differ from FESz (p=0.32). FESz MMN was larger than Sz (p=0.03).
Conclusions: These preliminary results suggest that FESz, unlike Sz, do not show deficits in tone pair complex MMN. It is unclear if tone-pair complex MMN deficits develop with disease duration. Further research with more complex patterns is underway to examine whether complex MMN may detect deviance-related processing abnormalities at first schizophrenic episode.
Background: Reduction in mismatch negativity (MMN) to tone pitch and duration deviants is well-documented in long term schizophrenia (Sz), but whether participants with a first episode of schizophrenia (FESz) show MMN reductions to the same degree as Sz remains controversial. We measured MMN to tone pitch deviants and duration deviants in FESz, Sz, and healthy controls (HC).
Methods: Twenty-nine FESz, 51 Sz, and 80 HC watched a silent video while ignoring tones played over headphones. Tones were presented at a 330ms SOA and comprised standard tones (1000Hz, 50ms, 80%), pitch deviant tones (1200Hz, 50ms, 10%), and duration deviant tones (1000Hz, 100ms, 10%). HC were split into two age-, gender-, and verbal IQ-matched groups to separately match FESz and Sz.
Results: Preliminary analysis of MMN at electrode site FCz showed large MMN reductions both in response to pitch (p<0.001) and duration deviants (p=0.001) in Sz compared to matched controls. However, no difference was detected between FESz and HC in response to either pitch (p=0.32) or duration deviants (p=0.95).
Conclusion: Sz show clear deficits in both pitch and duration MMN. By contrast, neither pitch nor duration MMN differed in amplitude in FESz from HC. It is possible existing deficits at first break are ameliorated by acute psychotropic medication, or that MMN deficits track progressive gray matter loss in the disorder, arising only late in the progressive course. Exactly when these deficits arise in the course of schizophrenia remains undetermined.