Sarah M. Haigh

Cortical Variability in the Sensory-Evoked Response in Autism

Previous findings have shown that individuals with autism spectrum disorder (ASD) evince greater intra-individual variability (IIV) in their sensory-evoked fMRI responses compared to typical control participants. We explore the robustness of this finding with a new sample of high-functioning adults with autism. Participants were presented with visual, somatosensory and auditory stimuli in the scanner whilst they completed a one-back task. While ASD and control participants were statistically indistinguishable with respect to behavioral responses, the new ASD group exhibited greater IIV relative to controls. We also show that the IIV was equivalent across hemispheres and remained stable over the duration of the experiment. This suggests that greater cortical IIV may be a replicable characteristic of sensory systems in autism.

Discomfort and the cortical haemodynamic response to coloured gratings

In five experiments we measured the amplitude of the haemodynamic response to visual patterns using near infrared spectroscopy of the visual cortex. The patterns were gratings with bars that differed in chromaticity but not in luminance. In all experiments, with a wide range of chromaticities of the grating bars, the amplitude of the haemodynamic response increased with the separation of the chromaticities in the CIE 1976 UCS diagram. The amplitude did not vary consistently with the cone activation, or with the signal in colour difference channels. In four further experiments, again with a wide range of chromaticities, the gratings were rated for visual comfort. Discomfort increased consistently with the separation of the chromaticities. Given that a large haemodynamic response to patterns is generally associated with headache, we suggest that the discomfort may be a homeostatic signal to reduce sustained metabolic load on the visual cortex.

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.

Cortical hyperexcitability in migraine and aversion to patterns

Background: Patients with migraine are averse to certain visual stimuli, such as flicker and striped patterns that evoke paroxysmal EEG activity in patients with photosensitive epilepsy. Migraineurs demonstrate a hyper-responsiveness to such stimuli, and there is debate as to whether the aversion and hyper-responsiveness are due to a hyperexcitability of the cortex similar to that in patients with photosensitive epilepsy. In these patients grating patterns with certain spatial characteristics can be epileptogenic, depending critically on their movement. If the contours of the grating drift continually, the grating is not epileptogenic, but if the contours are static or if their direction is repeatedly and rapidly reversed so as to vibrate, the grating then becomes highly epileptogenic. Methods: We compared aversion to vibrating, drifting and static gratings in migraineurs and controls. The contrast of each grating was gradually increased, but only until the participant felt discomfort, so as to obtain a contrast threshold for aversion with minimal exposure. Results: Migraineurs had lower thresholds than the control group, indicating greater aversion. For both groups the threshold was higher (aversion was lower) for static than for both types of moving gratings. The drifting gratings were more aversive than the vibrating gratings when both groups were combined. Conclusion: The findings suggest that the aversion shown by migraineurs is not attributable to a cortical hyperexcitability similar to that in photosensitive epilepsy.

Pitch and Duration Mismatch Negativity and Premorbid Intellect in the First Hospitalized Schizophrenia Spectrum

Mismatch negativity (MMN) is a robustly abnormal brainwave in chronically ill schizophrenia that has generated interest as a disease presence biomarker. Reports of MMN reduction in first-episode schizophrenia have been equivocal, raising uncertainty about its reduction at first psychotic break. Here we tested 29 schizophrenia-spectrum participants under 1 year from their first hospitalization for psychosis and 40 age-, gender-, parental socioeconomic status-, and Wechsler Adult Intelligence Scales III Information-matched healthy controls on both pitch and duration MMN. Participants performed a visual checkerboard tracking task while standard (1kHz, 50ms, 80%), pitch-deviant (1.2kHz, 50ms, 10%) and duration-deviant (1kHz, 100ms, 10%) tones were presented over headphones (75 dB) and EEG was recorded. Independent component analysis was used to remove eye movements and visual stimulus processing activity. Groups did not differ in pitch MMN or duration MMN amplitudes. Smaller pitch and duration MMN amplitudes were associated with lower estimates of premorbid intellect in all participants and independently with greater positive symptoms in first hospitalized schizophrenia. Overall MMN reduction was not present in these relatively high functioning individuals at the first episode of schizophrenia, and therefore is not a good disease presence biomarker for this sample. Future research is warranted to determine the degree of MMN reduction at the first episode of psychosis across a greater range of cognitive impairment, the utility of MMN as an indicator of risk or diagnosis, and its role for understanding pathophysiological mechanisms in emerging psychosis.

Over‐Responsiveness and Greater Variability in Roughness Perception in Autism

Although sensory problems, including tactile hypersensitivity and hyposensitivity (DSM‐5) are commonly associated with autism, there is a dearth of systematic and rigorous research in this domain. Here, we report findings from a psychophysical experiment that explored differences in tactile perception between individuals with autism and typically developing control participants, who, using their index finger, rated a series of surfaces on the extent of their roughness. Each surface was rated multiple times and we calculated both the average rating and the variability across trials. Relative to controls, the individuals with autism perceived the surfaces as rougher overall and exhibited greater variability in their ratings across trials. These findings characterize altered tactile perception in autism and suggest that sensory problems in autism may be the product of overly responsive and variable sensory processing. Autism Res 2016, 9: 393–402.

Cortical excitability and the shape of the haemodynamic response.

Individual differences in the temporal dynamics of the haemodynamic response can reflect cortical excitation and can reveal underlying cortical physiology. Here, we show differences in the shape of the haemodynamic response that are dependent on stimulus parameters. Two sets of visual stimuli were used varying in parameters that are known to manipulate the haemodynamic response in the visual cortex. We measured the oxyhaemoglobin response using near infrared spectroscopy. The first set of stimuli comprised chromatic square-wave gratings that varied with respect to the separation in the CIE UCS chromaticities of the alternating bars. The gratings with large separations in chromaticity evoked an oxyhaemoglobin response with greater amplitude, consistent with greater activation of the visual cortex. The second set of stimuli comprised horizontal achromatic gratings that (1) were static, (2) drifted at a constant velocity towards fixation, or (3) reversed direction every half spatial cycle to create a vertical vibrating motion. Although the three types of grating had a similar effect on the amplitude of the oxyhaemoglobin response, the moving gratings (2 and 3) evoked a steeper decrease in oxyhaemoglobin concentration after stimulus-offset. The steeper slope appears to reflect the post-stimulus undershoot and the slope may provide a correlate of cortical excitability when the amplitude of the haemodynamic response has saturated.

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.

Differential sensory fMRI signatures in autism and schizophrenia: Analysis of amplitude and trial-to-trial variability

Autism and schizophrenia share multiple phenotypic and genotypic markers, and there is ongoing debate regarding the relationship of these two disorders. To examine whether cortical dynamics are similar across these disorders, we directly compared fMRI responses to visual, somatosensory and auditory stimuli in adults with autism (N=15), with schizophrenia (N=15), and matched controls (N=15). All participants completed a one-back letter detection task presented at fixation (to control attention) while task-irrelevant sensory stimulation was delivered to the different modalities. We focused specifically on the response amplitudes and the variability in sensory fMRI responses of the two groups, given the evidence of greater trial-to-trial variability in adults with autism. Both autism and schizophrenia individuals showed weaker signal-to-noise ratios (SNR) in sensory-evoked responses compared to controls (d>0.42), but for different reasons. For the autism group, the fMRI response amplitudes were indistinguishable from controls but were more variable trial-to-trial (d=0.47). For the schizophrenia group, response amplitudes were smaller compared to autism (d=0.44) and control groups (d=0.74), but were not significantly more variable (d<0.29). These differential group profiles suggest (1) that greater trial-to-trial variability in cortical responses may be specific to autism and is not a defining characteristic of schizophrenia, and (2) that blunted response amplitudes may be characteristic of schizophrenia. The relationship between the amplitude and the variability of cortical activity might serve as a specific signature differentiating these neurodevelopmental disorders. Identifying the neural basis of these responses and their relationship to the underlying genetic bases may substantially enlighten the understanding of both disorders.

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.