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

Abstract

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.

Introduction

Autism and schizophrenia share similar phenotypes including impairments in social, cognitive, and sensory behavior (Eack et al., 2013, Sugranyes et al., 2011, King and Lord, 2011, Cheung et al., 2010, Couture et al., 2010). Whereas autism manifests in childhood, the first psychotic break for schizophrenia occurs between late adolescence and young adulthood. The DSM-II included autism under the umbrella of schizophrenia, although later editions separated the two diagnoses (for a review, see Parnas and Bovet, 1991). Despite the segregation, the overlap between the disorders is quite apparent: in one study, half the individuals with autism met the criteria for schizophrenia (Konstantareas and Hewitt, 2001, Ghaziuddin et al., 1992), and in another, the neurocognitive and social-cognitive performance across a large neuropsychological battery was nearly identical between autism and schizophrenia (Eack et al., 2013).

Closer scrutiny of the biology of autism and schizophrenia reveals many similarities, including in genetics (Burbach and van der Zwaag, 2009, Leblond et al., 2012, Peykov et al., 2015, Sebat et al., 2007, Malhotra et al., 2011, Sullivan et al., 2012). One review investigating ‘at risk’ genotypes in autism and schizophrenia, Crespi et al. (2010) found that the two conditions may be genetically diametric or dose-dependent: certain CNV replications in autism were deleted in schizophrenia and vice versa. There are also similarities in brain function. Relative to controls, individuals with either disorder showed under-activation in prefrontal cortex (autism: Baron-Cohen et al., 1999, Happé et al., 1996; schizophrenia: Callicott et al., 2000, Russell et al., 2000, Schneider et al., 1998) and in fusiform gyrus (autism: Hall et al., 2003, Pierce et al., 2001, Schultz et al., 2000; schizophrenia: Quintana et al., 2003, Streit et al., 2001).

Despite abnormal sensory behavior being a key commonality, there are differential cortical dynamics of sensory responses. The majority of sensory fMRI studies in schizophrenia have reported weaker activation (i.e. weaker signal-to-noise ratios, SNR) in sensory cortices (Silverstein et al., 2009, Gaebler et al., 2015, Kircher et al., 2004, Woodruff et al., 1997). Autism individuals show either greater (Green et al., 2015, Kaiser et al., 2015, Takarae et al., 2014, Green et al., 2013) or weaker fMRI activation compared to healthy controls (Dinstein et al., 2012, Haigh et al., 2014, Cascio et al., 2012). Very few studies have compared the two groups directly under identical conditions. Doing so is critical to reach definitive conclusions about transdiagnostic similarities between the groups.

We have shown perturbations in neural processing in autism in response to sensory stimuli (Dinstein et al., 2012, Haigh et al., 2014). Relative to matched controls, autism individuals evinced greater trial-to-trial variability in fMRI responses, despite responses being indistinguishable in amplitude, resulting in weaker SNRs. Greater variability has been reported in the amplitude and latency of P1 ERP responses to visual stimuli (Milne, 2011). There are similar reports in schizophrenia (Jordanov et al., 2011, Müller et al., 1986), which could potentially contribute to smaller average responses (Iyer et al., 2011). Greater trial-to-trial variability may be the result of an imbalance between neural excitation and inhibition, which is associated with autism (Jamain et al., 2002, Markram et al., 2007, Vattikuti and Chow, 2010, Rubenstein and Merzenich, 2003, Sigurdsson, 2015, Uhlhaas, 2013, Lisman, 2012), and with schizophrenia (Baron-Cohen et al., 2009, Gomot et al., 2002, Simmons et al., 2009). One hypothesis is that there is excess excitation due to either increased glutamatergic activity, or reduced GABAergic signaling. The neural variability may be correlated across time and clusters of neurons, thereby affecting the fMRI signal. Variability in sensory responses could impact more complex information processing: if the individual is unable to gain reliable information about their surroundings, then this might make complex environments like social situations confusing and potentially over-whelming, leading to social withdrawal (Dinstein et al., 2015).

Greater trial-to-trial variability offers a potential signature of the cortical response in autism and the key question is whether greater variability in sensory-evoked activity is specific to autism, or is apparent in schizophrenia as well. If the latter, this would offer a transdiagnostic endophenotype related to the sensory abnormalities seen in autism and schizophrenia, and may relate to their shared genetic markers. Differences in response variability across the two groups would alternatively indicate that the overt manifestation of the underlying neurobiology may differ or be differentially modulated by environmental or other genetic factors.