Neuroscience and Biobehavioral Reviews 101 (2019) 68–77

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Neuroscience and Biobehavioral Reviews

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Review article A review of visual aftereffects in schizophrenia T ⁎ Katharine N. Thakkara,b, , Steven M. Silversteinc, Jan W. Brascampa a Department of Psychology, Michigan State University, East Lansing, MI, United States b Division of Psychiatry and Behavioral Medicine, Michigan State University, East Lansing, MI, United States c Departments of Psychiatry and Ophthalmology, Rutgers University, Piscataway, NJ, United States

ARTICLE INFO ABSTRACT

Keywords: Psychosis—a cardinal symptom of schizophrenia—has been associated with a failure to appropriately create or Schizophrenia use stored regularities about past states of the world to guide the interpretation of incoming information, which Vision leads to abnormal and beliefs. The provides a test bed for investigating the role of prior Aftereffect experience and prediction, as accumulated knowledge of the world informs our current . More spe- Adaptation cifically, the strength of visual aftereffects, illusory percepts that arise after prolonged viewing ofavisualsti- Predictive coding mulus, can serve as a valuable measure of the influence of prior experience on current . Inthis Excitation/inhibition balance Plasticity paper, we review findings from a largely older body of work on visual aftereffects in schizophrenia, attemptto reconcile discrepant findings, highlight the role of antipsychotic medication, consider mechanistic interpreta- tions for behavioral effects, and propose directions for future research.

1. Background system for understanding the role of experience in how individuals perceive and interpret the world and holds a clear translational value in Understanding the computational and neural mechanisms that understanding abnormalities in psychosis. function abnormally in psychosis—a complex constellation of symp- One form of altered neural coding and perception due to prior sen- toms that reflect a separation from reality—has long been a challenge. sory input, in which continuous exposure to a stimulus leads to satura- This understanding is essential, however, to developing effective and tion in the responses of neurons coding the available stimulus features, is targeted pharmacological and psychological treatments for schizo- called adaptation. In the visual domain, there are well-established phrenia—the illness in which psychotic symptoms are most enduring, methods of quantifying the magnitude of sensory adaptation at the severe, and disabling. Implicit or explicit in many mechanistic accounts perceptual level and clear indications as to how these perceptual phe- of schizophrenia is that psychotic symptoms arise due to inappropriate nomena map onto neural sensitivity changes. Namely, the magnitude of creation or use of stored regularities to guide the interpretation of in- adaptation can be quantified by measuring the strength of what are coming information (Gray et al., 1991; Hemsley, 2005; Sterzer et al., known as visual aftereffects: illusory perceptions that follow continuous 2018). The idea here is that perception is sculpted by a combination of presentation of a real visual stimulus. Aftereffects are thought to be due current sensory input, context, and past experience, and that schizo- to extended firing, during the initial stimulus presentation, of neurons phrenia is associated with an abnormality in this integrative, mod- selective to the features of that initial stimulus, leading to inhibition/ ulatory, and inferential process, which leads to abnormal perceptions saturation of the response of those neurons and associated disinhibition and beliefs. of neurons that are selective to complementary features, as part of the The visual system provides a test bed for investigating the role of brain's effort to maintain homeostasis with regards to neuronal firing prior experience and prediction: accumulated knowledge of the world rates (Fig. 1; Bednar, 2012). The perceptual result, the aftereffect, is il- informs our current perception (Barlow, 1990; Clifford et al., 2000; Knil lusory perception of ‘the opposite’ of the initial stimulus (e.g., the com- and Richards, 1996; Rao and Ballard, 1999). Importantly, robust be- plementary color, opposite direction of motion, etc.). For example, stare havioral paradigms have been developed to precisely quantify predic- at the cross at the center of Fig. 2 for about one minute, then stare at a tions in the visual system, and parallel work in non-human primates blank wall. The image of a face you likely perceive while your eyes are provides a basis for interpretation at the level of single neurons. Ac- closed is an example of a negative and arises due to adapta- cordingly, the visual system holds a unique advantage as a model tion to luminance. Analogous aftereffects are found for other features,

⁎ Corresponding author at: 316 Physics Road, Room 110C, East Lansing, MI 48824, United States. E-mail address: [email protected] (K.N. Thakkar). https://doi.org/10.1016/j.neubiorev.2019.03.021 Received 12 November 2018; Received in revised form 13 March 2019; Accepted 24 March 2019 Available online 30 March 2019 0149-7634/ © 2019 Elsevier Ltd. All rights reserved. K.N. Thakkar, et al. Neuroscience and Biobehavioral Reviews 101 (2019) 68–77

global disease mechanisms, may also shed light on the origins of spe- cific aspects of clinical phenomenology. Despite this potential for visual aftereffects to inform current me- chanistic theories of schizophrenia, the bulk of the studies of visual aftereffects in schizophrenia were conducted prior to the 1970s. Our aim here is to revive and critically review this literature, reconcile discrepant findings, highlight the role of antipsychotic medication, consider mechanistic interpretations for behavioral effects, and propose directions for future research.

2. Experimental paradigms

Fig. 1. Schematic depiction of how single neurons implement visual after- Before reviewing findings, we begin by describing the types ofvi- effects, in this case, the tilt aftereffect. The response of a neuron thatresponds sual aftereffects that have been investigated in schizophrenia, which are preferentially to leftward orientations is depicted in the solid line, and the re- depicted in Fig. 3, and the outcome measures that have been reported. sponse to a neuron that responds preferentially to rightward orientations is After that, we summarize how aftereffects are quantified experimen- depicted in the dotted line. Stimulus presentation is depicted on the x-axis. tally, as well as which factors are known to influence these aftereffects Upon presentation of a leftward orientation grating, the neuron with a preferred in healthy individuals. We will also briefly highlight what is known leftward direction begins to respond vigorously, but soon begins to adapt with repeated presentation of this stimulus (i.e. neural firing is attenuated). Upon the about the neuronal bases of these aftereffects. Common to all aftereffect offset of this leftward grating and onset of a blank screen, the neuron returnsto paradigms is an adapter stimulus that the subject views for some period a below-baseline level of firing. The neuron with a rightward orientation pre- of time, typically followed by a test stimulus on which the subject is ference remains at baseline, thus resulting in an increase in firing rate of the instructed to report. The influence of the adapter stimulus on the per- neuron with a rightward orientation preference relative to the neuron with a ception of the test stimulus is the general measure of interest. leftward orientation preference, which gives rise to the perceptual phenomenon of a rightward bias in the perception of stimulus orientation (i.e. aftereffect). 2.1. Negative (Craik, 1940; Kelly and Martinezuriegas, 1993; Adaptation is illustrated using orientation as an example here, but it transpires Virsu and Laurinen, 1977) in an analogous fashion with other stimulus properties. Upon adapting to a visual stimulus with a given color, subjects will report an illusory image that has the same spatial configuration, i.e. outlines, as the original stimulus but in which each location has a color that is complementary to that shown at the corresponding location in the original stimulus (e.g. green becomes red). Grayscale stimuli can also induce negative afterimages (cf. Fig. 2), and in that case each lo- cation in the illusory image has a brightness that is the complement of the corresponding location in the original stimulus (i.e. bright becomes dim and vice versa).

2.2. Tilt aftereffect (Gibson and Radner, 1937; Greenlee and Magnussen, 1987; Wolfe and O’Connell, 1986)

Upon adapting to a grating (or other pattern) that is oriented at a Fig. 2. Negative afterimage. Stare at the crosshair for 30–60 s, then close your particular angle, subjects are presented with a similar grating that has a eyes. The inverse of this image should be visible and is an example of a visual slightly different orientation. The original adaptation period results ina aftereffect. perceptual bias so that the angle of the subsequent grating is perceived as farther removed from that of the original grating than it actually is. from basic ones such as color and orientation to more derived ones such as facial expression and gender. Importantly, primate neurophysiology 2.3. Movement aftereffect (Anstis et al., 1998; Mather et al., 2008; work has provided insights into the specific neuronal populations that Wohlgemuth, 1911) are adapting for various types of aftereffects to occur—indeed, the notion that different aftereffects relate to adaptation in different and specific Upon adapting to movement in a particular direction, subjects are neuronal populations has led to the adaptation paradigms’ moniker of asked to report on the movement direction of a test stimulus. The ‘the psychophysicists’ microelectrode’ (Frisby, 1979). aftereffect consists of the illusory perception that this test stimulus Characterizing abnormalities in the predictions that derive from moves in a direction opposite to that of the adapting stimulus. Studies different types of prior sensory experiences and in their influence on in schizophrenia have, by and large, measured what is known as the current , then, has the potential to provide a nuanced Archimedes spiral motion aftereffect. In this paradigm, the adapting and biologically-informed perspective on prediction abnormalities in stimulus is a spiral rotating in a particular direction. Once the spiral psychosis generally, but also stands to inform etiological con- stops rotating, the now-stationary stimulus appears to rotate in the ceptualizations of the subjective alterations in visual perception re- direction opposite to the adapting stimulus. ported by individuals with schizophrenia more specifically (e.g. Freedman and Chapman, 1973; Silverstein et al., 2017). Experimental 2.4. Figural aftereffect evidence for such perceptual alterations comes from a range of tasks (reviewed in Butler et al., 2008; Chen, 2011; Silverstein, 2016; Skottun This term is used in a number of ways in the psychological litera- and Skoyles, 2007; Yoon et al., 2013), and a role of abnormal prediction ture. In a broader sense, the term covers several different aftereffects, in these alterations has previously been proposed (Silverstein, 2016). including the tilt aftereffect (Day et al., 1959; Wohlgemuth, 1911). In Thus, studying visual aftereffects, along with providing insights into the context of research related to schizophrenia, a series of studies have used this term for an aftereffect that is evident when a set oftwo

69 K.N. Thakkar, et al. Neuroscience and Biobehavioral Reviews 101 (2019) 68–77

Fig. 3. Illustration of aftereffect paradigms. In the top left is a legend to all panels. Each panel shows one paradigm, all involving an adapter stimulus (leftcolumnin each panel) followed by a test stimulus (right columns). Aftereffects constitute altered perception of the test stimulus, so each panel also illustrates subjective perception (bottom rows) in addition to on-screen stimuli (top rows). Aftereffects shown: negative afterimages (A), tilt aftereffect (B), movement aftereffect (C), figural aftereffect (D), and McCollough effect (E). See text for further details. vertical lines, one placed straight above the other, is viewed following and Magnussen, 1987). Another straightforward method involves exposure to an adapting stimulus (Kohler and Wallach, 1944; measuring the duration of the aftereffect rather than its subjective Prysiazniuk and Kelm, 1965). The adapting stimulus consists of a si- magnitude, by asking subjects to indicate when the aftereffect ends milar set of two vertical lines but, in addition to being placed above (Leguire and Blake, 1982; Suzuki and Grabowecky, 2003; van de Grind each other, the two are shifted horizontally: one leftward and the other et al., 2001; Verstraten et al., 1998) and sometimes also when it starts rightward. As a result, the lines in the test stimulus are perceived as (i.e. latency; Suzuki and Grabowecky, 2003). A final, less direct, shifted horizontally in the opposite directions (i.e. rightward and left- method involves physically adjusting the test stimulus itself to coun- ward, respectively). teract the aftereffect that affects perception of the test stimulus, inorder to quantify the amount of physical change required to exactly cancel 2.5. McCollough effect (McCollough, 1965) the aftereffect. For instance, to measure the strength of anupward movement aftereffect such a nulling, or canceling, procedure would The McCollough effect is an aftereffect that is substantially different involve presenting a test stimulus that contains some downward motion from the ones discussed so far. It centers not on adaptation to a parti- rather than being fully stationary, and determining how much down- cular visual feature, but on adaptation to a conjunction of two features. ward motion is required for the test stimulus to appear stationary Typically, the subject adapts to a red-colored grating that has one or- (Blake and Hiris, 1993; Castet et al., 2002). For other aftereffects ana- ientation (e.g. horizontal) as well as a green-colored grating that has an logous procedures have been used (Georgeson and Turner, 1985; Kelly orientation orthogonal to the first grating (e.g. vertical). Then, the and Martinezuriegas, 1993; Thakkar et al., 2018; Wagner, 1971). Each subject is presented with a test image that is one of the gratings (or, in of these methods of measuring aftereffects comes with advantages and the classic demonstration, a patchwork of both) but that has no color. disadvantages that matter in specific cases (Brascamp et al., 2010; The aftereffect consists of the illusory perception that (any part of)a Castet et al., 2002; Pantle, 1998), but the methods qualitatively agree in test stimulus that matches one of the adapters in orientation, has a color the majority of cases. that is complementary to the color of that adapter. Across essentially all aftereffects, one factor that influences after- effect strength is timing: aftereffects get stronger with more prolonged adaptation, and their strength decays over time after the adapter is 3. Experimental measures of aftereffects, and factors that removed (Greenlee and Magnussen, 1987; Harris and Calvert, 1989; influence them van de Grind et al., 2004; Wolfe and O’Connell, 1986). In addition, different kinds of aftereffects are affected by visual stimulation para- Work on healthy individuals has identified several methods for meters such as contrast or retinal location. We will briefly address such quantifying the strength of aftereffects. Some studies simply ask sub- influences below because they play a role in our later discussions re- jects to report whether an aftereffect is present or how strong it is,ty- lated to schizophrenia. Specifically, for any influence of disease status pically by comparing it to some physical reference stimulus that is not, on aftereffect strength we need to consider whether disease-related itself, affected by the aftereffect (Georgeson and Turner, 1985; Greenlee

70 K.N. Thakkar, et al. Neuroscience and Biobehavioral Reviews 101 (2019) 68–77 alterations in the way a stimulus is represented in early visual proces- aftereffect paradigms. The perceptual phenomena that define after- sing (e.g., due to impairments in gain control, contrast sensitivity, effects, however, are likely the result of a more complex interplay be- ability to fixate ones’ , perceptual organization, coherent motion tween many neurons that differ in the degree to which their re- detection) can mediate the strength of aftereffects. One prominent sponsivity is affected during the adaptation period (Grunewald and factor that influences effectively all aftereffects is the spatial corre- Lankheet, 1996; Mather, 1980; Sutherland, 1961; Tolhurst and spondence between the adapter stimulus and the test stimulus. Some Thompson, 1975). For instance, the perception of a contour's orienta- aftereffects have a great deal of such spatial specificity: for negative tion is plausibly rooted in the collective pattern of neural responses afterimages, for example, the afterimage appears at the exact retinal among neurons that are tuned to orientation, i.e. that each responds location where the adapter stimulus was processed before. For other optimally to a given, preferred, orientation and less to different or- aftereffects the degree of spatial specificity is reduced, in that after- ientations. Individual neurons differ in their preferred orientation, and effects are still experienced for test stimuli with a location thatis neurons with different tuning preferences interact through both ex- somewhat displaced from the adapter location (Afraz and Cavanagh, citatory and inhibitory connections (Li, 1998). The tilt aftereffect, then, 2009; Knapen et al., 2009; Wenderoth and Wiese, 2008). Nevertheless, would correspond to an overall imbalance, due to differential sensi- even in those cases aftereffect magnitude is largest at the exact location tivity to the earlier adapter, in response to the test stimulus across this of the test stimulus. population of orientation-tuned neurons. In addition to these general effects of time and spatial location, One relevant implication that emerges from this broad summary of which affect aftereffects of all kinds, there are stimulus factors thatplay the neural basis of aftereffects is that different aftereffects arise from a role for specific kinds of aftereffects. As with the factor of spatial different neural populations, depending on the populations’ selectivity correspondence, these factors typically relate to the degree of neural to visual input. For instance, negative afterimages emerge, to a sub- overlap between the adapter stimulus and the test stimulus. For in- stantial degree, due to adaptation at the level of retinal and subcortical stance, when the movement aftereffect is viewed on a stationary test neurons (Craik, 1940; Li et al., 2017; Zaidi, 2012), whereas tilt after- stimulus, it is strongest after adapting to a slowly moving stimulus; yet effects are likely related to changes among the orientation-tuned neu- for a test stimulus that jitters rapidly (like TV static), faster adapters rons of the primary (Clifford, 2002) and motion after- yield the strongest motion aftereffects (van Boxtel et al., 2006; effects plausibly depend on the responses of movement-tuned neurons Verstraten et al., 1998). To give another example: the tilt aftereffect is in higher visual cortical regions (Huk et al., 2001; Mather, 1980). stronger when the physical orientation of the test stimulus is only slightly different from that of the adapting stimulus (by about 10–20 5. Critical review of findings in schizophrenia degrees) than when the orientation difference is larger (Clifford, 2002; Schwartz et al., 2007). In both these examples, and also with regard to In the following section, we review findings in schizophrenia. location correspondence between adapter and test stimulus, the most Because existing findings do not paint a coherent picture when com- plausible explanation is that aftereffects have their origin in neurons paring across different studies, we also explore clinical and experi- that are tuned, i.e. that respond to only a limited range of stimulus mental factors that may account for variability across studies. Table 1 features. As a result, the degree to which perception of a given test summarizes the mixed existing evidence for altered visual aftereffects in stimulus draws on neurons that have actually been affected during the schizophrenia, with some studies finding evidence for a greater influ- adaptation period depends on the degree of correspondence between ence in patients of the adapter stimulus on perception of the test sti- adapter stimulus and test stimulus in the relevant dimensions. The role mulus, some finding less influence, and some finding no difference. of neural tuning in aftereffects will be discussed in more detail inthe Note that null results should be interpreted with caution as sample sizes next section. are small and studies are likely underpowered. A factor of influence that is not captured by the above descriptions One clear source of variability across studies is the type of after- in terms of neural correspondence, is stimulus contrast—a measure of effect measured. This factor is relevant as different aftereffects involve the difference in brightness between a stimulus’ darkest and brightest adaptation occurring in different neuronal populations. All of the stu- regions. Several studies in healthy populations have investigated the dies finding greater aftereffect strengths and durations in schizophrenia degree to which adapter contrast impacts aftereffect strength. measured the movement and tilt aftereffect. On the other hand, studies Unsurprisingly, negative afterimages (which reflect adaptation to of the figural aftereffect found, by and large, reduced aftereffect darker and brighter regions in an image) become stronger when adapter strength in schizophrenia patients. In addition, the one study of the contrast is increased (Gilroy and Blake, 2005; Kelly and McCollough effect also reported reduced afterimage strength inpa- Martinezuriegas, 1993). For both movement aftereffects and tilt after- tients. It is worth noting here that the validity of what has been referred effects, strength depends on the contrast of both the adapter andthe to as the figural aftereffect in clinical studies is debatable. Morespe- test stimulus. In particular, aftereffect strength increases with in- cifically, the direction of effects in many individuals is in the opposite creasing adapter contrast but decreases with increasing contrast of the direction to what you would expect given neural adaptation, thus test stimulus (Keck et al., 1976; Nishida et al., 1997; Parker, 1972). bringing into question its comparability with other measures of visual These effects, however, may interact with other stimulus parameters, as aftereffects (Day et al., 1967). one study reported the relation between test stimulus contrast and the Another source of variability across studies involves the experi- strength of the tilt aftereffect to reverse as a function of test stimulus mental parameters—namely, duration and visual properties of the test duration (Harris and Calvert, 1989). and adapter stimuli. Few studies have manipulated these parameters within a single experiment; however, differences in parameter values 4. The neural basis of aftereffects may explain discrepancies across studies. Of those studies comparing the duration of movement aftereffects between schizophrenia and In general terms, aftereffects are thought to arise from a netre- healthy controls, two studies reported longer aftereffect durations in duction in responsivity, gradually arising during the adaptation period, schizophrenia (Abraham and McCallum, 1973; Claridge, 1960), five of neurons that respond to the adapting stimulus (Fig. 1). This reduced studies reported null findings (Herrington and Claridge, 1965; Hersen responsivity carries over to the neurons’ response to a subsequent test et al., 1972; Krishnamoorti and Shagass, 1963; Schein, 1960; Tress and stimulus, resulting in the perceptual effect. This type of change in Kugler, 1979), and no studies observed longer durations in controls. neural responsivity over time is commonly observed at the single- With the aforementioned caveat regarding null findings in mind, it is neuron level (Albrecht et al., 1984; Barlow and Hill, 1963; Kohn and nevertheless interesting that those studies reporting greater duration of Movshon, 2003), and there is no doubt that it happens during the movement aftereffect in patients used relatively long adapter

71 ..Takr tal. et Thakkar, K.N. Table 1

Study Aftereffect Measure Groups and sample sizes Medication status Group effect Relationship with other measures

Abraham and McCallum Spiral aftereffect Duration 1) Psychotic inpatients with first-rank (n Not reported SZP > HC SAE duration decreased with improvement in clinical (1973) unknown) status following treatment 2) Psychotic inpatients without first-rank symptoms (n unknown) 3) Healthy controls (n unknown) Barrett and Logue (1974) Spiral aftereffect Occurrence 1) Inpatients with schizophrenia (n = 35) Not reported SZP > brain injury 2) Inpatients with organic brain disease (n = 35) Calvert et al. (1991) Tilt aftereffect Strength 1) SZP (n = 8; tested before and after Medicated SZP > HC Greater tilt aftereffect in SZP before injection than after medication injection) injection 2) HC (n = 8) Claridge (1960) Spiral aftereffect Duration 1) Hysteria inpatients (n = 16) Not reported SZP > HC 2) Dysthymia inpatients (n = 16) Hysteria = HC < Dysthymia 3) Schizophrenia inpatients (n = 16) 4) Healthy controls (n = 16) Day et al. (1967) Tilt aftereffect Strength 1) SZP inpatients (n = 20) Mostly medicated No group difference Figural aftereffect 2) non-SZP inpatients (n = 20) 3) Healthy controls (n = 20) Hersen et al. (1972) Spiral aftereffect Occurrence 1) SZP inpatients (n = 20) Not reported Occurrence: HC > SZP > Brain disease Latency 2) Organic brain disease (n = 20) Latency: HC < SZP and brain disease Duration 3) Healthy controls (n = 20) Duration: no difference Herrington and Claridge Spiral aftereffect Duration 1) First-episode psychosis inpatients Not reported No difference No effect of antipsychotic treatment (1965) (n = 30) 2) Healthy controls (n = 18) Kelm (1962) Figural aftereffect Strength Experiment 1 Not reported SZP < HC

72 1) SZP inpatients (n = 5) 2) HC (n = 5) Experiment 2 1) SZP inpatients (n = 10) 2) Alcoholic inpatients (n = 10) Kelm (1968) Figural aftereffect Strength 1) SZP inpatients (n = 12) Unmedicated for SZP < non-SZP 2) non-SZP inpatients (n = 8) 48 hours Krishnamoorti and Shagass Spiral aftereffect Duration 1) Psychotic inpatients (n = 26) Unmedicated for 7 days No difference (1963) 2) Healthy controls (n = 20) Rokem et al. (2011) Tilt aftereffect Strength 1) Schizophrenia outpatients (n = 16) Mostly medicated No difference 2) HC (n = 20) Schein (1960) Spiral aftereffect Duration 1) Psychotic inpatients (n = 12) Not reported No difference No difference between subjects taking different classes

2) HC (n = 23) of medications Neuroscience andBiobehavioralReviews101(2019)68– Surguladze et al. (2012) McCollough effect Occurrence 1) SZP (n = 50, inpatients and All medicated Frequency: SZP < HC and relatives No relationship to medication dose Latency outpatients) Latency: SZP > REL > HC Longer latency correlated with greater positive 2) First-degree relatives (n = 61) symptoms in SZP and schizotypy scores in relatives 2) 50 HC Thakkar et al. (2018) Negative afterimage Strength 131 HC Unmedicated – Negative afterimage: no relationship with schizotypy Tilt aftereffect Tilt aftereffect: negatively related to schizotypy scores Tress and Kugler (1979) Movement Duration 1) SZP inpatients (n = 11) Not reported No difference aftereffect 2) HC (n = 15) Wertheimer (1954) Figural aftereffect Strength 1) SZP inpatients (n = 15) Not reported SZP < HC 2) HC (n = 15) Wertheimer (1957) Figural aftereffect Strength Experiment 1: Not reported SZP < HC 1) SZP inpatients (n = 15) 2) HC (n = 15) Experiment 2: 1) SZP inpatients (n = 17) 2) HC (n = 17) 77 K.N. Thakkar, et al. Neuroscience and Biobehavioral Reviews 101 (2019) 68–77 durations (1 min), whereas those that reported null results used shorter across those studies that do report medication status. A handful of adapter durations (15–30 s). In this context, it is worth noting that studies have explicitly reported the effects of medication. Consistent aftereffect strength depends not only on stimulus timing (see above), with studies in healthy individuals administered antipsychotic medi- but also that the physiological events that underlie aftereffects may cations, the strength of the tilt aftereffect was greater in patients im- differ depending on the timescale of adaptation (Kanai and Verstraten, mediately prior to a neuroleptic injection (when levels of the medica- 2005; Wolfe and O’Connell, 1986). Indeed, there is some evidence that tion were presumably low) compared to immediately after (Calvert results of aftereffect studies involving schizophrenia patients may et al., 1991). Additionally, duration of the movement aftereffect de- differ, even qualitatively, depending on stimulus timing as well as other creased following a treatment-related decrease in first-rank symptoms parameters. Specifically, in their investigation of the tilt aftereffect in in an inpatient population (Abraham and McCallum, 1973). Although individuals with schizophrenia (before and after antipsychotic injec- the nature of the treatment is not described, there was most likely a tion), Calvert et al. (1991) manipulated the spatial frequency of the pharmacological component. On the other hand, Lloyd and Newbrough adapter stimulus as well as the duration of the test stimulus. For higher (1964) observed no change in duration of the movement aftereffect contrast adapter stimuli, patients before injection had larger tilt after- before and after antipsychotic administration in schizophrenia patients. effects than controls at short test durations; this difference wasnot Notably, these patients only underwent a 10-day wash-out period, and observed at longer test durations and was, in fact, reversed in sign. That previous medication use may have had a lingering effect on aftereffects. is, for lower contrast stimuli, patients prior to injection had a larger tilt However, even in a never-medicated group of first-episode patients that aftereffect only at long test durations. However, these findings should improved following antipsychotic treatment, cessation of drugs 8–15 be interpreted with caution given the very small sample sizes (see weeks later did not influence the duration of the movement aftereffect Table 1). Using the figural aftereffect, Kelm (1962, 1968) also ma- (Herrington and Claridge, 1965). Additionally, studies that have re- nipulated adapter durations and the duration between adapter and test ported correlations between aftereffect measures and normalized stimuli. Predictably, aftereffects diminished in strength with increasing medication dose have found no evidence for a relationship (Rokem duration between adapter and test stimuli; for patients, the direction of et al., 2011; Surguladze et al., 2012). In summary, there is clear and the aftereffect actually reversed at long adapter-test intervals. Group strong evidence from healthy observers that antipsychotic drugs reduce differences in aftereffect strength in these studies are difficult toin- aftereffect strength and duration. Although some patient studies also terpret, however, as they only reported differences in the absolute support such a relationship between antipsychotic use and reduced magnitude of aftereffects. In summary, there is some tantalizing, albeit aftereffects, other studies report no such relationship. Findings from incomplete, evidence that hints at the importance of characterizing the patient studies are trickier to interpret however given the possibility of temporal dynamics of visual aftereffects in schizophrenia, and how they receptor changes due to long-term medication use and the likely con- vary under different perceptual conditions, for understanding the lo- founding effect of improvement in clinical status with medication ad- cation of functional abnormalities within the visual processing hier- ministration. Importantly, because of the direction of the effect of an- archy. tipsychotic drugs in healthy individuals, findings of increased (rather A further source of experimental variability across studies is the than decreased) aftereffect strength and duration in schizophrenia pa- operational measure of aftereffects used, with different studies re- tients cannot plausibly be accounted for by neuroleptics. porting occurrence, strength, duration, and/or latency. It is difficult to Another potential factor leading to variability across studies is ill- disentangle the extent to which variability in conclusions across studies ness stage and clinical status. Unfortunately, many studies do not report is due to differences in outcome measure used as the outcome measure illness stage or clinical status of participants. In his review of movement is often confounded with aftereffect type. For motion aftereffects, only aftereffect duration in schizophrenia, Harris (1994) made inferences the occurrence, latency, and duration of effects have been reported; for about the clinical status of participants based on age and argued that the figural aftereffect, only strength has been reported. This lackof duration of the movement aftereffect was greatest in acutely ill, un- overlap between the measures used to quantify the two types of after- treated schizophrenia patients. These findings are akin to data on effects should be kept in mind when considering the generally opposite contrast sensitivity, with observations of increased contrast sensitivity directions of effect that have been reported when comparing patients in unmedicated, first-episode patients (Kelemen et al., 2013; Kiss et al., and controls in terms of these aftereffects. For instance, it is certainly 2010; Shoshina et al., 2015) and decreased contrast sensitivity in possible that the time course of aftereffects differs in schizophrenia chronic patients, regardless of medication status (Butler et al., 2005; patients, such that duration and strength are differentially affected, but O’Donnell et al., 2006; Skottun and Skoyles, 2007; Slaghuis, 1998). no studies have systematically addressed this. The use of latency and Indeed, Abraham and McCallum (1973) found that duration of the duration measures is also problematic, as it is confounded with general movement aftereffect decreased with improvement in clinical status reaction time, which is known to be slowed in schizophrenia across following treatment. On the other hand, Surguladze et al. (2012) found most response domains (reviewed in Nuechterlein, 1977). that more severe positive symptoms were associated with increased Another factor that certainly merits consideration in explaining al- latency to report the McCollough effect. It is certainly possible that the tered aftereffects in schizophrenia is antipsychotic medication. These influence of clinical status on visual aftereffects is domain- (i.e. motion drugs achieve therapeutic effects by blocking dopamine (Seeman and versus color) and/or measure-specific (i.e. duration versus latency). Lee, 1975; Seeman et al., 1976), but also act on other neurotransmitter Alternatively, longer illusion latency and longer illusion duration may systems. Adaptation at the cellular level is plausibly modulated by these both be caused by response slowing, possibly secondary to distraction, systems (McCormick and Williamson, 1989). Indeed, healthy observers which has been found to be more related to positive than negative administered antipsychotic medications experience a reduction in the symptomatology (Green and Walker, 1986). aftereffect strength related to tilt, motion, and color(Harris et al., 1986; Harris et al., 1983; but see Janke and Debus, 1972; Lehmann and Csank, 6. Mechanisms for altered visual aftereffects in schizophrenia 1957). These findings cannot be accounted for by drug effects on retinal blurring, perceived luminance of the adapter, drowsiness, blinking, or In the following section, we consider possible CNS and non-CNS loss of fixation (Harris et al., 1983, 1986). Studies comparing the effect explanations for altered visual aftereffects in schizophrenia and, fol- of antipsychotics with other psychotropic medications suggest that drug lowing these explanations, we interpret these data in the context of effects on aftereffects are primarily due to dopaminergic action. The recent comprehensive theoretical accounts of the disorder. Arguably, influence of medication in schizophrenia patients is less clear fromthe the most compelling explanation for altered visual aftereffects is that literature. As evidenced in Table 1, many studies do not report medi- patients with schizophrenia differ from healthy controls in the adapt- cation status of patient samples, and there is no clear pattern of findings ability of neuronal populations. The plausible difference, discussed

73 K.N. Thakkar, et al. Neuroscience and Biobehavioral Reviews 101 (2019) 68–77 above, in exact cortical origin of various aftereffects therefore offers the aftereffects in the context of both computational accounts ofvisual potential to distinguish visual processing levels in which adaptation is, aftereffects and unified and biologically plausible theoretical frame- and is not, affected. works for understanding schizophrenia. One such framework holds that Differences in visual aftereffects may also be secondary todiffer- symptoms arise from an imbalance in cortical excitation and inhibition ences in perceived contrast. As noted above, contrast sensitivity is de- (E/I imbalance) due to NMDA receptor hypofunction (Coyle, 2012; creased in chronic schizophrenia patients (Butler et al., 2005; O’Donnell Kantrowitz and Javitt, 2010; Olney et al., 1999) and GABA-ergic dys- et al., 2006; Skottun and Skoyles, 2007; Slaghuis, 1998) and increased function (Egerton et al., 2017; Phillips et al., 2015; Schmidt and in those early in the course of illness (Kelemen et al., 2013; Kiss et al., Mirnics, 2015; Thakkar et al., 2017). In this context it is noteworthy 2010; Shoshina et al., 2015). Given that aftereffect strength typically that a prominent theory of visual aftereffects postulates that they arise increases with increased contrast (see earlier section), it is certainly due to short-term changes in lateral interaction strength between fea- possible that the observed increases in aftereffect strength and duration ture detectors in a process analogous to the Hebbian process by in younger, more acutely ill samples may be explained, at least in part, which feature selectivity develops in sensory cortices across develop- by increases in perceived contrast of the adapter stimulus. ment (Bednar and Miikkulainen, 2000). Thus, alterations in visual Increased visual processing duration or activity may also contribute aftereffects may reflect E/I imbalance and, more specifically, abnormal to findings of increased aftereffect strength and duration in schizo- lateral interactions within visual cortex in schizophrenia. In the early phrenia. For example, visible persistence, which refers to the duration phase of schizophrenia, one possible mechanism for stronger than for which a stimulus is visible following termination, has been found to normal aftereffects is an increase in the rate at which the weightsof be longer in patients with schizophrenia—as much as twice as excitatory connections between inhibitory neurons (Gibson et al., 1999) long—compared to healthy controls (Schwartz et al., 1994). Longer are updated (or between pyramidal cells and interneurons; Thomson visible persistence effectively lengthens the adapter stimulus duration, et al., 2002). The increased inhibition for features present in an which would be expected to increase aftereffect strength. Whether the adapting stimulus would then lead to increases in activity at normally relatively short absolute duration by which visible persistence is inhibited neurons (i.e., especially those that signal features com- lengthened in schizophrenia can account for findings of longer and plementary to those whose processing has been inhibited), as part of the stronger motion and tilt aftereffects is unknown. brain's efforts to maintain homeostasis in firing rates. This hypothesis of Non-CNS explanations for altered visual aftereffects must also be increased connection strength during the acute phase of schizophrenia considered. One such factor is eye movements. As noted above, after- is based on evidence of (a) hyperactivation of the locus coeruleus (LC) effects all display some degree of spatial selectivity, so breaks infixa- in schizophrenia (Alsene and Bakshi, 2011; Yamamoto and Hornykie- tion would be expected to yield weaker aftereffects. Indeed, there isa wicz, 2004) and modeling data indicating that elevated LC firing rate robust literature citing impairments in fixation and gaze control in increases both gain and the rate of Hebbian learning (Verguts and schizophrenia (e.g. Barton et al., 2007; Hutton and Ettinger, 2006; Notebaert, 2009); (b) modeling data demonstrating that when cortical Thakkar et al., 2011, 2015) and fixation losses may explain those stu- activity levels increase, membrane time constants are lowered, causing dies reporting weaker aftereffects in patients. Only one study to date increases in synchronized firing between cells and aberrant local net- (Rokem et al., 2011) used an eye tracker to monitor eye movements and work formation (Chawla et al., 1999); and c) increased baseline syn- exclude trials with large losses of fixation; in this study, there wasno chrony in early schizophrenia (Rivolta et al., 2014; Silverstein et al., difference between patients and controls in the strength of thetilt 2012; Sun et al., 2013), and increased synchrony being associated with aftereffect. Two older studies visually inspected eye position during the presence of hallucinations in people with schizophrenia in general induction of the figural aftereffect. Wertheimer (1954) did not observe (reviewed in Uhlhaas and Singer, 2010). With increasing illness any appreciable deviations from fixation, and Kelm (1968) excluded chronicity, many patients would transition to a state of weakened lat- those subjects with large deviations from fixation. In both of these eral interactions, which we would expect to be associated with weaker studies, a smaller figural aftereffect was still observed. Although that aftereffects, consistent with some of the data reviewed above. This suggests that smaller figural aftereffects cannot be accounted forby change from the acute stage to the chronic stage has been observed in losses of fixation, they do not rule out the possibility of smaller fixa- the domain of contrast sensitivity as described above, as well as in the tional eye movements, that are not easily detected by visual inspection, domain of perceptual organization (Silverstein, 2016; Silverstein and contributing to reduced figural aftereffects in patients. Notably, in- Keane, 2011), and it may account for attenuated contextual modulation creased fixational eye movements certainly cannot account for findings of vision more broadly (Butler et al., 2008; Phillips et al., 2015), as well of increased strength and duration of aftereffects. Furthermore, there is as other aspects of disorganization (Olypher et al., 2006; Phillips et al., no evidence for differences in microsaccade rate in individuals with 2015; Phillips and Silverstein, 2003, 2013) and perception (Butler et al., schizophrenia (unpublished analyses in Demmin et al., 2018; Egana 2008; Phillips et al., 2015; Rokem et al., 2011; Silverstein, 2016; et al., 2013). Nevertheless, considerations related to eye movements Silverstein and Keane, 2011) in chronic schizophrenia. While much could also form a motivation for future work to focus on aftereffects data fit within this overall framework, longitudinal testing of thesame that have a limited degree of spatial selectivity, such as face aftereffects, people across different stages of illness are needed to provide strong and that would therefore not be strongly affected by differences in confirmatory evidence. It would also be helpful, in the short-term, to fixation control, and certainly not by small fixational eye movements obtain, in parallel within the same individuals, putative measures of (Afraz and Cavanagh, 2009). both baseline inhibition strength, for instance as indexed by measures Group differences in response bias and criterion must also becon- of surround suppression (Anderson et al., 2017; Tibber et al., 2013), sidered as possible confounding factors. For instance, there may be and of changes in inhibition strength, as indexed by aftereffects. group differences in the criterion level of visibility of an aftereffect A second prominent candidate explanation of schizophrenia is al- needed to report its offset or onset, or there may be group differences in tered predictive coding. Predictive coding accounts of brain function the cognitive tendency with which subjects report the test stimulus as posit that perception is an inferential process by which higher cortical opposite to the adapter stimulus, particularly as the decision becomes areas generate models of the world based on context and past experi- more difficult. To date, these factors have not been appropriately ence, which are communicated to sensory areas. Mismatches between controlled for. One way to address these possible response-level con- predictions and sensory information (i.e. prediction errors) lead to ei- founds is to use specific variants of the nuller/cancelation method of ther an update in the model or action by the organism to change the measuring aftereffect strength, that render an influence of response bias sensory input to be more consistent with predictions (Clark, 2013; or criterion less likely (Brascamp et al., 2018; Thakkar et al., 2018). Friston, 2005). Formalized within a Bayesian framework, sensory in- On a broader scale, we can interpret findings of altered visual formation (likelihood) is combined with predictions (priors) to compute

74 K.N. Thakkar, et al. Neuroscience and Biobehavioral Reviews 101 (2019) 68–77 the most likely cause of that sensory data (posterior)—which is then relevant stimulus dimensions (i.e. tilt, motion, etc.) and stimulus experienced as the percept. Psychosis is argued to arise due to per- properties (i.e. duration, spatial frequency, etc.). Indeed, there is evi- ceptual experiences being more influenced by the likelihood distribu- dence for stronger motion and tilt aftereffects in schizophrenia but tion (i.e. sensory data) and less influenced by prior beliefs, due either to weaker figural aftereffects, and these findings appear to be moderated reduced reliability, or precision, of priors, increased precision of sen- by adapter and test durations as well as spatial frequency. One im- sory data, or a combination thereof (reviewed in Sterzer et al., 2018; portant direction for future work will be to explore what kinds of but see Powers et al., 2017). Visual adaptation, and by extension visual aftereffects are altered in schizophrenia and to map out the temporal aftereffects, have also been explained in the context of prediction and featural stimulus conditions under which the group differences (Clifford et al., ).2007 In formal Bayesian observer models (Stocker and emerge. In addition, future experimental work should aim to rule out Simoncelli, 2005), exposure to the adapter stimulus results in an in- confounds related to response bias and criterion as well as eye move- crease in the precision of the likelihood function in the range of values ments. To the extent that results can be explained by CNS factors, these around the adapter's parameters. Although aftereffect paradigms do not types of studies can clarify the extent to which altered visual aftereffects typically measure visual discrimination per se, visual adaptation does originate in the , the subcortical visual pathway, V1, and/or regularly result in increased discrimination, depending on the precise higher visual areas involved in integration and visual cognition. This relation between the adapter and test stimulus (Clifford, 2002; Clifford will further shed light on which neuronal populations are involved in et al., 2001; Regan and Beverley, 1985). In this framework, larger altered adaptation and its dynamics in schizophrenia. aftereffects in individuals with schizophrenia can be interpreted as Clinical factors, including duration of psychotic illness, symptom larger increases in the precision of the likelihood function, which would profile, and diagnostic criteria used to define the disorder, are further have the net effect of shifting percepts toward the sensory data, rather sources of variability. Because most of the research on aftereffects was than prior beliefs, as has been posited in schizophrenia (Sterzer et al., done prior to the publication of the DSM-III, it is not clear to what 2018). degree older findings apply to DSM-5-defined schizophrenia. Consistent with the notion that perceptual inference is biased to- Furthermore, aftereffects seem to be stronger in unmedicated in- ward sensory data in psychosis, individuals with schizophrenia have dividuals in the acute phase of the illness, and antipsychotic medica- been found to be less susceptible to those visual illusions that arise due tions reduce adaptation duration and strength in healthy observers. to the influence of higher-level information on current sensory input Thus, a second important direction of future research will be to gather (e.g. Dakin et al., 2005; Keane et al., 2013; Schneider et al., 2002; data using current diagnostic criteria and to account for the effects of Tibber et al., 2013). A notable example here is the hollow mask illusion, medication and illness stage. Future work should also explore the extent in which a concave face is perceived to be convex. This illusion is ar- to which altered visual adaptation, as measured by visual aftereffects, gued to arise due to the powerful influence of top-down knowledge that may explain abnormalities in subjective visual experience as well as faces are convex (Gregory, 1970). This illusion is weaker in individuals psychotic symptoms more broadly. Indeed, prior work has noted a re- with schizophrenia, particularly those that are acutely psychotic (Keane lationship between an altered use of context on visual perception that is et al., 2013; Schneider et al., 2002). However, there is also data sug- strongest in acutely ill patients and is related to disorganization (Keane gestive of a greater influence of history and knowledge on perception et al., 2014; Silverstein et al., 2000, 2013; Uhlhaas et al., 2005, 2006; (Corlett et al., 2019). In the visual system, previous exposure to an un- Uhlhaas and Silverstein, 2005). confers better discrimination of that same image Another potentially fruitful direction for future research is to in- presented later in a degraded (i.e. ambiguous) form, and this advantage vestigate the extent to which altered abnormalities in neuronal adap- is greater in individuals prone to psychosis (Davies et al., 2018; Teufel tation, measured using aftereffects, may reflect illness vulnerability. et al., 2015). These apparently contradictory findings have been re- There are two studies that suggest this to be the case. In healthy un- conciled by highlighting the potentially critical role of where in a dergraduates, weaker tilt aftereffects, but not negative afterimages, sensory hierarchy predictions are formed, noting that weaker priors were related to positive schizotypal traits (Thakkar et al., 2018). In the from within the visual system, in this case, might lead to greater re- only study of visual aftereffects in unaffected relatives of schizophrenia liance on top-down information from outside the visual system to help patients, relatives tended toward increased latency of the McCollough structure the input. Generally, these effects of more or less influence of effect (Surguladze et al., 2012), and longer latencies were associated prior history and context on current processing are cast, in Bayesian with greater positive schizotypal traits in these relatives. terms, as a change in the prior distribution. However, modeling work Finally, experimental data from visual aftereffect paradigms are would suggest that for aftereffects, past history (in this case, exposure to amenable to computational modeling approaches, which can aid in the adapter) exerts an influence on current processing by increasing the dissecting component processes that may be altered in schizophrenia precision of the likelihood function. Such an explanation may also spectrum disorders. Future model-fitting efforts may provide insights warrant consideration for other paradigms and illusions. Finally, it into the extent to which putatively altered visual aftereffects in schi- should be noted that a predictive coding failure for aftereffects would zophrenia are explained by abnormal lateral interactions within visual be consistent with the hypothesis of excessive updating of weights at cortex (Bednar and Miikkulainen, 2000) and/or abnormal Bayesian excitatory connections onto inhibitory cells in schizophrenia (an aspect inference (Stocker and Simoncelli, 2005). of the excitation/inhibition perspective, described above), and so an In conclusion, visual aftereffects may serve as a useful paradigm for integration between the two accounts may be possible. understanding both altered visual experience in schizophrenia and more global dysfunction related to predictive processes and short-term 7. Conclusions and future directions synaptic plasticity. Although there is compelling evidence for altered aftereffects in schizophrenia, future work using more rigorous psycho- In conclusion, there is tantalizing evidence from a largely older physics and comprehensive and current clinical characterization is ne- body of work suggesting an abnormal use of prior experience in cessary to paint a clearer and more complete picture of aftereffects in sculpting perception in schizophrenia in the form of altered visual schizophrenia and to fully realize their potential for understanding the aftereffects. However, there are clear inadequacies in the current lit- disease. erature. We thus intend this paper to function as much a review of the current literature as a motivation for further investigating visual Acknowledgements aftereffects and a call for more rigorous studies. There are clearly sig- nificant sources of variability in these findings that prevent conclusive The authors would like to thank Rachael Slate and Jessica Fattal for interpretation and that are rooted, at least in part, in differences in their help with the literature search and for an anonymous reviewer for

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