Order effects in task-free learning: Tuning to information-carrying sound features.

Event-related potentials (ERPs) acquired during task-free passive listening can be used to study how sensitivity to common pattern repetitions and rare deviations changes over time. These changes are purported to represent the formation and accumulation of precision in internal models that anticipate future states based on probabilistic and/or statistical learning. This study features an unexpected finding; a strong order-dependence in the speed with which deviant responses are elicited that anchors to first learning. Participants heard four repetitions of a sequence in which an equal number of short (30 msec) and long (60 msec) pure tones were arranged into four blocks in which one was common (the standard, p = .875) and the other rare (the deviant, p = .125) with probabilities alternating across blocks. Some participants always heard the sequences commencing with the 30 msec deviant block, and others always with the 60 msec deviant block first. A deviance-detection component known as mismatch negativity (MMN) was extracted from responses and the point in time at which MMN reached maximum amplitude was used as the dependent variable. The results show that if participants heard sequences commencing with the 60 msec deviant block first, the MMN to the 60 msec and 30 msec deviant peaked at an equivalent latency. However, if participants heard sequences commencing with the 30 msec deviant first, the MMN peaked earlier to the 60 msec deviant. Furthermore, while the 30 msec MMN latency did not differ as a function of sequence composition, the 60 msec MMN latency did and was earlier when the sequences began with a 30 msec deviant first. By examining MMN latency effects as a function of age and hearing level it was apparent that the differentiation in 30 msec and 60 msec MMN latency expands with older age and raised hearing threshold due to prolongation of the time taken for the 30 msec MMN to peak. The observations are discussed with reference to how the initial sound composition may tune the auditory system to be more sensitive to different cues (i.e., offset responses vs perceived loudness). The order-effect demonstrates a remarkably powerful anchoring to first learning that might reflect initial tuning to the most valuable discriminating feature within a given listening environment, an effect that defies explanation based on statistical information alone.

The impact of spatial variance on precision estimates in an auditory oddball paradigm.

Predictive processing theories suggest that a principal function of the brain is to reduce the surprise of incoming sensory information by creating accurate and precise models of the environment. These models are commonly explored by looking at the prediction errors elicited when experience departs from predictions. One such prediction error is the mismatch negativity (MMN). Using this component, it is possible to examine the effect of external noise on the precision of the developed model. Recent studies have shown that the brain may not update its model every time there is a change in the environment, rather it will only update it when doing so will increase precision and or accuracy of the model. The current study examined this process using oddball sound sequences with high and low spatial variability and examining how this affected the elicited MMN to a duration deviant sound. The results showed a strong null effect of spatial variance both at a local and sequence levels. These results indicate that variability in the sound sequence will not invariably affect model precision estimates and thus the amplitude of the MMN component.

The effect of schizophrenia risk factors on mismatch responses in a rat model.

Reduced mismatch negativity (MMN), a robust finding in schizophrenia, has prompted interest in MMN as a preclinical biomarker of schizophrenia. The rat brain can generate human-like mismatch responses (MMRs) which therefore enables the exploration of the neurobiology of reduced MMRs. Given epidemiological evidence that two developmental factors, maternal infection and adolescent cannabis use, increase the risk of schizophrenia, we determined the effect of these two developmental risk factors on rat MMR amplitude in different auditory contexts. MMRs were assessed in awake adult male and female Wistar rats that were offspring of pregnant dams treated with either a viral infection mimetic (poly I:C) inducing maternal immune activation (MIA) or saline control. In adolescence, subgroups of the prenatal treatment groups were exposed to either a synthetic cannabinoid (adolescent cannabinoid exposure: ACE) or vehicle. The context under which MMRs were obtained was manipulated by employing two different oddball paradigms, one that manipulated the physical difference between rare and common auditory stimuli, and another that manipulated the probability of the rare stimulus. The design of the multiple stimulus sequences across the two paradigms also allowed an investigation of context on MMRs to two identical stimulus sequences. Male offspring exposed to each of the risk factors for schizophrenia (MIA, ACE or both) showed a reduction in MMR, which was evident only in the probability paradigm, with no effects seen in the physical difference. Our findings highlight the importance of contextual factors induced by paradigm manipulations and sex for modeling schizophrenia-like MMN impairments in rats.

Modeling Distraction: How Stimulus-driven Attention Capture Influences Goal-directed Behavior.

The importance of paying attention to a task at hand is emphasized from an early age and extends throughout life. The costs of attentional focus, however, include the potential to miss important changes in the environment, so some process for monitoring nontask information is essential. In this study, a model of latent cognitive variables was applied to data obtained from a two-alternative forced-choice task where participants identified the longer of two sounds. Using an adaptive procedure task, accuracy was maintained at a higher or lower level creating two difficulties, and the sounds were heard either where frequency changes in the sound were rare or common (oddball and multistandard conditions, respectively). Frequency changes created stimulus-driven "distraction" effects in the oddball sequence only, and cognitive modeling (using the linear ballistic accumulator) attributed these effects to slowed accumulation of evidence about tone length on these trials. Concurrent recording of auditory ERPs revealed these delays in evidence accumulation to be related to the amplitude of N2 or mismatch negativity period and P300 response components. In contrast, the response time on trials after a rare frequency change was associated with increased caution in decision-making. Results support the utility of mapping behavioral and ERP measures of performance to latent cognitive processes that contribute to performance and are consistent with a momentary diversion of resources to evaluate the deviant sound feature and remodel predictions about sound.

Primacy biases endure the addition of frequency variability.

The primacy bias (PB) is a phenomenon that indicates the brain does not always process sensory information as an 'ideal Bayesian observer', but rather is disproportionately influenced by first impressions. This study was designed to establish whether a PB observed in auditory event-related potentials (ERPs) to a sequence of sound remained evident in the presence of increased levels of tone frequency variation. Two groups of participants were presented with a novel oddball paradigm, while simultaneously having cortical activity recorded with an EEG. In the control group, participants heard a two-tone sequence where the probability of the two tones of different duration switched after 480 sounds/2.4 min block, so that the tone initially encountered as rare became common and vice versa. The key manipulation introduced in the test group was a change of frequency in each block, removing a key element of regularity. The additional frequency variation resulted in no significant difference in the PB between the groups. The data suggest powerful first learning effects are not disrupted by frequency changes, indicating the robustness of learning heuristics.

Reduced Primacy Bias in Autism during Early Sensory Processing.

Recent theories of autism propose that a core deficit in autism would be a less context-sensitive weighting of prediction errors. There is also first support for this hypothesis on an early sensory level. However, an open question is whether this decreased context sensitivity is caused by faster updating of one's model of the world (i.e., higher weighting of new information), proposed by predictive coding theories, or slower model updating. Here, we differentiated between these two hypotheses by investigating how first impressions shape the mismatch negativity (MMN), reflecting early sensory prediction error processing. An autism and matched control group of human adults (both n = 27, 8 female) were compared on the multi-timescale MMN paradigm, in which tones were presented that were either standard (frequently occurring) or deviant (rare), and these roles reversed every block. A well-replicated observation is that the initial model (i.e., the standard and deviant sound in the first block) influences MMN amplitudes in later blocks. If autism is characterized by faster model updating, and thus a smaller primacy bias, we hypothesized (and demonstrate using a simple reinforcement learning model) that their MMN amplitudes should be less influenced by the initial context. In line with this hypothesis, we found that MMN responses in the autism group did not differ between the initial deviant and initial standard sounds as they did in the control group. These findings are consistent with the idea that autism is characterized by faster model updating during early sensory processing, as proposed by predictive coding accounts of autism.SIGNIFICANCE STATEMENT Recent theories of autism propose that a core deficit in autism is that they are faster to update their models of the world based on new sensory information. Here, we tested this hypothesis by investigating how first impressions shape brain responses during early sensory processing, and hypothesized that individuals with autism would be less influenced by these first impressions. In line with earlier studies, our results show that early sensory processing was influenced by first impressions in a control group. However, this was not the case in an autism group. This suggests that individuals with autism are faster to abandon their initial model, and is consistent with the proposal that they are faster to update their models of the world.

Hierarchical Learning of Statistical Regularities over Multiple Timescales of Sound Sequence Processing: A Dynamic Causal Modeling Study.

Our understanding of the sensory environment is contextualized on the basis of prior experience. Measurement of auditory ERPs provides insight into automatic processes that contextualize the relevance of sound as a function of how sequences change over time. However, task-independent exposure to sound has revealed that strong first impressions exert a lasting impact on how the relevance of sound is contextualized. Dynamic causal modeling was applied to auditory ERPs collected during presentation of alternating pattern sequences. A local regularity (a rare p = .125 vs. common p = .875 sound) alternated to create a longer timescale regularity (sound probabilities alternated regularly creating a predictable block length), and the longer timescale regularity changed halfway through the sequence (the regular block length became shorter or longer). Predictions should be revised for local patterns when blocks alternated and for longer patterning when the block length changed. Dynamic causal modeling revealed an overall higher precision for the error signal to the rare sound in the first block type, consistent with the first impression. The connectivity changes in response to errors within the underlying neural network were also different for the two blocks with significantly more revision of predictions in the arrangement that violated the first impression. Furthermore, the effects of block length change suggested errors within the first block type exerted more influence on the updating of longer timescale predictions. These observations support the hypothesis that automatic sequential learning creates a high-precision context (first impression) that impacts learning rates and updates to those learning rates when predictions arising from that context are violated. The results further evidence automatic pattern learning over multiple timescales simultaneously, even during task-independent passive exposure to sound.

The influence of variability on mismatch negativity amplitude.

Mismatch Negativity (MMN) to pattern deviations reveals exquisite pattern detection ability in the brain. MMN amplitude is proposed to be precision-weighted, being inversely proportional to variability within a patterned sound sequence. Two experiments were conducted to determine whether pattern variability, shown to influence MMN to simple pattern deviance, also extends to MMN elicited to abstract pattern deviants. Participants were presented with 3-tone triplet sequences that were defined by regular frequency ascendance with adjacent (A C deviants for adjacent and non-adjacent dependencies, was smaller for the latter, was impervious to variance in tone loudness, but showed prolonged sensitivity to the level of variability at sequence onset.

Do rat auditory event related potentials exhibit human mismatch negativity attributes related to predictive coding?

Rodent models play a significant role in understanding disease mechanisms and the screening of new treatments. With regard to psychiatric disorders such as schizophrenia, however, it is difficult to replicate the human symptoms in rodents because these symptoms are often either 'uniquely human' or are only conveyed via self-report. There is a growing interest in rodent mismatch responses (MMRs) as a translatable 'biomarker' for disorders such as schizophrenia. In this review, we will summarize the attributes of human MMN, and discuss the scope of exploring the attributes of human MMN in rodents. Here, we examine how reliably MMRs that are measured in rats mimic human attributes, and present original data examining whether manipulations of stimulus conditions known to modulate human MMN, do the same for rat MMRs. Using surgically-implanted epidural electroencephalographic electrodes and wireless telemetry in freely-moving rats, we observed human-like modulations of MMRs, namely that larger MMRs were elicited to unexpected (deviant) stimuli that a) had a larger change in pitch compared to the expected (standard) stimulus, b) were less frequently presented (lower probability), and c) had no jitter (stable stimulus onset asynchrony) compared to high jitter. Overall, these findings contribute to the mounting evidence for rat MMRs as a good analogue of human MMN, bolstering the development of a novel approach in future to validate the preclinical models based on a translatable biomarker, MMN.

Context is everything: How context shapes modulations of responses to unattended sound.

The concept of perceptual inferences taking place over multiple timescales simultaneously raises questions about how the brain can balance the demands of remaining sensitive to local rarity while utilising more global longer-term predictability to modulate cortical responses. In the present study auditory evoked potentials to four presentations of the same sound sequence containing predictable structure on a local (milliseconds to seconds) and more global (many minutes) timescales were recorded. The results from 33 participants are used to demonstrate that predictions about both local (internal predictive models) and global (meta-models that define expected precisions associated with familiar internal model states) regularities are formed. The study exposes more local context-based modulations of the P1 but more global order-based modulations of the auditory evoked N2 components. The results are discussed in terms of theoretical links advocating that uncertainty at multiple timescales could lead to differential component modulations, and the importance of considering the broader learning context in auditory evoked potential studies.

The importance of precision to updating models of the sensory environment.

The existence and updating of "sensory beliefs" or internal models can be studied using auditory evoked potentials (AEPs) when there is some form of predictable pattern in sound. Internal models are proposed to enable predictions about the most likely next sound-activation-state leading to small AEPs to standard sounds matching model predictions, and larger AEPs to sound that deviate. Internal models are precision-weighted with the standard-deviant difference being largest when precision is high (variability is low). Here we expose how order-effects determine whether a change in variability impacts model-precision estimates. Thirty participants heard 3000 t (30 ms standard p = 0.90 and 60 ms deviant p = 0.10) that either moved from a more precise stimulus onset asymmetry (n = 15, first 1000 tones 500 ms ± 10 ms) to a more variable one (n = 15, subsequent 2000 tones 500 ms ± 200 ms) or from variable (first 1000 t) to more precise (subsequent 2000 t). AEPs were equivalent between groups for the first 1000 tones but differed dramatically in the face of timing changes. Where timing precision decreased, the standard-deviant difference was impervious to the change but where precision increased, the standard-deviant difference increased dramatically after the timing change signalling a transient increase in model precision that subsided over the final 1000 tones. The results support contemporary models proposing that updates to an active internal model will be a function of the quality of the evidence upon which it has been built and the information value of subsequent errors in improving the predictive success of the active model.

Hierarchical timescales of statistical learning revealed by mismatch negativity to auditory pattern deviations.

The amplitude of mismatch negativity (MMN) elicited following an unexpected sound reflects a pattern-violation signal that will increase with estimated precision. Precision is inversely related to environmental variance, and should be higher the longer that current regularities have been stable. However, MMN amplitude can be impacted by initial learning such that the relative probability of sounds when first encountered distorts the precision estimates later associated with those sounds. The present study tested the hypothesis that MMN to a pattern violation would be differentially sensitive to both local and global patterning within a sequence, depending on whether the sound was common or rare at sequence onset. Sound sequences consisted of two levels of nested regularity: (1) two tones alternated probabilities as the local standard (p = .875) and deviant (p = .125), and (2) these alternations occurred regularly across four blocks of 2.4 min (stable components) or twelve blocks of 0.8 min (unstable components). Sequences were delivered first in an unstable-stable ("increasing-stability") and next a stable-unstable ("decreasing-stability") structure, both inducing a violation to the regular block length at the transition between components. MMN to the tone initially heard as a common repeating standard when later heard as a deviant was not affected by stability of either local (tone probabilities) or global (block length) patterns, reaching equivalent amplitude in all components. In contrast, MMN amplitude to the tone initially heard as deviant was significantly impacted by both local and global pattern stability. MMN amplitude was larger in stable than unstable blocks only if they were heard first (decreasing-stability sequence), and was significantly smaller in both stable and unstable block types after a violation of regular block length. Results are interpreted as local MMN amplitude being "weighted down" by decreased precision in the global structure, but only for the first deviant encountered.

The cognitive resource and foreknowledge dependence of auditory perceptual inference.

Auditory perceptual inference engages learning of complex statistical information about the environment. Inferences assist us to simplify perception highlighting what can be predicted on the basis of prior learning (through the formation of internal "prediction" models) and what might be new, potentially necessitating an investment of resources to remodel predictions. In the present study, we tested the hypothesis that sound sequences with multiple levels of predictability may rely on cognitive resources and be cognitively penetrable to a greater extent than was previously shown by studies presenting simpler sound sequences. Auditory-evoked potentials (AEPs) were recorded from 117 participants. All participants heard the exact same sound sequence but under different conditions: 51 while watching a DVD movie and 66 while performing a cognitively demanding task. Participants were asked to ignore the sounds and focus their attention on the movie/task. However, prior to commencing the experiment we manipulated what participants knew about the sound sequence by providing explicit sequence information to 15 and 34 of the participants in the DVD and cognitive-task conditions, respectively, and no information to the others. The results demonstrated that although local pattern violations elicited distinctive AEP responses (namely, mismatch negativity), the way the amplitude of this response was modulated by sequence learning over time was dependent upon both task and explicit sequence knowledge. The implications are discussed with reference to how the division of available attention resources between the primary task and concurrent sound impacts what is learned.

Initial Uncertainty Impacts Statistical Learning in Sound Sequence Processing.

This paper features two studies confirming a lasting impact of first learning on how subsequent experience is weighted in early relevance-filtering processes. In both studies participants were exposed to sequences of sound that contained a regular pattern on two different timescales. Regular patterning in sound is readily detected by the auditory system and used to form "prediction models" that define the most likely properties of sound to be encountered in a given context. The presence and strength of these prediction models is inferred from changes in automatically elicited components of auditory evoked potentials. Both studies employed sound sequences that contained both a local and longer-term pattern. The local pattern was defined by a regular repeating pure tone occasionally interrupted by a rare deviating tone (p=0.125) that was physically different (a 30msvs. 60ms duration difference in one condition and a 1000Hz vs. 1500Hz frequency difference in the other). The longer-term pattern was defined by the rate at which the two tones alternated probabilities (i.e., the tone that was first rare became common and the tone that was first common became rare). There was no task related to the tones and participants were asked to ignore them while focussing attention on a movie with subtitles. Auditory-evoked potentials revealed long lasting modulatory influences based on whether the tone was initially encountered as rare and unpredictable or common and predictable. The results are interpreted as evidence that probability (or indeed predictability) assigns a differential information-value to the two tones that in turn affects the extent to which prediction models are updated and imposed. These effects are exposed for both common and rare occurrences of the tones. The studies contribute to a body of work that reveals that probabilistic information is not faithfully represented in these early evoked potentials and instead exposes that predictability (or conversely uncertainty) may trigger value-based learning modulations even in task-irrelevant incidental learning.

Time as context: The influence of hierarchical patterning on sensory inference.

Time, or more specifically temporal structure, is a critical variable in understanding how the auditory system uses acoustic patterns to predict input, and to filter events based on their relevance. A key index of this filtering process is the auditory evoked potential component known as mismatch negativity or MMN. In this paper we review findings of smaller MMN in schizophrenia through the lens of time as an influential contextual variable. More specifically, we review studies that show how MMN to a locally rare pattern-deviation is modulated by the longer-term context in which it occurs. Empirical data is presented from a non-clinical sample confirming that the absence of a stable higher-order structure to sound sequences alters the way MMN amplitude changes over time. This result is discussed in relation to how hierarchical pattern learning might enrich our understanding of how and why MMN amplitude modulation is disrupted in schizophrenia.

First-impression bias effects on mismatch negativity to auditory spatial deviants.

Internal models of regularities in the world serve to facilitate perception as redundant input can be predicted and neural resources conserved for that which is new or unexpected. In the auditory system, this is reflected in an evoked potential component known as mismatch negativity (MMN). MMN is elicited by the violation of an established regularity to signal the inaccuracy of the current model and direct resources to the unexpected event. Prevailing accounts suggest that MMN amplitude will increase with stability in regularity; however, observations of first-impression bias contradict stability effects. If tones rotate probabilities as a rare deviant (p = .125) and common standard (p = .875), MMN elicited to the initial deviant tone reaches maximal amplitude faster than MMN to the first standard when later encountered as deviant-a differential pattern that persists throughout rotations. Sensory inference is therefore biased by longer-term contextual information beyond local probability statistics. Using the same multicontext sequence structure, we examined whether this bias generalizes to MMN elicited by spatial sound cues using monaural sounds (n = 19, right first deviant and n = 22, left first deviant) and binaural sounds (n = 19, right first deviant). The characteristic differential modulation of MMN to the two tones was observed in two of three groups, providing partial support for the generalization of first-impression bias to spatially deviant sounds. We discuss possible explanations for its absence when the initial deviant was delivered monaurally to the right ear.

Schizotypy and auditory mismatch negativity in a non-clinical sample of young adults.

Schizophrenia may be conceptualised using a dimensional approach to examine trait-like expression such as schizotypy within non-clinical populations to better understand pathophysiology. A candidate psychosis-risk marker, the auditory mismatch negativity (MMN) is thought to index the functionality of glutamatergic NMDA receptor mediated neurotransmission. Although the MMN is robustly reduced in patients with schizophrenia, the association between MMN and schizotypy in the general population is under-investigated. Thirty-five healthy participants completed the Schizotypal Personality Questionnaire (SPQ) and a multi-feature MMN paradigm (standards 82%, 50ms, 1000Hz, 80dB) with duration (100ms), frequency (1200Hz) and intensity (90dB) deviants (6% each). Spearman's correlations were used to explore the association between schizotypal personality traits and MMN amplitude. Few associations were identified between schizotypal traits and MMN. Higher Suspiciousness subscale scores tended to be correlated with larger frequency MMN amplitude. A median-split comparison of the sample on Suspiciousness scores showed larger MMN (irrespective of deviant condition) in the High compared to the Low Suspiciousness group. The trend-level association between MMN and Suspiciousness is in contrast to the robustly attenuated MMN amplitude observed in schizophrenia. Reductions in MMN may reflect a schizophrenia-disease state, whereas non-clinical schizotypy may not be subserved by similar neuropathology.

Mismatch Negativity and P50 Sensory Gating in Abstinent Former Cannabis Users.

Prolonged heavy exposure to cannabis is associated with impaired cognition and brain functional and structural alterations. We recently reported attenuated mismatch negativity (MMN) and altered P50 sensory gating in chronic cannabis users. This study investigated the extent of brain functional recovery (indexed by MMN and P50) in chronic users after cessation of use. Eighteen ex-users (median 13.5 years prior regular use; median 3.5 years abstinence) and 18 nonusers completed (1) a multifeature oddball task with duration, frequency, and intensity deviants and (2) a P50 paired-click paradigm. Trend level smaller duration MMN amplitude and larger P50 ratios (indicative of poorer sensory gating) were observed in ex-users compared to controls. Poorer P50 gating correlated with prior duration of cannabis use. Duration of abstinence was positively correlated with duration MMN amplitude, even after controlling for age and duration of cannabis use. Impaired sensory gating and attenuated MMN amplitude tended to persist in ex-users after prolonged cessation of use, suggesting a lack of full recovery. An association with prolonged duration of prior cannabis use may indicate persistent cannabis-related alterations to P50 sensory gating. Greater reductions in MMN amplitude with increasing abstinence (positive correlation) may be related to either self-medication or an accelerated aging process.

Mismatch negativity (MMN) in freely-moving rats with several experimental controls.

Mismatch negativity (MMN) is a scalp-recorded electrical potential that occurs in humans in response to an auditory stimulus that defies previously established patterns of regularity. MMN amplitude is reduced in people with schizophrenia. In this study, we aimed to develop a robust and replicable rat model of MMN, as a platform for a more thorough understanding of the neurobiology underlying MMN. One of the major concerns for animal models of MMN is whether the rodent brain is capable of producing a human-like MMN, which is not a consequence of neural adaptation to repetitive stimuli. We therefore tested several methods that have been used to control for adaptation and differential exogenous responses to stimuli within the oddball paradigm. Epidural electroencephalographic electrodes were surgically implanted over different cortical locations in adult rats. Encephalographic data were recorded using wireless telemetry while the freely-moving rats were presented with auditory oddball stimuli to assess mismatch responses. Three control sequences were utilized: the flip-flop control was used to control for differential responses to the physical characteristics of standards and deviants; the many standards control was used to control for differential adaptation, as was the cascade control. Both adaptation and adaptation-independent deviance detection were observed for high frequency (pitch), but not low frequency deviants. In addition, the many standards control method was found to be the optimal method for observing both adaptation effects and adaptation-independent mismatch responses in rats. Inconclusive results arose from the cascade control design as it is not yet clear whether rats can encode the complex pattern present in the control sequence. These data contribute to a growing body of evidence supporting the hypothesis that rat brain is indeed capable of exhibiting human-like MMN, and that the rat model is a viable platform for the further investigation of the MMN and its associated neurobiology.

Chronic effects of cannabis on sensory gating.

Chronic cannabis use has been associated with neurocognitive deficits, alterations in brain structure and function, and with psychosis. This study investigated the effects of chronic cannabis use on P50 sensory-gating in regular users, and explored the association between sensory gating, cannabis use history and the development of psychotic-like symptoms. Twenty controls and 21 regular cannabis users completed a P50 paired-click (S1 and S2) paradigm with an inter-pair interval of 9s. The groups were compared on P50 amplitude to S1 and S2, P50 ratio (S2/S1) and P50 difference score (S1-S2). While cannabis users overall did not differ from controls on P50 measures, prolonged duration of regular use was associated with greater impairment in sensory gating as indexed by both P50 ratio and difference scores (including after controlling for tobacco use). Long-term cannabis users were found to have worse sensory gating ratios and difference scores compared to short-term users and controls. P50 metrics did not correlate significantly with any measure of psychotic-like symptoms in cannabis users. These results suggest that prolonged exposure to cannabis results in impaired P50 sensory-gating in long-term cannabis users. While it is possible that these deficits may have pre-dated cannabis use and reflect a vulnerability to cannabis use, their association with increasing years of cannabis use suggests that this is not the case. Impaired P50 sensory-gating ratios have also been reported in patients with schizophrenia and may indicate a similar underlying pathology.