State Cannabis Legalization and Psychosis-Related Health Care Utilization.

Importance: Psychosis is a hypothesized consequence of cannabis use. Legalization of cannabis could therefore be associated with an increase in rates of health care utilization for psychosis. Objective: To evaluate the association of state medical and recreational cannabis laws and commercialization with rates of psychosis-related health care utilization. Design, Setting, and Participants: Retrospective cohort design using state-level panel fixed effects to model within-state changes in monthly rates of psychosis-related health care claims as a function of state cannabis policy level, adjusting for time-varying state-level characteristics and state, year, and month fixed effects. Commercial and Medicare Advantage claims data for beneficiaries aged 16 years and older in all 50 US states and the District of Columbia, 2003 to 2017 were used. Data were analyzed from April 2021 to October 2022. Exposure: State cannabis legalization policies were measured for each state and month based on law type (medical or recreational) and degree of commercialization (presence or absence of retail outlets). Main Outcomes and Measures: Outcomes were rates of psychosis-related diagnoses and prescribed antipsychotics. Results: This study included 63 680 589 beneficiaries followed for 2 015 189 706 person-months. Women accounted for 51.8% of follow-up time with the majority of person-months recorded for those aged 65 years and older (77.3%) and among White beneficiaries (64.6%). Results from fully-adjusted models showed that, compared with no legalization policy, states with legalization policies experienced no statistically significant increase in rates of psychosis-related diagnoses (medical, no retail outlets: rate ratio [RR], 1.13; 95% CI, 0.97-1.36; medical, retail outlets: RR, 1.24; 95% CI, 0.96-1.61; recreational, no retail outlets: RR, 1.38; 95% CI, 0.93-2.04; recreational, retail outlets: RR, 1.39; 95% CI, 0.98-1.97) or prescribed antipsychotics (medical, no retail outlets RR, 1.00; 95% CI, 0.88-1.13; medical, retail outlets: RR, 1.01; 95% CI, 0.87-1.19; recreational, no retail outlets: RR, 1.13; 95% CI, 0.84-1.51; recreational, retail outlets: RR, 1.14; 95% CI, 0.89-1.45). In exploratory secondary analyses, rates of psychosis-related diagnoses increased significantly among men, people aged 55 to 64 years, and Asian beneficiaries in states with recreational policies compared with no policy. Conclusions and Relevance: In this retrospective cohort study of commercial and Medicare Advantage claims data, state medical and recreational cannabis policies were not associated with a statistically significant increase in rates of psychosis-related health outcomes. As states continue to introduce new cannabis policies, continued evaluation of psychosis as a potential consequence of state cannabis legalization may be informative.

Relationship of imprecise corollary discharge in schizophrenia to auditory hallucinations.

CONTEXT: A forward model of intended thoughts and actions prepares sensory cortex for sensations that are a consequence of those actions. Imprecision of the corollary discharge in schizophrenia may contribute to the misperception of inner experiences and thoughts as "voices" or auditory hallucinations. OBJECTIVES: To assess the precision of the forward model in schizophrenia using the N100 component of the auditory event-related potential to speech that is altered or unaltered, in real time, as it is being spoken. To assess the relationship between auditory hallucinations and the imprecision of the corollary discharge. DESIGN: Prospective case-control study. SETTING: Community mental health centers and Palo Alto Veterans Affairs Health Care System, Palo Alto, Calif. PARTICIPANTS: Twenty patients with schizophrenia and 17 sex- and age-matched healthy control subjects. MAIN OUTCOME MEASURES: N100 responses to auditory feedback, which was altered by pitch-shifting the self-voice, substituting an alien voice, or pitch-shifting the alien voice. On each trial, subjects judged whether feedback was "self," "other," or "unsure." Clinical ratings were used to assess severity of auditory hallucinations in patients. RESULTS: In controls, N100 to unaltered self-voice feedback was dampened relative to N100 to altered self-voice or alien auditory feedback. This pattern was not seen in hallucinating patients. This imprecision correlated with the severity of hallucinations and with the percentage of misattribution errors. CONCLUSION: These data support a connection between auditory verbal hallucinations and the imprecision of the corollary discharge heralding the sensory consequences of thoughts and actions.

Synch before you speak: auditory hallucinations in schizophrenia.

OBJECTIVE: Synchronization of neural activity preceding self-generated actions may reflect the operation of the forward model, which acts to dampen sensations resulting from those actions. If this is true, pre-action synchrony should be related to subsequent sensory suppression. Deficits in this mechanism may be characteristic of schizophrenia and related to positive symptoms, such as auditory hallucinations. If so, schizophrenia patients should have reduced neural synchrony preceding movements, especially patients with severe hallucinations. METHOD: In 24 patients with schizophrenia or schizoaffective disorder and 25 healthy comparison subjects, the authors related prespeech neural synchrony to subsequent auditory cortical responsiveness to the spoken sound, compared prespeech neural synchrony in schizophrenia patients and healthy comparison subjects, and related prespeech neural synchrony to auditory hallucination severity in patients. To assess neural synchrony, phase coherence of single-trial EEG preceding talking was calculated at a single site across repeated trials. To assess auditory cortical suppression, the N1 event-related brain potentials to speech sound onset during talking and listening were compared. RESULTS: In healthy comparison subjects, prespeech neural synchrony was related to subsequent suppression of responsiveness to the spoken sound, as reflected in reduction of N1 during talking relative to listening. There was greater prespeech synchrony in comparison subjects than in patients, especially those with severe auditory hallucinations. CONCLUSIONS: These data suggest that EEG synchrony preceding speech reflects the action of a forward model system, which dampens auditory responsiveness to self-generated speech and is deficient in patients who hallucinate.

N400 and automatic semantic processing abnormalities in patients with schizophrenia.

BACKGROUND: One factor hypothesized to underlie thinking disturbance in patients with schizophrenia is abnormal or disinhibited automatic spreading activation of semantic networks, which can be assessed using the N400 event-related potential. N400 is a negative-going component elicited at about 400 milliseconds following semantic stimuli that are not primed by the preceding context. Semantic priming refers to facilitated semantic processing gained through preexposure to semantic context, which can happen automatically or strategically. Using N400, inferences can be drawn regarding the extent to which a given context primes a word. METHODS: During a picture-word matching task, N400s to primed (exact match) and unprimed (remotely related) words were recorded from 18 healthy control subjects and 18 patients with schizophrenia performing a picture-word matching task. A short interval (325 milliseconds) between picture and word onset (stimulus-onset asynchrony) was used to optimize the role of automatic spreading semantic activation and to minimize the role of attention, expectancy, preparation, and working memory. RESULTS: Despite behavioral evidence of normal semantic priming, patients generated an abnormally small N400 (ie, less negative) to unprimed words. The N400 to primed words was neither larger nor smaller in patients than in controls, suggesting normal use of context. CONCLUSIONS: A reduced N400 to unprimed words in patients with schizophrenia suggests that there was inappropriate priming of words by remotely related semantic contexts. This is consistent with an overly broad automatic spread of activation through semantic networks in patients with schizophrenia.

Acquiring and inhibiting prepotent responses in schizophrenia: event-related brain potentials and functional magnetic resonance imaging.

BACKGROUND: Schizophrenia is associated with deficits in using context to establish prepotent responses in complex paradigms and failures to inhibit prepotent responses once established. OBJECTIVE: To assess prepotent response establishment and inhibition in patients with schizophrenia using event-related brain potential (ERP) and functional magnetic resonance imaging (fMRI) in a simple NoGo task. To combine fMRI and ERP data to focus on fMRI activations associated with the brief (approximately 200 ms) moment of context updating reflected in the NoGo P300 ERP component. DESIGN AND SETTING: We collected ERP and fMRI data while subjects performed a NoGo task requiring a speedy button press to X stimuli (P=.88) but not to K stimuli (P=.12). The ERPs were collected at the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif; fMRIs were collected at Stanford University, Stanford, Calif. PARTICIPANTS: We recruited patients with DSM-IV schizophrenia (n=11) from the community and the VA hospital and sex- and age-matched healthy control subjects (n=11) from the community. MAIN OUTCOME MEASURES: Behavioral accuracy, P300 amplitudes and latencies, and fMRI activations suggested that patients with schizophrenia did not establish as strong a prepotent tendency to respond to the Go stimulus as healthy subjects. In healthy subjects, NoGo P300 was related to activations in the anterior cingulate cortex, dorsal lateral prefrontal cortex, and right inferior parietal lobule and caudate nucleus, perhaps reflecting conflict experienced when withholding a response, control needed to inhibit a response, and stopping a response in action, respectively. In patients with schizophrenia, NoGo P300 was modestly related to activations in the anterior cingulate cortex, which is consistent with experiencing conflict. CONCLUSIONS: The difference in ERP and fMRI responses to Go and NoGo stimuli suggested that inhibiting a response was easier for patients with schizophrenia than for healthy subjects. Correlations of P300 and fMRI data suggested that patients with schizophrenia and healthy subjects used different neural structures to inhibit responses, with healthy subjects using a more complex system.

Reduced gamma-band coherence to distorted feedback during speech when what you say is not what you hear.

BACKGROUND: Communication between the frontal lobes, where speech is generated, and the temporal lobes, where it is perceived, may occur through the action of an efference copy/corollary discharge mechanism that prepares the temporal lobes for the expected sound. We suggest that coherence of EEG in gamma-band between frontal and temporal lobes may reflect the successful action of such a mechanism. We tested the hypothesis that there would be a disruption of gamma-band coherence when the expected auditory consequence of speech does not match the auditory experience. METHOD: EEG was recorded from 21 healthy adult subjects as they uttered the sound [a:] (Talking condition) and as they heard these recorded sounds played back (Listening condition). As they spoke, subjects heard real-time feedback of the sounds that were: (1) pitch-shifted down one semi-tone, (2) pitch-shifted down one-half of a semi-tone, or (3) not pitch-shifted (veridical), each in separate runs. Event-related gamma coherence between frontal and temporal sites was calculated relative to the onset of the sound, as it was being spoken during Talking, and as it was being played back during Listening. RESULTS: Frontal-temporal gamma-band coherence spanning 33-43 Hz was greater during Talking than Listening and greater when speech was veridical than when it was distorted a whole semi-tone. CONCLUSIONS: Gamma-band fronto-temporal synchrony may reflect a "binding of expectation with experience." Disruption of this synchrony may provide feedback to the frontal lobes, particularly regions subserving vocalization, to implement sensorimotor adaptations to either adjust motor programs for speech production in the short run, or to reorganize expectations in the long run.

Reduced communication between frontal and temporal lobes during talking in schizophrenia.

BACKGROUND: Communication between the frontal lobes, where speech and verbal thoughts are generated, and the temporal lobes, where they are perceived, may occur through the action of a corollary discharge. Its dysfunction may underlie failure to recognize inner speech as self-generated and account for auditory hallucinations in schizophrenia. METHODS: Electroencephalogram was recorded from 10 healthy adults and 12 patients with schizophrenia (DSM-IV) in two conditions: talking aloud and listening to their own played-back speech. Event-related electroencephalogram coherence to acoustic stimuli presented during both conditions was calculated between frontal and temporal pairs, for delta, theta, alpha, beta, and gamma frequency bands. RESULTS: Talking produced greater coherence than listening between frontal-temporal regions in all frequency bands; however, in the lower frequencies (delta and theta), there were significant interactions of group and condition. This finding revealed that patients failed to show an increase in coherence during talking, especially over the speech production and speech reception areas of the left hemisphere, and especially in patients prone to hallucinate. CONCLUSIONS: Reduced fronto-temporal functional connectivity may contribute to the misattribution of inner thoughts to external voices in schizophrenia.

Response-monitoring dysfunction in schizophrenia: an event-related brain potential study.

Error-monitoring abnormalities may underlie positive symptoms of schizophrenia. Response-synchronized event-related potentials during picture-word matching yielded error- and correct-response-related negativity (ERN, CRN) and positivity (Pe, Pc) and preresponse lateralized readiness potentials (LRP) from 18 schizophrenic patients and 18 controls. Both groups responded faster to matches than nonmatches, although patients were generally slower and made more errors to nonmatches. Compared with controls, patients, particularly with paranoid subtype, had smaller ERNs and larger CRNs, which were indistinguishable. LRPs showed evidence of more response conflict before errors than before correct responses in controls but not patients. Despite ERN/CRN abnormalities, post-error slowing and Pe were normal in patients, suggesting a dissociation of ERN and error awareness. Anterior cingulate and dorsolateral prefrontal cortical dysfunction in schizophrenia are implicated.

Out-of-synch and out-of-sorts: dysfunction of motor-sensory communication in schizophrenia.

BACKGROUND: Phase synchronization of neural activity preceding a motor act may reflect an efference copy of the motor plan and its expected sensory consequences (corollary discharge), which is sent to sensory cortex to herald the arrival of self-generated sensations and dampen the resulting sensory experience. We performed time-frequency decomposition of response-locked electroencephalogram (EEG) to examine phase synchronization of oscillations across trials (phase-locking factor [PLF]) to self-paced button presses. If prepress PLF reflects the activity in motor cortex, it should be contralateralized. If it reflects the action of the efference copy, it should be related to subsequent sensory suppression. If efference copy/corollary discharge mechanisms are abnormal in schizophrenia, it should be reduced in patients with schizophrenia. METHODS: Electroencephalogram was collected while 23 patients (20 schizophrenia; 3 schizoaffective) and 25 age-matched control subjects pressed a button, at will, every 1 to 2 sec. Phase-locking factor preceding and following button presses was calculated from single-trial EEG; averaging single trials yielded response-locked event-related potentials (ERPs) to the tactile response associated with button pressing. RESULTS: Consistent with its hypothesized reflection of efference copy/corollary discharge signals, prepress gamma band neural synchrony was 1) maximal over the contralateral sensory-motor cortex in healthy subjects, 2) correlated with the ipsilateralized somatosensory ERP amplitude evoked by the press, and 3) reduced in patients. Prepress neural synchrony in the beta band was also reduced in patients, especially those with avolition/apathy. CONCLUSIONS: These data are consistent with dysfunction of forward model circuitry in schizophrenia and suggest that the specific motor-sensory system affected is selectively linked to symptoms involving that system.

Dissecting corollary discharge dysfunction in schizophrenia.

During talking, a corollary discharge prepares cortex for self-generated sounds, minimizing responsiveness and providing a way to recognize sounds as self-generated. When we talk, we are the agent producing the sound and know what sound to expect. The auditory ERP N1 is normally suppressed during talking, but less so in schizophrenia, perhaps due to deficits in agency and expectancy inherent to talking. N1 was assessed in 27 patients (23 schizophrenia, 4 schizoaffective) and 26 controls. During talking, subjects said "ah" every 1-2 s. During agency, subjects pressed a button to deliver "ah" every 1-2 s. During expectancy, "ah" followed a visual warning. Talking yielded greatest N1 suppression in controls and greatest suppression failure in patients. Agency and expectancy had modest suppression effects on N1 and only in controls. Group differences in expectancy and agency could not account for failed corollary discharge during talking in patients.

Delayed hemodynamic responses in schizophrenia.

While there are many reports of reduced amplitude of hemodynamic responses in schizophrenia, there are no reports of delayed hemodynamic responses, in spite of event-related brain potential (ERP) evidence of slowed neural responses. Recently, Henson et al. (2002) [Henson, R., Price, C., Rugg, M., Turner, R., Friston, K., 2002. Detecting latency differences in event-related BOLD responses: application to words versus nonwords and initial versus repeated face presentations. NeuroImage, 15:83-97] proposed a new method for testing small latency effects (<2 s) in hemodynamic responses. fMRI data were collected during a visual oddball task with infrequent (12%) targets (K) and frequent (88%) standards (X), presented every 1-3 s pseudorandomly, with 7-24 s between targets. SPM99 yielded parameter estimates for the hemodynamic response and its temporal derivative (TD). Beta images reflecting hemodynamic response magnitude to target stimuli were minimally thresholded (P < 0.05, uncorrected), and latencies were estimated for surviving voxels using TD and hemodynamic response beta values. DSM-IV schizophrenia patients (n = 12) and sex- and age-matched healthy control subjects (n = 12) were recruited from the community. Although groups differed only minimally in activation height, hemodynamic responses were significantly delayed in basal ganglia, thalamus, and anterior cingulate in patients with schizophrenia. Psychomotor slowing reflected in reaction times to targets recorded outside the magnet was related to hemodynamic slowing in basal ganglia, anterior cingulate, thalamus, as well as left cerebellum in controls. Delays in the hemodynamic response have far-reaching implications for understanding the pathophysiology of schizophrenia from slowed neural responses to slowed substrate delivery, and depending of the degree of delay, may raise methodological issues regarding modeling hemodynamic responses in patients and controls.