Michael Kiang

Cognitive, neurophysiological, and functional correlates of proverb interpretation abnormalities in schizophrenia

A hallmark of schizophrenia is impaired proverb interpretation, which could be due to: (1) aberrant activation of disorganized semantic associations, or (2) working memory (WM) deficits. We assessed 18 schizophrenia patients and 18 normal control participants on proverb interpretation, and evaluated these two hypotheses by examining within patients the correlations of proverb interpretation with disorganized symptoms and auditory WM, respectively. Secondarily, we also explored the relationships between proverb interpretation and a spectrum of cognitive functions including auditory sensory-memory encoding (as indexed by the mismatch negativity (MMN) event-related brain potential (ERP)); executive function; and social/occupational function. As expected, schizophrenia patients produced less accurate and less abstract descriptions of proverbs than did controls. These proverb interpretation difficulties in patients were not significantly correlated with disorganization or other symptom factors, but were significantly correlated (p < .05) with WM impairment, as well as with impairments in sensory-memory encoding, executive function, and social/occupational function. These results offer no support for disorganized associations in abnormal proverb interpretation in schizophrenia, but implicate WM deficits, perhaps as a part of a syndrome related to generalized frontal cortical dysfunction.

Abnormal typicality of responses on a category fluency task in schizotypy

Existing hypotheses about semantic processing in schizophrenia and schizotypy suggest that both conditions are associated with a less than normal difference in the degree to which some concept activates the mental representation of other concepts that are strongly versus weakly related to it in meaning. To seek further evidence for this, we examined response typicality on the Category Fluency Test (CFT) as a function of schizotypy. Individuals from a non-clinical population verbally generated as many exemplars as they could in 1 min for each of four categories (fruits, four-footed animals, articles of clothing, vehicles). Participants subsequently completed the Schizotypal Personality Questionnaire (SPQ). SPQ score was not significantly correlated with the total number of responses generated for any of the categories. Individuals with higher (as opposed to lower) SPQ scores, however, generated more atypical members of the fruit category both in their initial responses and overall (as indexed by the average ratio of each responses ordinal position to its position in population typicality norms). These results support the hypothesis that semantic memory organization in non-clinical individuals with higher schizotypy is functionally altered.

An event-related brain potential study of schizotypal personality and associative semantic processing

To examine whether schizotypal personality is associated with the degree to which concepts activate each other in semantic memory, event-related brain potentials (ERPs) were recorded during a delayed lexical decision task from healthy volunteers rated for schizotypy. Each target word was directly, indirectly, or not at all related to a prime word preceding it at a 300- or 750-ms stimulus-onset asynchrony (SOA). Overall, N400 amplitudes were largest for unrelated targets, smallest for directly related targets, and intermediate for indirectly related targets. Higher total Schizotypal Personality Questionnaire (SPQ) scores correlated with smaller N400 indirect priming effects (i.e., smaller N400 amplitude differences between unrelated and indirectly related targets) at both SOAs. In addition, schizotypal subscale scores were differentially associated with N400 effects. Higher SPQ Cognitive-Perceptual scores correlated with smaller N400 direct priming effects (smaller N400 amplitude differences between unrelated and directly related targets) at both SOAs, and with smaller N400 indirect priming effects at the shorter SOA. These correlations are consistent with the hypothesis that decreased use of meaningful context to activate related concepts in general, and/or to inhibit unrelated concepts, may play some role in the development of unusual beliefs.

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [ 18 F]FEPPA

Several lines of evidence implicate microglial activation and abnormal immune response in the etiology of psychosis. Previous positron emission tomography (PET) neuroimaging studies of the translocator protein 18 kDa, TSPO, were limited by low affinity of the first-generation radioligand, low-resolution scanners, and small sample sizes. Moreover, there is a dearth of literature on microglial activation in individuals at clinical high risk (CHR) for psychosis. We used a novel second-generation TSPO radioligand, [18F]FEPPA, to examine whether microglial activation is elevated in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of antipsychotic-naive CHR. Twenty-four CHR (antipsychotic-naive n=22) and 23 healthy volunteers (HV) completed a high resolution [18F]FEPPA PET scan and MRI. The PET data were analyzed using the validated two-tissue compartment model with arterial plasma input function with total volume of distribution (VT) as outcome measure. All analyses were controlled for the TSPO rs6971 polymorphism. We did not observe any significant differences in microglial activation, as indexed by [18F]FEPPA VT, between CHR and HV in either the DLPFC (F(1, 44)=0.41, p=0.52) or the hippocampus (F(1, 44)=2.78, p=0.10). Exploratory associations show that in CHR, [18F]FEPPA VT was positively correlated with apathy (DLPFC: r=0.55, p=0.008; hippocampus: r=0.52, p=0.013) and state anxiety (DLPFC: r=0.60, p=0.003; hippocampus: r=0.48, p=0.024). The lack of significant group differences in [18F]FEPPA VT suggests that microglial activation is not significantly elevated in the clinical high risk state that precedes psychosis.

Association of abnormal semantic processing with delusion-like ideation in frequent cannabis users: an electrophysiological study

RationaleFrequent cannabis use is a risk marker for schizophrenia and delusions, but the neurocognitive mechanisms of this relationship remain unclear.ObjectivesWe sought evidence that cannabis users have deficits in processing relationships between meaningful stimuli, similar to abnormalities reported in schizophrenia, and that these deficits are associated with delusion-like ideation. We used the N400 event-related brain potential (ERP) waveform as a neurophysiological probe of activation of concepts in semantic memory. We hypothesized that cannabis users would exhibit larger (more negative) than normal N400 amplitudes in response to stimuli meaningfully related to a preceding prime—reflecting deficient activation of concepts related to the prime. We further hypothesized that the magnitude of this abnormality would correlate with severity of delusion-like ideation.MethodsWe recorded ERPs in 24 frequent cannabis users and 24 non-using comparison participants who viewed prime words followed by targets which were either words related or unrelated to the prime or pronounceable nonwords. The participants’ task was to indicate whether the target was a word. Delusion-like ideation was measured via the Schizotypal Personality Questionnaire.ResultsContrary to our hypothesis, cannabis users exhibited smaller than normal N400s to both related and unrelated targets. These abnormalities correlated with delusion-like ideation in cannabis users only.ConclusionsThe results are consistent with a generalized abnormality of activation within semantic memory neural networks in cannabis users. Further research is needed to investigate whether such an abnormality plays a role in the development of delusion-like ideation in cannabis users.

The relationship between insight and autobiographical memory for emotional events in schizophrenia.

The relation of episodic and semantic memory for emotional- (positive, negative) and neutral-valenced autobiographical events to illness insight was examined in individuals with schizophrenia. Reduced recall of episodic details for negative events was significantly associated with impaired awareness of having a past mental disorder and its social consequences. Deficits in episodic memory for negative autobiographical events may underlie impaired insight in schizophrenia.

Glutathione, the Major Redox Regulator, in the Prefrontal Cortex of Individuals at Clinical High Risk for Psychosis

Abstract Introduction Oxidative stress and glutathione dysregulation have been implicated in the etiology of schizophrenia. To date, most in vivo studies have investigated alterations in cerebral glutathione levels in patients in which the disorder is already established; however, whether oxidative stress actually predates the onset of psychosis remains unknown. In the current study, we investigated cerebral glutathione levels of antipsychotic-naïve individuals at clinical high risk for psychosis. As exploratory analyses, we also investigated the associations between cerebral glutathione levels and peripheral glutathione peroxidase activity and clinical and neuropsychological measures. Methods Glutathione levels were measured in the medial prefrontal cortex of 30 clinical high risk (n=26 antipsychotic naïve) and 26 healthy volunteers using 3T proton magnetic resonance spectroscopy. Each participant was assessed for glutathione peroxidase activity in plasma and genotyped for the glutamate cysteine ligase catalytic subunit polymorphism. Results No significant differences were observed in glutathione levels between clinical high risk and healthy volunteers in the medial prefrontal cortex (F(1,54)=0.001, P =0.98). There were no significant correlations between cerebral glutathione levels and clinical and neuropsychological measures. Similarly, no significant differences were found in peripheral glutathione peroxidase activity between clinical high risk and healthy volunteers (F(1,37)=0.15, P =0.70). However, in clinical high risk, we observed a significant effect of lifetime history of cannabis use on glutathione peroxidase activity (F(1,23)=7.41, P =0.01). Discussion The lack of significant differences between antipsychotic naïve clinical high risk and healthy volunteers suggests that alterations in glutathione levels in medial prefrontal cortex are not present in the clinical high risk state.

Nigral Stress-Induced Dopamine Release in Clinical High Risk and Antipsychotic-Naïve Schizophrenia

Background Striatal dopamine (DA) synthesis capacity and release are elevated in schizophrenia (SCZ) and its putative prodrome, the clinical high risk (CHR) state. Striatal DA function results from the activity of midbrain DA neurons projecting mainly from the substantia nigra (SN). Elevated stress-induced DA release in SCZ and CHR was observed in the striatum; however, whether it is also elevated in the SN is unclear. The current study aims to determine whether nigral DA release in response to a validated stress task is altered in CHR and in antipsychotic-naïve SCZ. Further, we explore how DA release in the SN and striatum might be related. Methods 24 CHR subjects, 9 antipsychotic-naïve SCZ and 25 healthy volunteers (HV) underwent 2 positron emission tomography (PET) scans using the DA D2/3 agonist radiotracer, [11C]-(+)-PHNO, which allows simultaneous investigations of DA in the SN and striatum. Psychosocial stress-induced DA release was estimated as the percentage differences in BPND (%[11C]-(+)-PHNO displacement) between stress and sensory-motor control sessions. Results We observed a significant diagnostic group by session interaction, such that SCZ exhibited greater stress-induced [11C]-(+)-PHNO % displacement (25.90% ± 32.2%; mean ± SD), as compared to HVs (-10.94% ± 27.1%). Displacement in CHRs (-1.13% ± 32.2%) did not differ significantly from either HV or SCZ. Conclusion Our findings suggest that elevated nigral DA responsiveness to stress is observed in antipsychotic-naïve SCZ.

Effects of Extended Cannabis Abstinence on Cognitive Outcomes in Cannabis Dependent Patients with Schizophrenia vs Non-Psychiatric Controls

Cross-sectional studies of the effects of cannabis on cognition in schizophrenia have produced mixed results. Heavy and persistent cannabis use in schizophrenia is a common clinical problem, and effects of controlled abstinence from cannabis in these patients have not been carefully evaluated. The present study sought to determine the effects of cannabis abstinence on cognition in patients with schizophrenia and co-occurring cannabis dependence. We utilized a 28-day cannabis abstinence paradigm to investigate the state-dependent effects of cannabis on select cognitive outcomes in cannabis-dependent patients with schizophrenia and non-psychiatric controls. Nineteen patients and 20 non-psychiatric male cannabis-dependent participants underwent 28 days of cannabis abstinence. Cognition was assessed on day 0, 14, and 28 using a comprehensive neuropsychological battery. Clinical symptoms were assessed weekly. Abstinence was facilitated by contingency reinforcement confirmed by twice weekly urinalysis. Forty-two percent of patients and 55% of controls achieved end-point abstinence (p=0.53), which was biochemically-verified (day 28 urinary THC-COOH <20 ng/ml). In this preliminary study, schizophrenia-abstainers demonstrated improvements in Hopkins Verbal Learning Test-Revised (HVLT-R) performance over time [F(2,14)=4.73, p<0.03] (d=1.07). Lesser improvements on HVLT-R were observed in non-psychiatric control abstainers (d=0.66), and with abstinence on other cognitive test measures, in both patients and controls. Verbal memory and learning may improve in schizophrenia and control subjects with cannabis abstinence, but larger more definitive studies are needed. Our findings underscore the importance of developing effective interventions for cannabis use disorders in schizophrenia.

Mitochondrial function in individuals at clinical high risk for psychosis

Alterations in mitochondrial function have been implicated in the etiology of schizophrenia. Most studies have investigated alterations in mitochondrial function in patients in which the disorder is already established; however, whether mitochondrial dysfunction predates the onset of psychosis remains unknown. We measured peripheral mitochondrial complex (I–V) function and lactate/pyruvate levels in 27 antipsychotic-naïve individuals at clinical high risk for psychosis (CHR) and 16 healthy controls. We also explored the association between mitochondrial function and brain microglial activation and glutathione levels using a translocator protein 18 kDa [18F]FEPPA PET scan and 1H-MRS scan, respectively. There were no significant differences in mitochondrial complex function and lactate/pyruvate levels between CHR and healthy controls. In the CHR group, mitochondrial complex III function (r = −0.51, p = 0.008) and lactate levels (r = 0.61, p = 0.004) were associated with prodromal negative symptoms. As previously reported, there were no significant differences in microglial activation and glutathione levels between groups, however, mitochondrial complex IV function was inversely related to microglial activation in the hippocampus in CHR (r = −0.42, p = 0.04), but not in healthy controls. In conclusion, alterations in mitochondrial function are not yet evident in CHR, but may relate to the severity of prodromal symptoms, particularly negative symptoms.