Lauren V. Moran

High vs Low Frequency Neural Oscillations in Schizophrenia

There is growing recognition that neural oscillations are important in a wide range of perceptual and cognitive functions. One of the key issues in electrophysiological studies of schizophrenia is whether high or low frequency oscillations, or both, are related to schizophrenia because many brain functions are modulated with frequency specificities. Many recent electrophysiological studies of schizophrenia have focused on high frequency oscillations at gamma band and in general support gamma band dysfunction in schizophrenia. We discuss the concept that gamma oscillation abnormalities in schizophrenia often occur in the background of oscillation abnormalities of lower frequencies. The review discusses the basic neurobiology for the emergence of oscillations of all frequency bands in association with networks of inhibitory interneurons and the convergence and divergence of such mechanisms in generating high vs low frequency oscillations. We then review the literature of oscillatory frequency abnormalities identified in each frequency band in schizophrenia. By describing some of the key functional roles exerted by gamma, low frequencies, and their cross-frequency coupling, we conceptualize that even isolated alterations in gamma or low frequency oscillations may impact the interactions of high and low frequency bands that are involved in key cognitive functions. The review concludes that studying the full spectrum and the interaction of gamma and low frequency oscillations may be critical for deciphering the complex electrophysiological abnormalities observed in schizophrenia patients.

Disruption of anterior insula modulation of large-scale brain networks in schizophrenia.

BACKGROUND Systems level modeling of functional magnetic resonance imaging data has demonstrated dysfunction of several large-scale brain networks in schizophrenia. Anomalies across multiple functional networks associated with schizophrenia could be due to diffuse pathology across multiple networks or, alternatively, dysfunction at converging control(s) common to these networks. The right anterior insula has been shown to modulate activity in the central executive and default mode networks in healthy individuals. We tested the hypothesis that right anterior insula modulation of central executive and default mode networks is disrupted in schizophrenia and associated with cognitive deficits. METHODS In 44 patients with schizophrenia and 44 healthy control subjects, we used seed-based resting state functional connectivity functional magnetic resonance imaging analysis to examine connectivity between right insular subregions and central executive/default mode network regions. We also performed two directed connectivity analyses of resting state data: Granger analysis and confirmatory structural equation modeling. Between-group differences in path coefficients were used to evaluate anterior insula modulation of central executive and default mode networks. Cognitive performance was assessed with the rapid visual information processing task, a test of sustained attention. RESULTS With multiple connectivity techniques, we found compelling, corroborative evidence of disruption of right anterior insula modulation of central executive and default mode networks in patients with schizophrenia. The strength of right anterior insula modulation of these networks predicted cognitive performance. CONCLUSIONS Individuals with schizophrenia have impaired right anterior insula modulation of large-scale brain networks. The right anterior insula might be an emergent pathophysiological gateway in schizophrenia.

Brain Circuits That Link Schizophrenia to High Risk of Cigarette Smoking

Schizophrenia is associated with a high prevalence of smoking. Functional connectivity between the dorsal anterior cingulate (dACC) and limbic regions including the ventral striatum, extended amygdala and parahippocampal areas has been previously implicated in the genetics and clinical severity of smoking. In this study, we test the hypothesis that dACC functional circuits are key paths for the high risk of smoking comorbidity in schizophrenia. Resting state functional magnetic resonance imaging (fMRI) was performed using the dACC as a seed region in smoking and nonsmoking patients with schizophrenia (n = 54), matched controls (n = 65), and nonpsychotic first-degree relatives (n = 24). Multiple regions had decreased connectivity with the dACC in schizophrenia patients when compared with matched controls (n = 65). Several of these functional circuits were also associated with nicotine addiction severity; the largest cluster included limbic areas such as the parahippocampal, extended amygdala, ventral striatal, and posterior insula regions, indicating an overlap of schizophrenia and nicotine addiction on to this circuit. These same functional connectivity-defined circuits were also significantly impaired in schizophrenia nonsmokers compared with control nonsmokers and in nonpsychotic first-degree relatives. Functional connectivity between the dACC and limbic regions is inherently abnormal in schizophrenia, related to its genetic liability regardless of smoking, and overlaps with a nicotine addiction-related circuit. Our findings establish a biologically defined brain circuit mechanism that contributes to the high prevalence of smoking.

Insular and anterior cingulate circuits in smokers with schizophrenia

Schizophrenia (SZ) is associated with high rates of smoking. We previously found that resting state functional connectivity (rsFC) between the dorsal anterior cingulate (dACC) and striatum is independently associated with nicotine addiction and psychiatric illness. Since the insula is implicated in nicotine dependence, we hypothesized that SZ smokers will have greater dysfunction in smoking-related insular and dACC circuits than normal control smokers (NC) independent of smoking severity, consistent with an inherent disease-related weakening of smoking-related circuits. Nicotine challenge was used to demonstrate that decreased rsFC in identified circuits reflects addiction trait and is not affected by pharmacological state. Twenty-four NC smokers and 20 smokers with SZ matched on nicotine addiction severity participated in a resting state fMRI study and were scanned during two separate sessions while receiving a placebo or nicotine patch, in a randomized, cross-over design. Using individualized, anatomically defined anterior and posterior insula and dACC as regions of interest (ROI), whole brain rsFC was performed using each ROI as a seed. Significant negative correlations between smoking severity and rsFC between insula, dACC and striatum were found for both groups. Furthermore, smokers with SZ demonstrated additive reductions in circuit strength between the dACC and insula compared to NC smokers independent of smoking severity. Nicotine challenge did not significantly alter rsFC in insula-dACC-striatal circuits. Reduced rsFC strength between the insula, dACC and striatum is associated with nicotine addiction severity in both non-psychiatrically ill and in SZ smokers. Decreased insula-dACC rsFC may index overlapping circuitry associated with smoking and SZ.

Acute nicotine administration effects on fractional anisotropy of cerebral white matter and associated attention performance

Introduction: Nicotinic acetylcholine receptors are present in the cerebral white matter (WM). We hypothesized that WM response to nicotine can be detected by diffusion tensor imaging (DTI); and that such responses may be associated with nicotine-led cognitive enhancement in sustained attention. Methods: A randomized, nicotine-placebo patch, crossover, double-blind clinical trial in two non-overlapping cohorts of smokers was used to test the hypothesis. The discovery cohort consisted of 39 subjects (N = 20/19 controls/schizophrenic patients, age = 36.8 ± 10.1 years) and the replication cohorts consisted of 38 healthy smokers (31.7 ± 10.5 years). WM integrity was measured by fractional anisotropy (FA) values for the whole brain and nine preselected WM tracts using tract-based-spatial-statistics. Results: Nicotine significantly enhanced FA values for the genu of corpus callosum compared with placebo (ΔFAgenu) (p = 0.01) in smokers with low recent smoking exposure as measured by low average cotinine level. This finding was replicated in the second cohort (p = 0.02). ΔFAgenu values explained 22% of variance in performance of a sustained attention task during the nicotine session (p = 0.006). However, this effect was limited to schizophrenia patients (r = 0.62 and 0.09; p = 0.003 and 0.7 for patients and controls, respectively). Conclusion: Acute pharmacological influence of nicotine patch on WM integrity appeared present, but was dependent on nicotine intake from recent smoking. Change in the WM integrity in the genu of corpus callosum was associated with a significant proportion of variability of nicotine-led changes in sustained attention/working memory of the smokers. Further studies will be necessary to understand biophysical underpinning of the nicotine-related changes in FA.

Prescription stimulant use is associated with earlier onset of psychosis

A childhood history of attention deficit hyperactivity disorder (ADHD) is common in psychotic disorders, yet prescription stimulants may interact adversely with the physiology of these disorders. Specifically, exposure to stimulants leads to long-term increases in dopamine release. We therefore hypothesized that individuals with psychotic disorders previously exposed to prescription stimulants will have an earlier onset of psychosis. Age of onset of psychosis (AOP) was compared in individuals with and without prior exposure to prescription stimulants while controlling for potential confounding factors. In a sample of 205 patients recruited from an inpatient psychiatric unit, 40% (n = 82) reported use of stimulants prior to the onset of psychosis. Most participants were prescribed stimulants during childhood or adolescence for a diagnosis of ADHD. AOP was significantly earlier in those exposed to stimulants (20.5 vs. 24.6 years stimulants vs. no stimulants, p < 0.001). After controlling for gender, IQ, educational attainment, lifetime history of a cannabis use disorder or other drugs of abuse, and family history of a first-degree relative with psychosis, the association between stimulant exposure and earlier AOP remained significant. There was a significant gender × stimulant interaction with a greater reduction in AOP for females, whereas the smaller effect of stimulant use on AOP in males did not reach statistical significance. In conclusion, individuals with psychotic disorders exposed to prescription stimulants had an earlier onset of psychosis, and this relationship did not appear to be mediated by IQ or cannabis.

Nicotine Increases Activation to Anticipatory Valence Cues in Anterior Insula and Striatum

Introduction Smoking is associated with significant morbidity and mortality. Understanding the neurobiology of the rewarding effects of nicotine promises to aid treatment development for nicotine dependence. Through its actions on mesolimbic dopaminergic systems, nicotine engenders enhanced responses to drug-related cues signaling rewards, a mechanism hypothesized to underlie the development and maintenance of nicotine addiction. Methods We evaluated the effects of acute nicotine on neural responses to anticipatory cues signaling (nondrug) monetary reward or loss among 11 nonsmokers who had no prior history of tobacco smoking. In a double-blind, crossover design, participants completed study procedures while wearing nicotine or placebo patches at least 1 week apart. In each drug condition, participants underwent functional magnetic resonance imaging while performing the monetary incentive delay task and performed a probabilistic monetary reward task, probing reward responsiveness as measured by response bias toward a more frequently rewarded stimulus. Results Nicotine administration was associated with enhanced activation, compared with placebo, of right fronto-anterior insular cortex and striatal regions in response to cues predicting possible rewards or losses and to dorsal anterior cingulate for rewards. Response bias toward rewarded stimuli correlated positively with insular activation to anticipatory cues. Conclusion Nicotinic enhancement of monetary reward-related brain activation in the insula and striatum in nonsmokers dissociated acute effects of nicotine from effects on reward processing due to chronic smoking. Reward responsiveness predicted a greater nicotinic effect on insular activation to salient stimuli. Implications Previous research demonstrates that nicotine enhances anticipatory responses to rewards in regions targeted by midbrain dopaminergic systems. The current study provides evidence that nicotine also enhances responses to rewards and losses in the anterior insula. A previous study found enhanced insular activation to rewards and losses in smokers and ex-smokers, a finding that could be due to nicotine sensitization or factors related to current or past smoking. Our finding of enhanced anterior insula response after acute administration of nicotine in nonsmokers provides support for nicotine-induced sensitization of insular response to rewards and losses.

Neural Responses to Smoking Cues in Schizophrenia

The high prevalence of nicotine dependence contributes to excess mortality in schizophrenia. Cue reactivity, or the encounter of drug-related cues or contexts, triggers craving, drug-seeking, and relapse. Prior functional magnetic resonance imaging (fMRI) research indicates that individuals with schizophrenia have blunted neural responses to rewarding stimuli in association with more severe negative symptoms. The objectives of this study are to determine if smokers with schizophrenia have altered neural reactivity to smoking cues compared with non-psychiatrically ill smokers and to evaluate the influence of negative symptoms on cue reactivity. Twenty smokers with schizophrenia and 19 control smokers underwent fMRI while viewing smoking-related and neutral cues. The primary analysis was group comparison of Smoking-Neutral contrast using whole-brain analysis (Pcorrected < .05). Smokers with schizophrenia had significantly greater baseline carbon monoxide levels and longer duration of smoking, suggesting more nicotine use. While both groups had greater brain reactivity to smoking vs neutral cues, smokers with schizophrenia had significantly decreased cue reactivity (Smoking-Neutral) compared to controls in bilateral frontal midline regions. There were significant negative correlations between negative symptoms and frontal midline reactivity. Despite greater nicotine use, smokers with schizophrenia exhibited decreased smoking cue-induced neural reactivity in frontal midline regions, suggesting that increased smoking and low cessation rates in schizophrenia are not primarily driven by responses to smoking-related cues. The finding of negative correlations between cue reactivity and negative symptoms is consistent with previous research demonstrating decreased neural responses to rewarding cues, particularly in patients with negative symptoms.

Nicotine-induced activation of caudate and anterior cingulate cortex in response to errors in schizophrenia

BackgroundNicotine improves attention and processing speed in individuals with schizophrenia. Few studies have investigated the effects of nicotine on cognitive control. Prior functional magnetic resonance imaging (fMRI) research demonstrates blunted activation of dorsal anterior cingulate cortex (dACC) and rostral anterior cingulate cortex (rACC) in response to error and decreased post-error slowing in schizophrenia.MethodsParticipants with schizophrenia (n = 13) and healthy controls (n = 12) participated in a randomized, placebo-controlled, crossover study of the effects of transdermal nicotine on cognitive control. For each drug condition, participants underwent fMRI while performing the stop signal task where participants attempt to inhibit prepotent responses to “go (motor activation)” signals when an occasional “stop (motor inhibition)” signal appears. Error processing was evaluated by comparing “stop error” trials (failed response inhibition) to “go” trials. Resting-state fMRI data were collected prior to the task.ResultsParticipants with schizophrenia had increased nicotine-induced activation of right caudate in response to errors compared to controls (DRUG × GROUP effect: pcorrected < 0.05). Both groups had significant nicotine-induced activation of dACC and rACC in response to errors. Using right caudate activation to errors as a seed for resting-state functional connectivity analysis, relative to controls, participants with schizophrenia had significantly decreased connectivity between the right caudate and dACC/bilateral dorsolateral prefrontal cortices.ConclusionsIn sum, we replicated prior findings of decreased post-error slowing in schizophrenia and found that nicotine was associated with more adaptive (i.e., increased) post-error reaction time (RT). This proof-of-concept pilot study suggests a role for nicotinic agents in targeting cognitive control deficits in schizophrenia.

Nicotine normalizes cortico-striatal connectivity in non-smoking individuals with major depressive disorder

Nicotine dependence and major depressive disorder (MDD) are highly comorbid, yet causal links between these prevalent disorders are unclear. One possible mechanism is that nicotine ameliorates MDD-related neurobiological dysfunction in specific networks. For instance, cortico-striatal circuitry is enhanced by nicotine, and such paths are disrupted in individuals with MDD. Specifically, MDD has been associated with reduced connectivity between the nucleus accumbens (NAc) and rostral anterior cingulate cortex (rACC) but enhanced connectivity between the dorsal striatum (DS) and dorsolateral prefrontal cortex (DLPFC). Determining whether nicotine normalizes these circuits in non-smokers with MDD may elucidate mechanisms underlying links between disorders. This was tested by administering placebo and a 2-mg dose of nicotine to unmedicated non-smokers with and without MDD prior to collecting resting-state functional magnetic imaging data using a cross-over design. On placebo, individuals with MDD showed significantly reduced NAc–rACC and a trend for enhanced DS–DLPFC functional connectivity relative to healthy controls. In MDD, acute nicotine administration normalized both pathways to the level of healthy controls, while having no impact on healthy controls. Nicotine’s effects on NAc–rACC connectivity was influenced by anhedonia, consistent with the role of this network in reward and nicotine’s ability to enhance reward deficiencies in MDD. These results indicate that nicotine normalizes dysfunctional cortico-striatal communication in unmedicated non-smokers with MDD. Nicotine’s influence on these circuitries highlights a possible mechanism whereby individuals with MDD are more vulnerable to develop nicotine dependence. Findings suggest that nicotinic agents may have therapeutic effects on disrupted cortico-striatal connectivity.