Raymond Y. Cho

Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia

OBJECTIVE Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABA(A)) receptors containing alpha(2) subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABA(A) receptors containing alpha(2) subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia. METHOD Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABA(A) receptors containing alpha(2) or alpha(3) subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task. RESULTS Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was well-tolerated. CONCLUSIONS These findings provide preliminary support for the hypothesis that enhanced GABA activity at alpha(2) subunit containing GABA(A) receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

Neuroprotective Effects of Cognitive Enhancement Therapy Against Gray Matter Loss in Early Schizophrenia Results From a 2-Year Randomized Controlled Trial

CONTEXT Cognitive rehabilitation has shown efficacy in improving cognition in patients with schizophrenia but the underlying neurobiologic changes that occur during these treatments and support cognitive improvement are not well known. OBJECTIVE To examine differential changes in brain morphology in early course schizophrenia during cognitive rehabilitation vs supportive therapy. DESIGN Randomized controlled trial. SETTING An outpatient research clinic at a university-based medical center that provides comprehensive care services for patients with severe mental illness. PATIENTS A total of 53 symptomatically stable but cognitively disabled outpatients in the early course of schizophrenia or schizoaffective disorder. INTERVENTIONS A 2-year trial with annual structural magnetic resonance imaging and cognitive assessments. Cognitive enhancement therapy is an integrated approach to the remediation of cognitive impairment in schizophrenia that uses computer-assisted neurocognitive training and group-based social-cognitive exercises. Enriched supportive therapy is an illness management approach that provides psychoeducation and teaches applied coping strategies. MAIN OUTCOME MEASURES Broad areas of frontal and temporal gray matter change were analyzed with longitudinal, voxel-based morphometry methods using mixed-effects models followed by volumetric analyses of regions that demonstrated significant differential changes between treatment groups. RESULTS Patients who received cognitive enhancement therapy demonstrated significantly greater preservation of gray matter volume over 2 years in the left hippocampus, parahippocampal gyrus, and fusiform gyrus, and significantly greater gray matter increases in the left amygdala (all corrected P < .04) compared with those who received enriched supportive therapy. Less gray matter loss in the left parahippocampal and fusiform gyrus and greater gray matter increases in the left amygdala were significantly related to improved cognition and mediated the beneficial cognitive effects of cognitive enhancement therapy. CONCLUSION Cognitive enhancement therapy may offer neurobiologic protective and enhancing effects in early schizophrenia that are associated with improved long-term cognitive outcomes.

Alterations in Cortical Network Oscillations and Parvalbumin Neurons in Schizophrenia

Cognitive deficits are a core clinical feature of schizophrenia but respond poorly to available medications. Thus, understanding the neural basis of these deficits is crucial for the development of new therapeutic interventions. The types of cognitive processes affected in schizophrenia are thought to depend on the precisely timed transmission of information in cortical regions via synchronous oscillations at gamma band frequency. Here, we review 1) data from clinical studies suggesting that induction of frontal cortex gamma oscillations during tasks that engage cognitive or complex perceptual functions is attenuated in schizophrenia; 2) findings from basic neuroscience studies highlighting the features of parvalbumin-positive interneurons that are critical for gamma oscillation production; and 3) results from recent postmortem human brain studies providing additional molecular bases for parvalbumin-positive interneuron alterations in prefrontal cortical circuitry in schizophrenia.

Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: A multiscale entropy analysis

Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naive schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting-state EEG from frontal, temporal, parietal, and occipital regions in drug-naive 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2-8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60-s epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies) than did healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia and elucidating the therapeutic mechanisms of antipsychotics.

Assessment of EEG dynamical complexity in Alzheimer's disease using multiscale entropy.

OBJECTIVE Multiscale entropy (MSE) is a recently proposed entropy-based index of physiological complexity, evaluating signals at multiple temporal scales. To test this method as an aid to elucidating the pathophysiology of Alzheimers disease (AD), we examined MSE in resting state EEG activity in comparison with traditional EEG analysis. METHODS We recorded EEG in medication-free 15 presenile AD patients and 18 age- and sex-matched healthy control (HC) subjects. MSE was calculated for continuous 60-s epochs for each group, concurrently with power analysis. RESULTS The MSE results from smaller and larger scales were associated with higher and lower frequencies of relative power, respectively. Group analysis demonstrated that the AD group had less complexity at smaller scales in more frontal areas, consistent with previous findings. In contrast, higher complexity at larger scales was observed across brain areas in AD group and this higher complexity was significantly correlated with cognitive decline. CONCLUSIONS MSE measures identified an abnormal complexity profile across different temporal scales and their relation to the severity of AD. SIGNIFICANCE These findings indicate that entropy-based analytic methods with applied at temporal scales may serve as a complementary approach for characterizing and understanding abnormal cortical dynamics in AD.

Parametric manipulation of the conflict signal and control-state adaptation

Mechanisms by which the brain monitors and modulates performance are an important focus of recent research. The conflict-monitoring hypothesis posits that the ACC detects conflict between competing response pathways which, in turn, signals for enhanced control. The N2, an ERP component that has been localized to ACC, has been observed after high conflict stimuli. As a candidate index of the conflict signal, the N2 would be expected to be sensitive to the degree of response conflict present, a factor that depends on both the features of external stimuli and the internal control state. In the present study, we sought to explore the relationship between N2 amplitude and these variables through use of a modified Eriksen flankers task in which target–distracter compatibility was parametrically varied. We hypothesized that greater target–distracter incompatibility would result in higher levels of response conflict, as indexed by both behavior and the N2 component. Consistent with this prediction, there were parametric degradations in behavioral performance and increases in N2 amplitudes with increasing incompatibility. Further, increasingly incompatible stimuli led to the predicted parametric increases in control on subsequent incompatible trials as evidenced by enhanced performance and reduced N2 amplitudes. These findings suggest that the N2 component and associated behavioral performance are finely sensitive to the degree of response conflict present and to the control adjustments that result from modulations in conflict.

Tiagabine increases [11C]flumazenil binding in cortical brain regions in healthy control subjects

Accumulating evidence indicates that synchronization of cortical neuronal activity at γ-band frequencies is important for various types of perceptual and cognitive processes and that GABA-A receptor-mediated transmission is required for the induction of these network oscillations. In turn, the abnormalities in GABA transmission postulated to play a role in psychiatric conditions such as schizophrenia might contribute to the cognitive deficits seen in this illness. We measured the ability to increase GABA in eight healthy subjects by comparing the binding of [11C]flumazenil, a positron emission tomography (PET) radiotracer specific for the benzodiazepine (BDZ) site, at baseline and in the presence of an acute elevation in GABA levels through the blockade of the GABA membrane transporter (GAT1). Preclinical work suggests that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands (termed ‘GABA shift’). Theoretically, such an increase in the affinity of GABA-A receptors should be detected as an increase in the binding of a GABA-A BDZ-receptor site-specific PET radioligand. GAT1 blockade resulted in significant increases in mean (± SD) [11C]flumazenil-binding potential (BPND) over baseline in brain regions representing the major functional domains of the cerebral cortex: association cortex +15.2±20.2% (p=0.05), sensory cortex +13.5±15.5% (p=0.03) and limbic (medial temporal lobe, MTL) +16.4±20.2% (p=0.03). The increase in [11C]flumazenil-BPND was not accounted for by differences in the plasma-free fraction (fP; paired t-test p=0.24) or changes in the nonspecific binding (pons VT, p=0.73). Moreover, the ability to increase GABA strongly predicted (r=0.85, p=0.015) the ability to entrain cortical networks, measured through EEG γ synchrony during a cognitive control task in these same subjects. Although additional studies are necessary to further validate this technique, these data provide preliminary evidence of the ability to measure in vivo, with PET, acute fluctuations in extracellular GABA levels and provide the first in vivo documentation of a relationship between GABA neurotransmission and EEG γ-band power in humans.

In Vivo Measurement of GABA Transmission in Healthy Subjects and Schizophrenia Patients

OBJECTIVE Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. METHOD The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT). RESULTS [(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power. CONCLUSIONS This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

[11C]flumazenil binding is increased in a dose-dependent manner with tiagabine-induced elevations in GABA levels.

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [11C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [11C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [11C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [11C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [11C]flumazenil VT in Group II in association cortices (6.8±0.8 mL g−1 vs. 7.3±0.4 mL g−1;p = 0.03), sensory cortices (6.7±0.8 mL g−1 vs. 7.3±0.5 mL g−1;p = 0.02) and limbic regions (5.2±0.6 mL g−1 vs. 5.7±0.3 mL g−1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [11C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.

Dopamine and gamma band synchrony in schizophrenia – insights from computational and empirical studies

Dopamine modulates cortical circuit activity in part through its actions on GABAergic interneurons, including increasing the excitability of fast‐spiking interneurons. Though such effects have been demonstrated in single cells, there are no studies that examine how such mechanisms may lead to the effects of dopamine at a neural network level. With this motivation, we investigated the effects of dopamine on synchronization in a simulated neural network composed of excitatory and fast‐spiking inhibitory Wang–Buzsaki neurons. The effects of dopamine were implemented through varying leak K+ conductance of the fast‐spiking interneurons and the network synchronization within the gamma band (∼40 Hz) was analyzed. Parametrically varying the leak K+ conductance revealed an inverted‐U shaped relationship, with low gamma band power at both low and high conductance levels and optimal synchronization at intermediate conductance levels. We also examined the effects of modulating excitability of the inhibitory neurons more generically using an idealized model with theta neurons, with similar findings. Moreover, such a relationship holds when the external input is both tonic and periodic. Our computational results mirror our empirical study of dopamine modulation in schizophrenia and healthy controls, which showed that amphetamine administration increased gamma power in patients but decreased it in controls. Together, our computational and empirical investigations indicate that dopamine can modulate cortical gamma band synchrony in an inverted‐U fashion and that the physiologic effects of dopamine on single fast‐spiking interneurons can give rise to such non‐monotonic effects at the network level.