Cortical Dysfunction In Schizophrenia Research Articles

Androgen effects on mesoprefrontal dopamine systems in the adult male brain

Epidemiological data show that males are more often and/or more severely affected by symptoms of prefrontal cortical dysfunction in schizophrenia, Parkinson’s disease and other disorders in which dopamine circuits associated with the prefrontal cortex are dysregulated. This review focuses on research showing that these dopamine circuits are powerfully regulated by androgens. It begins with a brief overview of the sex differences that distinguish prefrontal function in health and prefrontal dysfunction or decline in aging and/or neuropsychiatric disease. This review article then spotlights data from human subjects and animal models that specifically identify androgens as potent modulators of prefrontal cortical operations and of closely related, functionally critical measures of prefrontal dopamine level or tone. Candidate mechanisms by which androgens dynamically control mesoprefrontal dopamine systems and impact prefrontal states of hypo- and hyper-dopaminergia in aging and disease are then considered. This is followed by discussion of a working model that identifies a key locus for androgen modulation of mesoprefrontal dopamine systems as residing within the prefrontal cortex itself. The last sections of this review critically consider the ways in which the organization and regulation of mesoprefrontal dopamine circuits differ in the adult male and female brain, and highlights gaps where more research is needed.

Is source-resolved magnetoencephalographic mismatch negativity a viable biomarker for early psychosis?

Mismatch negativity (MMN) is an auditory event-related response reflecting the pre-attentive detection of novel stimuli and is a biomarker of cortical dysfunction in schizophrenia (SZ). MMN to pitch (pMMN) and to duration (dMMN) deviant stimuli are impaired in chronic SZ, but it is less clear if MMN is reduced in first-episode SZ, with inconsistent findings in scalp-level EEG studies. Here, we investigated the neural generators of pMMN and dMMN with MEG recordings in 26 first-episode schizophrenia spectrum (FEsz) and 26 matched healthy controls (C). We projected MEG inverse solutions into precise functionally meaningful auditory cortex areas. MEG-derived MMN sources were in bilateral primary auditory cortex (A1) and belt areas. In A1, pMMN FEsz reduction showed a trend towards statistical significance (F(1,50) = 3.31; p = .07), and dMMN was reduced in FEsz (F(1,50) = 4.11; p = .04). Hypothesis-driven comparisons at each hemisphere revealed dMMN reduction in FEsz occurred in the left (t(56) = 2.23; p = .03; d = .61) but not right (t(56) = 1.02; p = .31; d = .28) hemisphere, with a moderate effect size. The added precision of MEG source solution with high-resolution MRI and parcellation of A1 may be requisite to detect the emerging pathophysiology and indicates a critical role for left hemisphere pathology at psychosis onset. However, the moderate effect size in left A1, albeit larger than reported in scalp MMN meta-analyses, casts doubt on the clinical utility of MMN for differential diagnosis, as a majority of patients will overlap with the healthy individual's distribution.

P552. Reduced Left Hemisphere A1 MEG MMN Despite “Healthy” Scalp EEG MMN in First Episode Psychosis

Mismatch Negativity (MMN) is an auditory event-related potential reflecting the pre-attentive detection of novel non-predicted stimuli and is a biomarker of cortical dysfunction in schizophrenia (SZ). MMN to pitch (pMMN) and to duration (dMMN) deviant stimuli are impaired in chronic schizophrenia, but it is less clear if MMN is reduced in first episode schizophrenia.

Understanding Cortical Dysfunction in Schizophrenia With TMS/EEG.

In schizophrenia and related disorders, a deeper mechanistic understanding of neocortical dysfunction will be essential to developing new diagnostic and therapeutic techniques. To this end, combined transcranial magnetic stimulation and electroencephalography (TMS/EEG) provides a non-invasive tool to simultaneously perturb and measure neurophysiological correlates of cortical function, including oscillatory activity, cortical inhibition, connectivity, and synchronization. In this review, we summarize the findings from a variety of studies that apply TMS/EEG to understand the fundamental features of cortical dysfunction in schizophrenia. These results lend to future applications of TMS/EEG in understanding the pathophysiological mechanisms underlying cognitive deficits in schizophrenia.

Mismatch negativity as a biomarker of theta band oscillatory dysfunction in schizophrenia

Mismatch negativity (MMN) is among the best established biomarkers of cortical dysfunction in schizophrenia. MMN generators are localized primarily to primary and secondary auditory regions, and are known to reflect activity mediated by cortical N-methyl-d-aspartate-type glutamate receptors (NMDAR). Nevertheless, mechanisms underlying MMN generation at the local circuit level remain incompletely understood. This review synthesizes recent advances in circuit-level conceptualization of MMN based upon neuro-oscillatory findings. In the neuro-oscillatory (aka event-related spectral perturbation, ERSP) approach, responses to sensory stimuli are decomposed into underlying frequency bands prior to analysis. MMN reflects activity primarily in theta (4–7Hz) frequency band, which is thought to depend primarily upon interplay between cortical pyramidal neurons and somatostatin (SST)-type local circuit GABAergic interneurons. Schizophrenia-related deficits in theta generation are also observed not only in MMN, but also in other auditory and visual contexts. At the local circuit level, SST interneurons are known to maintain tonic inhibition over cortical pyramidal interneurons. SST interneurons, in turn, are inhibited by a class of interneurons expressing vasoactive intestinal polypeptide (VIP). In rodents, SST interneurons have been shown to respond differentially to deviant vs. standard stimuli, and inhibition of SST interneurons has been found to selectively inhibit deviance-related activity in rodent visual cortex. Here we propose that deficits in theta frequency generation, as exemplified by MMN, may contribute significantly to cortical dysfunction in schizophrenia, and may be tied to impaired interplay between cortical pyramidal neurons and local circuit SST-type GABAergic interneurons.

Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia.

Despite the well-established role of striatal dopamine in psychosis, current views generally agree that cortical dysfunction is likely necessary for the emergence of psychotic symptoms. The topographic organization of striatal-cortical connections is central to gating and integration of higher-order information, so a disruption of such topography via dysregulated dopamine could lead to cortical dysfunction in schizophrenia. However, this hypothesis remains to be tested using multivariate methods ascertaining the global pattern of striatal connectivity and without the confounding effects of antidopaminergic medication. To examine whether the pattern of brain connectivity across striatal subregions is abnormal in unmedicated patients with schizophrenia and whether this abnormality relates to psychotic symptoms and extrastriatal dopaminergic transmission. In this multimodal, case-control study, we obtained resting-state functional magnetic resonance imaging data from 18 unmedicated patients with schizophrenia and 24 matched healthy controls from the New York State Psychiatric Institute. A subset of these (12 and 17, respectively) underwent positron emission tomography with the dopamine D2 receptor radiotracer carbon 11-labeled FLB457 before and after amphetamine administration. Data were acquired between June 16, 2011, and February 25, 2014. Data analysis was performed from September 1, 2014, to January 11, 2016. Group differences in the striatal connectivity pattern (assessed via multivariable logistic regression) across striatal subregions, the association between the multivariate striatal connectivity pattern and extrastriatal baseline D2 receptor binding potential and its change after amphetamine administration, and the association between the multivariate connectivity pattern and the severity of positive symptoms evaluated with the Positive and Negative Syndrome Scale. Of the patients with schizophrenia (mean [SEM] age, 35.6 [11.8] years), 9 (50%) were male and 9 (50%) were female. Of the controls (mean [SEM] age, 33.7 [8.8] years), 10 (42%) were male and 14 (58%) were female. Patients had an abnormal pattern of striatal connectivity, which included abnormal caudate connections with a distributed set of associative cortex regions (χ229 = 53.55, P = .004). In patients, more deviation from the multivariate pattern of striatal connectivity found in controls correlated specifically with more severe positive symptoms (ρ = -0.77, P = .002). Striatal connectivity also correlated with baseline binding potential across cortical and extrastriatal subcortical regions (t25 = 3.01, P = .01, Bonferroni corrected) but not with its change after amphetamine administration. Using a multimodal, circuit-level interrogation of striatal-cortical connections, it was demonstrated that the functional topography of these connections is globally disrupted in unmedicated patients with schizophrenia. These findings suggest that striatal-cortical dysconnectivity may underlie the effects of dopamine dysregulation on the pathophysiologic mechanism of psychotic symptoms.

Alterations in Prefrontal Cortical Circuitry and Cognitive Dysfunction in Schizophrenia.

Deficits in working memory, a core disturbance of schizophrenia, appear to emerge from an impaired capacity to generate gamma oscillations in the neural networks of the prefrontal cortex. Cortical gamma oscillations arise principally in layer 3 where strong inhibitory inputs from the parvalbumin (PV) basket cell class of GABA neurons synchronize the activity of local groups of pyramidal neurons which in turn send excitatory inputs to PV basket cells. Schizophrenia is associated with deficits in markers of excitatory activity of layer 3 pyramidal cells and multiple pre- and postsynaptic abnormalities consistent with weaker inhibitory inputs to pyramidal cells from PV basket cells. These findings suggest that prefrontal cortical dysfunction in schizophrenia results from an “upstream” deficit in pyramidal cell excitation and that inhibition from PV basket cells is downregulated to compensate for this low network activity. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power in prefrontal neural networks required for optimal working memory performance.

On Altered Patterns of Brain Activation in At-Risk Adolescents and Young Adults

On Altered Patterns of Brain Activation in At-Risk Adolescents and Young Adults

Altered Cortical GABA Neurotransmission in Schizophrenia: Insights into Novel Therapeutic Strategies

Altered markers of cortical GABA neurotransmission are among the most consistently observed abnormalities in postmortem studies of schizophrenia. The altered markers are particularly evident between the chandelier class of GABA neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons. For example, in the dorsolateral prefrontal cortex of subjects with schizophrenia immunoreactivity for the GABA membrane transporter is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABAA receptor α2 subunit is increased in postsynaptic AIS. Both of these molecular changes appear to be compensatory responses to a presynaptic deficit in GABA synthesis, and thus could represent targets for novel therapeutic strategies intended to augment the brain's own compensatory mechanisms. Recent findings that GABA inputs from neocortical chandelier neurons can be powerfully excitatory provide new ideas about the role of these neurons in the pathophysiology of cortical dysfunction in schizophrenia, and consequently in the design of pharmacological interventions.

Downregulation of parvalbumin at cortical GABA synapses reduces network gamma oscillatory activity.

Postmortem and functional imaging studies of patients with psychiatric disorders, including schizophrenia, are consistent with a dysfunction of interneurons leading to compromised inhibitory control of network activity. Parvalbumin (PV)-expressing, fast-spiking interneurons interacting with pyramidal neurons generate cortical gamma oscillations (30-80 Hz) that synchronize cortical activity during cognitive processing. In postmortem studies of schizophrenia patients, these interneurons show reduced PV and glutamic acid decarboxylase 67 (GAD67), an enzyme that synthesizes GABA, but the consequences of this downregulation are unclear. We developed a biophysically realistic and detailed computational model of a cortical circuit including asynchronous release from GABAergic interneurons to investigate how reductions in PV and GABA affect gamma oscillations induced by sensory stimuli. Networks with reduced GABA were disinhibited and had altered gamma oscillations in response to stimulation; PV-deficient GABA synapses had increased asynchronous release of GABA, which decreased the level of excitation and reduced gamma-band activity. Combined reductions of PV and GABA resulted in a diminished gamma-band oscillatory activity in response to stimuli, similar to that observed in schizophrenia patients. Our results suggest a mechanism by which reduced GAD67 and PV in fast-spiking interneurons may contribute to cortical dysfunction in schizophrenia and related psychiatric disorders.

Frontal areas contribute to reduced global coordination of resting-state gamma activities in drug-naïve patients with schizophrenia

Schizophrenia has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical circuitry. Alterations in gamma band oscillations have attracted a great deal of interest as they appear to represent a pathophysiological process of cortical dysfunction in schizophrenia. Gamma band oscillations reflect local cortical activities, and the synchronization of these activities among spatially distributed cortical areas has been suggested to play a central role in the formation of networks. To assess global coordination across spatially distributed brain regions, Omega complexity (OC) in multichannel EEG was proposed. Using OC, we investigated global coordination of resting-state EEG activities in both gamma (30–50Hz) and below-gamma (1.5–30Hz) bands in drug-naïve patients with schizophrenia and investigated the effects of neuroleptic treatment. We found that gamma band OC was significantly higher in drug-naïve patients with schizophrenia compared to control subjects and that a right frontal electrode (F3) contributed significantly to the higher OC. After neuroleptic treatment, reductions in the contribution of frontal electrodes to global OC in both bands correlated with the improvement of schizophrenia symptomatology. The present study suggests that frontal brain processes in schizophrenia were less coordinated with activity in the remaining brain. In addition, beneficial effects of neuroleptic treatment were accompanied by improvement of brain coordination predominantly due to changes in frontal regions. Our study provides new evidence of improper intrinsic brain integration in schizophrenia by investigating the resting-state gamma band activity.

The chandelier neuron in schizophrenia

Markers of GABA neurotransmission between chandelier neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons, are altered in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. For example, immunoreactivity for the GABA membrane transporter (GAT1) is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABA(A) receptor α2 subunit is increased in postsynaptic AIS. These alterations are most marked in cortical layers 2-3. In addition, other determinants of the function of chandelier cell-pyramidal neuron synapses, such as ankyrin-G (which regulates the recruitment of sodium channels to the AIS), are also selectively altered in superficial layer pyramidal neurons in subjects with schizophrenia. Each of these components of chandelier cell-pyramidal neuron connectivity exhibits distinctive developmental trajectories in the primate DLPFC, suggesting that disturbances in these trajectories could contribute to the pathogenesis of schizophrenia. Recent findings that inputs from neocortical chandelier neurons are excitatory provide new ideas about the role of this circuitry in the pathophysiology of cortical dysfunction in schizophrenia.

Spatial localization deficits and auditory cortical dysfunction in schizophrenia

Background Schizophrenia is associated with deficits in the ability to discriminate auditory features such as pitch and duration that localize to primary cortical regions. Lesions of primary vs. secondary auditory cortex also produce differentiable effects on ability to localize and discriminate free-field sound, with primary cortical lesions affecting variability as well as accuracy of response. Variability of sound localization has not previously been studied in schizophrenia. Methods The study compared performance between patients with schizophrenia ( n = 21) and healthy controls ( n = 20) on sound localization and spatial discrimination tasks using low frequency tones generated from seven speakers concavely arranged with 30° separation. Results For the sound localization task, patients showed reduced accuracy ( p = 0.004) and greater overall response variability ( p = 0.032), particularly in the right hemifield. Performance was also impaired on the spatial discrimination task ( p = 0.018). On both tasks, poorer accuracy in the right hemifield was associated with greater cognitive symptom severity. Better accuracy in the left hemifield was associated with greater hallucination severity on the sound localization task ( p = 0.026), but no significant association was found for the spatial discrimination task. Conclusion Patients show impairments in both sound localization and spatial discrimination of sounds presented free-field, with a pattern comparable to that of individuals with right superior temporal lobe lesions that include primary auditory cortex (Heschl's gyrus). Right primary auditory cortex dysfunction may protect against hallucinations by influencing laterality of functioning.

The effects of sub-chronic clozapine and haloperidol administration on isolation rearing induced changes in frontal cortical N-methyl- d-aspartate and D 1 receptor binding in rats

Glutamate and dopamine disturbances are implicated in frontal cortical dysfunction in schizophrenia. Little, however, is known about the nature of dopamine D 1 and N-methyl- d-aspartate (NMDA) receptor interactions in the illness, nor of the extent of their co-involvement in antipsychotic drug response. It is well known that early life adversity may pre-date the development of schizophrenia. Using a neurodevelopmental model of schizophrenia, namely post weaning social isolation rearing (SIR), we studied the effect of SIR (post natal day 21–61) on frontal cortical NMDA and D 1 receptor binding characteristics with/without chronic haloperidol (0.1 mg/kg/day i.p.) or clozapine (5 mg/kg/day i.p.) treatment, undertaken from post-natal day 50–60. SIR increased frontal cortical NMDA-density, with decreased affinity (decreased pK D), but reduced D 1 receptor density (without effects on pK D). In socially reared animals, clozapine but not haloperidol increased NMDA receptor density without effects on pK D. Neither drug markedly affected D 1 receptor density, although clozapine increased D 1 affinity. Increased NMDA density in SIR animals was unaffected by haloperidol, but further increased by clozapine. However, SIR-associated decrease in NMDA affinity remained unaltered despite drug treatment. Reduced D 1 receptor density in SIR animals was exacerbated by haloperidol, but unaltered by clozapine, without changes in pK D. SIR thus induces opposing effects on frontal cortical NMDA and D 1 radio-receptor binding characteristics, which has direct bearing on the mutual interplay of these receptors in schizophrenia. The ability of SIR to affect NMDA receptor affinity warrants deeper study. Furthermore, at the doses examined, in contrast to haloperidol, clozapine bolsters frontal cortical glutamatergic but stabilizes D 1 dopaminergic pathways in a neurodevelopmental animal model of schizophrenia, possibly explaining the atypical clinical characteristics of this drug.

Dysbindin Modulates Prefrontal Cortical Glutamatergic Circuits and Working Memory Function in Mice

Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein coded for by DTNBP1, dysbindin, is expressed within forebrain glutamatergic neurons, where it interacts with proteins involved in vesicular trafficking and exocytosis. In order to further delineate the cellular, physiological and behavioral phenotypes associated with reduced dysbindin expression, we conducted studies in mice carrying a null mutation within the dtnbp1 gene. Dysbindin mutants exhibited impairments of spatial working memory as compared with wild-type controls; heterozygous mice exhibited intermediate levels of cognitive dysfunction. Deep layer pyramidal neurons recorded in the prefrontal cortex of mutant mice exhibited reductions in paired-pulse facilitation, and evoked and miniature excitatory post-synaptic currents, indicating a difference in the function of pre-synaptic glutamatergic terminals, as well as elevated spike thresholds. Taken together, these data indicate that dysbindin potently regulates excitatory transmission in prefrontal cortex, potentially through a pre-synaptic mechanism, and consequently modulates cognitive functions depending upon this brain region, providing new insights into the molecular mechanisms underlying cortical dysfunction in schizophrenia.

Altered markers of tonic inhibition in the dorsolateral prefrontal cortex of subjects with schizophrenia.

Cognitive impairments in schizophrenia are associated with lower expression of markers of gamma-aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABA(A) receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABA(A) receptor alpha4 and delta subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia. The authors used in situ hybridization to quantify expression patterns of GABA(A) receptor alpha4 and delta subunits in prefrontal cortex from 23 matched pairs of schizophrenia and comparison subjects. Levels of delta mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas alpha4 mRNA levels were lower only in subjects with schizophrenia receiving certain medications at the time of death. To understand the nature of this unexpected dissociation between alpha4 and delta subunit expression in schizophrenia, the authors used similar methods to quantify alpha4 and delta mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of alpha4 mRNA decreased, whereas delta mRNA levels increased. In addition, delta mRNA levels, but not alpha4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABA(A) receptor alpha1 subunit, and neither delta nor alpha4 mRNA levels were altered in rodent models of altered excitatory neurotransmission. Since GABA(A) receptor alpha1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with delta subunits to form functional GABA(A) receptors, lower delta mRNA levels in schizophrenia might reflect a reduced number of alpha(1)beta(x)delta GABA(A) receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.

Divergent Approaches Converge on Frontal Lobe Dysfunction in Schizophrenia

Divergent Approaches Converge on Frontal Lobe Dysfunction in Schizophrenia

GABA Neurons and the Mechanisms of Network Oscillations: Implications for Understanding Cortical Dysfunction in Schizophrenia

Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical gamma-aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type-specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value.

Reduction of synapsin III in the prefrontal cortex of individuals with schizophrenia

We analyzed the expression of a presynaptic protein, synapsin III, in individuals with schizophrenia. Since levels of synapsin III were previously found to be significantly reduced in the hippocampus of individuals with schizophrenia, we examined another brain region believed to be a major locus of dysfunction in schizophrenia, the dorsolateral prefrontal cortex (DLPFC). Western blot analyses using tissue obtained from the Stanley Foundation Neuropathology Consortium revealed that synapsin III levels were significantly decreased in the DLPFC of individuals with schizophrenia compared to controls. These findings are consistent with growing evidence of presynaptic abnormalities and prefrontal cortical dysfunction in schizophrenia.

Polishing the Windows of the Mind

Polishing the Windows of the Mind