Diminished synaptic gain—the sensitivity of postsynaptic responses to neural inputs—may be a fundamental synaptic pathology in schizophrenia. Evidence for this is indirect, however. Furthermore, it is unclear whether pyramidal cells or interneurons (or both) are affected, or how these deficits relate to symptoms. People with schizophrenia diagnoses (PScz) (n = 108), their relatives (n = 57), and control subjects (n = 107) underwent 3 electroencephalography (EEG) paradigms—resting, mismatch negativity, and 40-Hz auditory steady-state response—and resting functional magnetic resonance imaging. Dynamic causal modeling was used to quantify synaptic connectivity in cortical microcircuits. Classic group differences in EEG features between PScz and control subjects were replicated, including increased theta and other spectral changes (resting EEG), reduced mismatch negativity, and reduced 40-Hz power. Across all 4 paradigms, characteristic PScz data features were all best explained by models with greater self-inhibition (decreased synaptic gain) in pyramidal cells. Furthermore, disinhibition in auditory areas predicted abnormal auditory perception (and positive symptoms) in PScz in 3 paradigms. First, characteristic EEG changes in PScz in 3 classic paradigms are all attributable to the same underlying parameter change: greater self-inhibition in pyramidal cells. Second, psychotic symptoms in PScz relate to disinhibition in neural circuits. These findings are more commensurate with the hypothesis that in PScz, a primary loss of synaptic gain on pyramidal cells is then compensated by interneuron downregulation (rather than the converse). They further suggest that psychotic symptoms relate to this secondary downregulation.

Auditory mismatch negativity (MMN) is a negative electrical wave recorded by electroencephalography in response to new vs ongoing auditory inputs and is a replicated biomarker for schizophrenia.^1-4 Mismatch negativity is thought to index an auditory trace memory function that automatically detects a mismatch between a new stimulus in the background of the ongoing stimuli^5-8 and has been linked to the glutamatergic N-methyl-d-aspartate (NMDA) receptor and excitatory-inhibitory neurotransmission functions.⁹ However, the long-standing assumption of a glutamatergic contribution to abnormal MMN in schizophrenia has not been directly examined in this disorder, to our knowledge. A link between γ-aminobutyric acid (GABA) and MMN in schizophrenia is even less clear.

Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are generated from paired-pulse transcranial magnetic stimulations (ppTMS) using certain interstimulus intervals (ISIs). ppTMS provides an accessible technique to evaluate inhibitory and facilitatory motor neural circuits. However, SICI and ICF are highly variable such that individual variability is not captured by any one static ISI. The authors hypothesized that individuals may have individualized and relatively stable pattern of SICI-ICF profiles. They tested SICI and ICF profiles using ISIs from 1 to 500 ms, on 2 occasions about 3 weeks apart, and the test-retest reliability, in 23 healthy controls. Moderate-to-good test-retest reliabilities were found at ppTMS with 1 and 3 ms ISIs (SICI) and with 12, 15, 18, and 21 ms ISIs (ICF), but not with other control ISIs. A similar pattern of results was obtained for men and women. Interestingly, the peak facilitation, peak inhibition, and maximum inhibition and facilitation ranges were individualized, such that they varied considerably across individuals but had high repeatability within individual (Cronbach's α = 0.76 to 0.85). Therefore, individuals appear to have unique inhibition-facilitation profiles that are relatively stable. Although the functional implications of individualized profiles are currently unknown, the relatively stable profiles may index underlying neural inhibition and excitation traits.

Background: Altered brain connectivity is implicated in the development and clinical burden of schizophrenia. Relative to matched controls, schizophrenia patients show (1) a global and regional reduction in the integrity of the brain's white matter (WM), assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA), and (2) accelerated age‐related decline in FA values. In the largest mega‐analysis to date, we tested if differences in the trajectories of WM tract development influenced patient–control differences in FA. We also assessed if specific tracts showed exacerbated decline with aging.Methods: Three cohorts of schizophrenia patients (total n = 177) and controls (total n = 249; age = 18‐61 years) were ascertained with three 3T Siemens MRI scanners. Whole‐brain and regional FA values were extracted using ENIGMA‐DTI protocols. Statistics were evaluated using mega‐ and meta‐analyses to detect effects of diagnosis and age‐by‐diagnosis interactions.Results: In mega‐analysis of whole‐brain averaged FA, schizophrenia patients had lower FA (P = 10⁻¹¹) and faster age‐related decline in FA (P = 0.02) compared with controls. Tract‐specific heterochronicity measures, that is, abnormal rates of adolescent maturation and aging explained approximately 50% of the regional variance effects of diagnosis and age‐by‐diagnosis interaction in patients. Interactive, three‐dimensional visualization of the results is available at www.enigma-viewer.org.Conclusion: WM tracts that mature later in life appeared more sensitive to the pathophysiology of schizophrenia and were more susceptible to faster age‐related decline in FA values. Hum Brain Mapp 37:4673–4688, 2016. © 2016 Wiley Periodicals, Inc.

Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer’s disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter “regional vulnerability index” (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen’s d = 0.44, P = 1·10^–5, N = 173 patients/230 control) and replication (Cohen’s d = 0.78, P = 9·10^–7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients.