Person:

Spencer, Kevin

Schizophrenia is characterized by cortical circuit abnormalities, which might be reflected in γ-frequency (30–100 Hz) oscillations in the electroencephalogram. Here we used a computational model of cortical circuitry to examine the effects that neural circuit abnormalities might have on γ generation and network excitability. The model network consisted of 1000 leaky integrate-and-fire neurons with realistic connectivity patterns and proportions of neuron types [pyramidal cells (PCs), regular-spiking inhibitory interneurons, and fast-spiking interneurons (FSIs)]. The network produced a γ oscillation when driven by noise input. We simulated reductions in: (1) recurrent excitatory inputs to PCs; (2) both excitatory and inhibitory inputs to PCs; (3) all possible connections between cells; (4) reduced inhibitory output from FSIs; and (5) reduced NMDA input to FSIs. Reducing all types of synaptic connectivity sharply reduced γ power and phase synchrony. Network excitability was reduced when recurrent excitatory connections were deleted, but the network showed disinhibition effects when inhibitory connections were deleted. Reducing FSI output impaired γ generation to a lesser degree than reducing synaptic connectivity, and increased network excitability. Reducing FSI NMDA input also increased network excitability, but increased γ power. The results of this study suggest that a multimodal approach, combining non-invasive neurophysiological and structural measures, might be able to distinguish between different neural circuit abnormalities in schizophrenia patients. Computational modeling may help to bridge the gaps between post-mortem studies, animal models, and experimental data in humans, and facilitate the development of new therapies for schizophrenia and neuropsychiatric disorders in general.

Several studies have reported deficits in (\gamma) oscillatory activity elicited by sensory stimulation or cognitive processes in schizophrenia patients (SZ) compared to healthy control subjects (HC). However, the evidence for cortical hyperexcitability and reduced function of N-methyl-D-aspartate receptors (NMDARs) on parvalbumin-expressing inhibitory interneurons in schizophrenia leads to the prediction that (\gamma) activity should rather be increased in SZ, but data supporting this hypothesis have been lacking. One possibility is that baseline induced (\gamma) power is increased, an effect that might have gone unnoticed in studies of stimulus-locked oscillations. Here we addressed this question by re-analyzing the data from a previously published study on the 40 Hz auditory steady-state response (ASSR) in schizophrenia in which dipole source localization was used to examine (\gamma) responses in the left and right auditory cortices. Subjects were 16 HC and 18 chronic SZ, who listened to trains of clicks presented at 40 Hz during electroencephalogram recording. Independent component analysis was used to remove ocular artifacts. Power spectra were computed for the pre-stimulus baseline period. We found that baseline power was higher in SZ than HC at 40 Hz in the left auditory cortex. Baseline 40 Hz power in the left auditory cortex was also correlated with ASSR evoked power in SZ. Thus, (\gamma) oscillation abnormalities in schizophrenia may include abnormal increases in baseline power as well as deficits in evoked oscillations. These baseline increases could be the sign of NMDAR hypofunction on parvalbumin-expressing inhibitory interneurons, which would be consistent with acute NMDAR antagonism and genetic ablation models of schizophrenia.

Background—Several theories of schizophrenia have emphasized the role of aberrant neural timing in the etiology of the disease, possibly as a consequence of conduction delays caused by structural damage to the white-matter fasciculi. Consistent with this theory, increased interhemispheric transmission times (IHTTs) to unilaterally-presented visual stimuli have been reported in patients with schizophrenia. The present study investigated whether or not these IHTT abnormalities could be underpinned by structural damage to the visual fibers of the corpus callosum. Methods—30 schizophrenia patients and 22 matched controls underwent Event Related Potential (ERP) recording, and a subset of 19 patients and 16 controls also underwent 3T Diffusion-Tensor Imaging (DTI). Unilateral visual stimuli (squares, 2 × 2 degrees) were presented 6 degrees lateral to either side of a central fixation point. IHTTs (ipsilateral minus contralateral latencies) were calculated for the P1 and N1 components at occipital-temporal sites in current source densitytransformed ERPs. The visual fibers of the corpus callosum were extracted with streamline tractography and the diffusion metrics of Fractional Anisotropy (FA) and Mode calculated. Results—While both subject groups exhibited highly significant IHTTs across a range of posterior electrode pairs, and significantly shorter IHTTs from left-to-right hemisphere than vice versa, no significant groupwise differences in IHTT were observed. However, participants’ IHTTs were linearly related to their FA and Mode, with longer IHTTs being associated with lower FA and more prolate diffusion ellipsoids. Conclusions—These results suggest that IHTTs are estimable from DTI measures of white matter integrity. In light of the range of diffusion abnormalities that have been reported in patients with schizophrenia, particularly in frontal fasciculi, these results support the conjecture that schizophrenia is ultimately underpinned by abnormalities in neural timing.

Schizophrenia has been conceptualized as a failure of cognitive integration, and abnormalities in neural circuitry (particularly inhibitory interneurons) have been proposed as a basis for this disorder. We used measures of phase locking and phase coherence in the scalp-recorded electroencephalogram to examine the synchronization of neural circuits in schizophrenia. Compared with matched control subjects, schizophrenia patients demonstrated: (1) absence of the posterior component of the early visual gamma band response to Gestalt stimuli; (2) abnormalities in the topography, latency, and frequency of the anterior component of this response; (3) delayed onset of phase coherence changes; and (4) the pattern of anterior–posterior coherence increases in response to Gestalt stimuli found in controls was replaced by a pattern of interhemispheric coherence decreases in patients. These findings support the hypothesis that schizophrenia is associated with impaired neural circuitry demonstrated as a failure of gamma band synchronization, especially in the 40 Hz range.

We view schizophrenia as producing a failure of attentional modulation that leads to a breakdown in the selective enhancement or inhibition of semantic/lexical representations whose biological substrata are widely distributed across left (dominant) temporal and frontal lobes. Supporting behavioral evidence includes word recall studies that have pointed to a disturbance in connectivity (associative strength) but not network size (number of associates) in patients with schizophrenia. Paralleling these findings are recent neural network simulation studies of the abnormal connectivity effect in schizophrenia through ‘lesioning’ network connection weights while holding constant network size. Supporting evidence at the level of biology are in vitro studies examining N-methyl-d-aspartate (NMDA) receptor antagonists on recurrent inhibition; simulations in neural populations with realistically modeled biophysical properties show NMDA antagonists produce a schizophrenia-like disturbance in pattern association. We propose a similar failure of NMDA-mediated recurrent inhibition as a candidate biological substrate for attention and semantic anomalies of schizophrenia.

Background: Abnormalities in γ oscillations (30–100 Hz) in the scalp-recorded electroencephalogram (EEG) have been proposed to reflect neural circuitry abnormalities in schizophrenia. Oscillations in the γ band are thought to play an important role in visual perception, mediating the binding of visual features into coherent objects. However, there is relatively little evidence to date of deficits in γ-mediated processes associated with Gestalt perception in schizophrenia. Methods: Fourteen healthy control subjects (HC) and 17 chronic schizophrenia patients (SZ) discriminated between illusory Kanisza Squares and No-Square control stimuli, indicating their judgment with a manual button press. Time-frequency decomposition of the EEG was computed with the Morlet wavelet transform. Time-frequency maps of phase locking factor (PLF) values were calculated for stimulus- and response-locked oscillations. Results: HC and SZ did not differ in reaction time, error rate, an early ERP effect associated with Gestalt processing, nor an early visual-evoked γ oscillation. Two response-locked high γ effects had greater PLF for Square than No-Square stimuli in HC, and the reverse pattern in SZ. One of these effects was correlated with thought disorder symptom ratings in SZ. Conclusions: SZ demonstrated abnormalities in γ oscillations associated with the perception of Gestalt objects, while their early visual-evoked γ activity was mostly normal, contrary to previous results. This study supports the hypothesis that high-frequency oscillations are sensitive to aspects of psychosis.

We examined semantic vs. associational influences on word priming in schizophrenia. Tested on three occasions, subjects made speeded lexical decisions to three kinds of prime-word relationships: semantic-only (e.g., Deer-Pony), associated-only (e.g., Bee-Honey), or semantic-and-associated (e.g., Doctor-Nurse). Controls showed greater priming of words related via two relationships (semantic-and-associated) than for words related only semantically.. However, patients showed greater priming for associated-only words than for words related only semantically. Schizophrenic patients may show an associational bias, restricting semantic integration and contributing to their disturbed thinking.

Background: The early visual-evoked gamma oscillation (VGO) elicited by Gestalt stimuli is reduced in schizophrenia patients compared to healthy individuals, but it is unknown whether this effect is specific to these particular stimuli and task. In contrast, the early auditory-evoked gamma oscillation (AGO) was reported to be unaffected in a sample of unmedicated, mostly first-episode schizophrenics (Gallinat et al, 2004, Clin Neurophysiol), but it is unknown whether this oscillation is abnormal in chronic, medicated patients. We investigated these issues by examining the VGO and AGO in chronic schizophrenics (SZ) and matched healthy controls (HC). Methods: Subjects (21 HC, 23 SZ) performed visual and auditory oddball tasks. Visual stimuli were letters, and auditory stimuli were simple tones. Event-related spectral measures (phase locking factor and evoked power) were computed on Morlet wavelet-transformed single epochs from the standard trials. Results: VGO phase locking at occipital electrodes was reduced in SZ compared to HC. In contrast, AGO phase locking and evoked power did not differ between groups. Conclusions: The VGO deficit may be a general phenomenon in schizophrenia, while the AGO evoked by simple tone stimuli does not appear to be abnormal in chronic, medicated schizophrenics.

Background: In chronic schizophrenia and chronic bipolar disorder, gamma band (30–100 Hz) auditory steady-state EEG responses (ASSRs) are reduced in power and phase locking, likely reflecting neural circuit dysfunction. Here we examined whether gamma ASSR deficits are also present at first hospitalization for psychosis. Methods: Subjects were 16 first episode schizophrenia patients (SZ), 16 first episode affective disorder patients (AFF) (13 with bipolar disorder), and 33 healthy controls (HC). Stimuli were 20, 30, and 40 Hz binaural click trains. ASSR phase locking and evoked power were analyzed using the Morlet wavelet transform. Results: At 40 Hz stimulation, SZ and AFF had significantly reduced phase locking compared to HC. This deficit was more pronounced over the left hemisphere in SZ. Evoked power at 40 Hz was also reduced in the patients compared to HC. At 30 Hz stimulation phase locking and evoked power were reduced in both patient groups. The 20 Hz ASSR did not differ between groups, but phase locking and evoked power of the 40 Hz harmonic of the 20 Hz ASSR were reduced in both SZ and AFF. Phase locking of this 40 Hz harmonic was correlated with total positive symptoms in SZ. Conclusions: The gamma ASSR deficit is present at first hospitalization for both schizophrenia and affective disorder, but shows a left hemisphere bias in first hospitalized SZ. Some of the neural circuitry abnormalities underlying the gamma ASSR deficit may be common to psychoses in general, while others may be specific to particular disorders.

Thirty patients with chronic schizophrenia and 30 age-matched controls performed the Attention Network Test (ANT). A subset of the patient group (n=18) also had available magnetic resonance diffusion tensor imaging (DTI) measures of the cingulum bundle (CB) fractional anisotropy and volume. The patients showed a significantly different pattern of ANT performance, characterized primarily by decreased alerting efficiency. In addition, left CB fractional anisotropy correlated significantly with orienting of attention. Smaller right CB volume also correlated with reduced alertness, but not when covarying for medication and illness duration.