Context Converging evidence from electrophysiological studies suggests that in individuals with schizophrenia EEG fast frontal oscillations are reduced. It is still unclear whether this reduction reflects an intrinsic deficit of underlying cortical/thalamo-cortical circuits, and whether this deficit is specific for frontal regions. Recent electrophysiological studies in healthy individuals have established that, when perturbed, different brain regions oscillate at a specific, intrinsically generated dominant frequency, the natural frequency. Objective To assess the natural frequency of posterior parietal, motor, premotor, and prefrontal cortices, in schizophrenic and healthy controls. Design High-density electroencephalogram (Hd-EEG) recordings during Transcranial Magnetic Stimulation (TMS) of four cortical areas were performed. Several TMS-evoked EEG oscillation parameters, including synchronization, amplitude, and natural frequency were compared across the schizophrenia and healthy control groups. Setting Wisconsin Psychiatric Institute & Clinic, University of Wisconsin-Madison Participants Twenty patients with schizophrenia and twenty age-matched healthy controls. Main Outcome Measures Hd-EEG measurements of TMS-evoked activity in four cortical areas, the positive and negative syndrome scale (PANSS), and performance scores (reaction time, accuracy) in two computerized tasks: the word memory (CPW) and the facial memory (CPF) tests. Results Schizophrenia patients showed a slowing in the natural frequency of frontal/prefrontal regions compared to healthy controls (from an average of 2 Hz decrease for the motor area, to almost 10 Hz for the prefrontal cortex). The prefrontal natural frequency of individuals with schizophrenia was slower than in any healthy comparison subject, and correlated with both positive PANSS scores and reaction time in the CPW. Conclusions These findings suggest that patients with schizophrenia have an intrinsic slowing in the natural frequency of frontal cortical/thalamo-cortical circuits, that this slowing is not present in parietal areas, and that the prefrontal natural frequency can predict some of the symptoms as well as the cognitive dysfunctions of schizophrenia.

Context Schizophrenia is a devastating illness with an indeterminate pathophysiology. Several lines of evidence implicate dysfunction in the thalamus, a key node in the distributed neural networks underlying perception, emotion, and cognition. Existing evidence of aberrant thalamic function is based on indirect measures of thalamic activity, but dysfunction has not yet been demonstrated with a causal method. Objective Test the hypothesis that direct physiological stimulation of cortex will produce an abnormal thalamic response in individuals with schizophrenia. Design We stimulated the precentral gyrus with single-pulse transcranial magnetic stimulation (spTMS) and measured the response to this pulse in synaptically-connected regions (thalamus, medial superior frontal cortex [mSFG], insula) using concurrent functional magnetic resonance imaging (fMRI). The mean hemodynamic response from these regions was fit with the sum of two gamma functions and response parameters were compared across groups. Setting Academic research laboratory. Participants Patients with schizophrenia and sex- and age- matched psychiatrically healthy subjects were recruited from the community. Main Outcome Measures Peak amplitude of the thalamic hemodynamic response to spTMS of precentral gyrus. Results spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared to healthy subjects, schizophrenia patients showed a reduced response to spTMS in the thalamus (P=1.86 × 10−9) and mSFG (P=.02). Similar results were observed in the insula. Sham TMS indicated that these results could not be attributed to indirect effects of TMS coil discharge. Functional connectivity analyses revealed weaker thalamus-mSFG and thalamus-insula connectivity in schizophrenia patients compared to control subjects. Conclusions Individuals with schizophrenia showed reduced thalamic activation in response to direct perturbation delivered to the cortex. These results extend prior work implicating the thalamus in the pathophysiology of schizophrenia and suggest that the thalamus contributes to the patterns of aberrant connectivity characteristic of this disease.

Despite the diversity of cells available for transplantation into sites of spinal cord injury (SCI), and the known ability of transplanted cells to integrate into host tissue, functional improvement associated with cellular transplantation has been limited. One factor potentially limiting the efficacy of transplanted cells is poor cell survival. Recently we demonstrated rapid and early death of Schwann cells (SCs) within the first 24 h after transplantation, by both necrosis and apoptosis, which results in fewer than 20% of the cells surviving beyond 1 week. To enhance SC transplant survival, in vitro and in vivo models to rapidly screen compounds for their ability to promote SC survival are needed. The current study utilized in vitro models of apoptosis and necrosis, and based on withdrawal of serum and mitogens and the application of hydrogen peroxide, we screened several inhibitors of apoptosis and necrosis. Of the compounds tested, the calpain inhibitor MDL28170 enhanced SC survival both in vitro in response to oxidative stress induced by application of H 2 O 2 , and in vivo following delayed transplantation into the moderately contused spinal cord. The results support the use of calpain inhibitors as a promising new treatment for promoting the survival of transplanted cells. They also suggest that in vitro assays for cell survival may be useful for establishing new compounds that can then be tested in vivo for their ability to promote transplanted SC survival.

Schizophrenia is a severe mental illness with neurobiological bases that remain elusive. One hypothesis emphasizes disordered thalamic function. We previously used concurrent single pulse transcranial magnetic stimulation (spTMS) and functional magnetic resonance imaging (fMRI) to show that individuals with schizophrenia have a decreased spTMS-evoked response in the thalamus, and decreased effective connectivity between thalamus and insula and thalamus and superior frontal gyrus. To better understand the factors that may accompany or account for these findings, we investigated, in the same participants, resting state functional connectivity, white matter structural connectivity, and grey matter integrity. Patients with schizophrenia did not differ from healthy control subjects in resting state functional-or white matter structural connectivity, although they did show decreased measures of grey matter integrity in the insula. However, in this region, the spTMS-evoked response did not differ between groups. In a region of the thalamus that also had grey matter intensity abnormalities, although not at a level that survived correction for multiple comparisons, the spTMS-evoked response in patients was deficient. These results suggest that measures of structure and function are not necessarily complementary. Further, given its sensitivity for identifying deficits not evident with traditional imaging methods, these results highlight the utility of spTMS-fMRI, a method that directly and causally probes effective connectivity, as a tool for studying brain-based disorders.

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