Potential applications of concurrent transcranial magnetic stimulation and functional magnetic resonance imaging in acquired brain injury and disorders of consciousness.

BACKGROUND: Diagnostic assessment, prognosis and treatment monitoring in patients with disorders of consciousness (DoC) rest largely on behaviorally-based procedures. This approach can lead to misdiagnosis, inaccurate outcome prediction and inappropriate judgements regarding the effectiveness of treatment interventions. Concurrent transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) may provide a biological measure of conscious awareness, aid clinicians in clinical decision-making and provide a treatment alternative for DoC. STUDY: This paper reviews the use of TMS and fMRI in the assessment of patients with DoC and suggests potential applications for concurrent use of these procedures.

Conserved functional connectivity but impaired effective connectivity of thalamocortical circuitry in schizophrenia.

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.

Reduced natural oscillatory frequency of frontal thalamocortical circuits in schizophrenia.

CONTEXT: Converging evidence from electrophysiological studies suggests that in individuals with schizophrenia, electroencephalographic frontal fast oscillations are reduced. It is still unclear whether this reduction reflects an intrinsic deficit of underlying cortical/thalamocortical 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 the posterior parietal, motor, premotor, and prefrontal cortices in patients with schizophrenia and healthy control subjects. DESIGN: High-density electroencephalographic recordings during transcranial magnetic stimulation of 4 cortical areas were performed. Several transcranial magnetic stimulation­evoked electroencephalographic oscillation parameters, including synchronization, amplitude, and natural frequency, were compared across the schizophrenia and healthy control groups. SETTING: Wisconsin Psychiatric Institute and Clinic, University of Wisconsin­Madison. PARTICIPANTS: Twenty patients with schizophrenia and 20 age-matched healthy control subjects. MAIN OUTCOME MEASURES: High-density electroencephalographic measurements of transcranial magnetic stimulation­evoked activity in 4 cortical areas, scores on the Positive and Negative Syndrome Scale, and performance scores (reaction time, accuracy) on 2 computerized tasks (word memory [Penn Word Recognition Test] and facial memory [Penn Facial Memory Test]). RESULTS: Patients with schizophrenia showed a slowing in the natural frequency of the frontal/prefrontal regions compared with healthy control subjects (from an average of a 2-Hz decrease for the motor area to an almost 10-Hz decrease 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 Positive and Negative Syndrome Scale scores and reaction time on the Penn Word Recognition Test. CONCLUSIONS: These findings suggest that patients with schizophrenia have an intrinsic slowing in the natural frequency of frontal cortical/thalamocortical 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.

Probing thalamic integrity in schizophrenia using concurrent transcranial magnetic stimulation and functional magnetic resonance imaging.

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: To test the hypothesis that direct physiological stimulation of the 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, insula) using concurrent functional magnetic resonance imaging. The mean hemodynamic response from these regions was fit with the sum of 2 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 MEASURE: Peak amplitude of the thalamic hemodynamic response to spTMS of the precentral gyrus. RESULTS: The spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared with healthy subjects, patients with schizophrenia showed a reduced response to spTMS in the thalamus (P=1.86 × 10(-9)) and medial superior frontal cortex (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-medial superior frontal cortex and thalamus-insula connectivity in patients with schizophrenia compared with 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.

A calpain inhibitor enhances the survival of Schwann cells in vitro and after transplantation into the injured spinal cord.

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 H2O2, 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.