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Original Article | ONLINE FIRST

Probing Thalamic Integrity in Schizophrenia Using Concurrent Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging FREE

Yelena Guller, BS; Fabio Ferrarelli, MD, PhD; Alexander J. Shackman, PhD; Simone Sarasso, PhD; Michael J. Peterson, MD, PhD; Frederick J. Langheim, MD, PhD; Mary E. Meyerand, PhD; Giulio Tononi, MD, PhD; Bradley R. Postle, PhD
[+] Author Affiliations

Author Affiliations: Departments of Psychiatry (Ms Guller and Drs Ferrarelli, Shackman, Sarasso, Peterson, Langheim, Tononi, and Postle), Psychology (Ms Guller and Dr Postle), and Biomedical Engineering (Dr Meyerand), Neuroscience Training Program (Ms Guller and Drs Meyerand, Tononi, and Postle), and HealthEmotions Research Institute (Dr Shackman), University of Wisconsin–Madison.


Arch Gen Psychiatry. 2012;69(7):662-671. doi:10.1001/archgenpsychiatry.2012.23.
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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.

Figures in this Article

Schizophrenia is a devastating mental illness that has a significant impact on family, caregivers, society, and patients.13 More than 2.4 million Americans are diagnosed as having schizophrenia,4 and mortality rates are 2 to 3 times greater for these patients compared with the population as a whole.5,6 Although research has focused heavily on identifying diagnostic tools7 and treatments8 for the illness, schizophrenia is currently diagnosed based on clinical criteria,9 treatments are often ineffective,10 and the pathophysiology of the disease remains elusive. The work presented here builds on numerous prior studies that have implicated dysfunction of the thalamus in schizophrenia. We review the theoretical and empirical basis for this hypothesis of thalamic dysfunction in schizophrenia and conclude that much of the extant evidence is either indirect or subject to significant inferential limitations. For instance, some studies rely on cortical differences or effects measured at the scalp to draw inferences about thalamic dysfunction. Others infer functional differences on the basis of structural measures or rely on the assumption that patient and control groups perform behavioral tasks in a comparable manner. We designed our experiment to circumvent these limitations, using single-pulse transcranial magnetic stimulation (spTMS) to directly stimulate the cortex and concurrent functional magnetic resonance imaging (fMRI) to measure the resulting thalamic response.

Three lines of evidence suggest that schizophrenia is associated with thalamic dysfunction. First, aberrant scalp-recorded electrophysiological indices of sensory gating in schizophrenia have been interpreted as evidence for thalamic dysfunction, given nonhuman research confirming the critical role of the thalamus in conceptually similar processes.1115 Sensory gating deficits in schizophrenia have been demonstrated using P50 prepulse inhibition,16,17 a P300 auditory oddball paradigm,18 and mismatch negativity tasks.1921 All of these paradigms have been interpreted as requiring thalamically mediated filtering of novel or salient stimuli. On this basis, some have suggested that hallucinations are a result of impaired thalamic filtering of salient and external speech from nonsalient and internal speech.22,23

A second line of evidence comes from overnight electroencephalographic studies demonstrating sleep spindle deficits in individuals with schizophrenia. Sleep spindles are waxing and waning 12- to 16-Hz oscillations initiated by the thalamic reticular nucleus (TRN) and regulated by thalamoreticular and thalamocortical circuits.24,25 Individuals with schizophrenia display fewer and smaller sleep spindles. These metrics distinguish patients from healthy control subjects, medicated control subjects, and individuals with depression with high sensitivity and specificity.2628

A third line of evidence implicating the thalamus in schizophrenia comes from studies that directly measured the thalamus using structural and functional neuroimaging techniques. Structural imaging studies have consistently identified decreases in thalamic gray matter2931 and aberrant thalamic morphology32,33 in individuals with schizophrenia. In parallel, functional imaging studies have consistently found abnormal thalamic activation during sensory gating,32,33 working memory,34 and other executive function3540 tasks.

Although these studies have contributed to an important model of the pathophysiology of schizophrenia, most are subject to 1 of 3 key inferential limitations. One limitation is that studies using scalp-recorded electrophysiology, as in studies of sensory gating and sleep, do not measure thalamic activity directly. A second is that structural imaging studies cannot address thalamic physiology and are therefore unable to directly test hypotheses of thalamic dysfunction. A third is that most studies using fMRI measure thalamic activity in the context of task performance and are therefore susceptible to detecting group differences in physiology that are mediated by performance differences (eg, attention, compliance, comprehension, motivation, strategy) rather than differences in underlying disease-related neurobiology.3638

The aim of our study was to circumvent these limitations and more directly test the hypothesis that the thalamus functions abnormally in schizophrenia. We used spTMS to present a direct physiological challenge to the cortex while we simultaneously measured the transynaptic response to this challenge in the thalamus with fMRI. Transcranial magnetic stimulation uses electromagnetic induction to noninvasively produce weak currents in the tissue underlying the TMS coil.39 In addition to affecting the tissue that experiences the magnetic flux directly, depolarization at the stimulation site propagates to distal regions via synaptic transmission or spread of neural impulses.40,41 Whereas repetitive TMS is thought to create a transient “virtual lesion” by overwhelming a brain region with noise42 or otherwise altering ongoing neural functioning,43,44 spTMS transiently excites discrete cortical patches without producing prolonged changes in cortical excitability or function. The use of spTMS permits concurrent measurement of both the local response and the response in distal regions functionally connected to the stimulation site.41,45,46 In our study, the cortical and thalamic responses to spTMS were measured using blood oxygen level–dependent fMRI.47 Although concurrent TMS-fMRI has been used to evaluate brain function in healthy individuals48,49 and a number of commentators have highlighted the potential benefits of using this technique to probe the neurobiology of schizophrenia,50,51 to our knowledge it has never before been applied to the study of any psychiatric illness.

Here, spTMS was delivered to the precentral gyrus and the resulting hemodynamic response was parameterized (amplitude, peak latency, and width) in 4 regions of interest (ROIs). Hypothesis testing focused on group differences in peak amplitude in the thalamus. Differences in the hemodynamic response were also assessed in the cortex beneath the TMS coil (precentral gyrus), the medial superior frontal gyrus (mSFG), and the insula. Exploratory analyses were used to characterize group differences in the latter 2 cortical ROIs, and measures of functional connectivity were computed. Results were compared with sham TMS. A button-pressing (BP) task was also assessed to confirm that spTMS-evoked responses were qualitatively similar to those obtained with a standard motor task. We hypothesized and demonstrated that patients with schizophrenia show a reduced thalamic response to spTMS.

Procedures were approved by the University of Wisconsin–Madison Health Sciences Institutional Review Board. Written informed consent was obtained from all subjects.

SUBJECTS

Fourteen healthy subjects and 14 subjects with schizophrenia, recruited from local mental health care providers through newspaper and Internet advertisements and by word of mouth, participated in the study (Table 1). A psychiatrist interviewed all subjects to obtain psychiatric and medical histories and to exclude (healthy control subjects) or confirm (patients with schizophrenia) diagnoses using DSM-IV-TR criteria9 (eAppendix). The Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Patient Edition52 was also administered. Symptom severity was evaluated using the Positive and Negative Syndrome Scale.53

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Healthy Control Subjects and Patients With Schizophrenia

Patients were diagnosed as having the following subtypes: paranoid (n = 11), residual (n = 1), catatonic (n = 1), or undifferentiated (n = 1). They were receiving second-generation (n = 10), first- and second-generation (n = 2), or first-generation (n = 2) antipsychotic medications. All were outpatients with a stable chronic illness (mean [SD], 11 [7] years).

DESIGN OVERVIEW

The study consisted of 2 sessions occurring on separate days. During the first session, structural MRIs required for the subsequent spTMS-fMRI session were collected; data for the first session for some subjects were obtained from a prior study. The second session featured 2 challenges. The first was spTMS to the precentral gyrus of the left hemisphere. The second was a BP task known to produce a well-characterized hemodynamic response54 (11 subjects performed this task during the first session).

Four criteria led us to select the precentral gyrus as the spTMS target. First, to ensure that spTMS-induced input to thalamus would be comparable across groups, we required a target that is not dysfunctional in schizophrenia. Thus, we ruled out the prefrontal cortex, for example.55,56 Second, we required a target easily accessible in the scanner and not covered in musculature,57 ruling out the occipital and temporal lobes. Third, we preferred a target that has a well-characterized hemodynamic response, that has been studied in prior TMS-fMRI research, and whose activity is associated with robust thalamic activity.46,58 Fourth, given the sleep spindle abnormality described earlier,26,59 we preferred a target with robust projections to the TRN.60 The precentral gyrus satisfied all of these criteria.

Session 1: Structural MRI Data Acquisition

During the first session, T1-weighted high-resolution structural images (echo time [TE] = 3.2 milliseconds; repetition time [TR] = 8.2 milliseconds; field of view [FOV] = 25.6 cm; matrix = 256 × 256; 156 × 1.0-mm slices; no inversion recovery) were collected using a 3-T General Electric Discovery 750 MRI scanner. Single-subject data were transferred to a Navigated Brain Stimulation (frameless stereotaxy) system (Nexstim), and the TMS target (left precentral gyrus in the vicinity of the primary hand representation [knob]61) was identified.

Session 2: spTMS Targeting and fMRI Acquisition

Session 2 included (1) coregistering the subject's head with the high-resolution T1 image to determine TMS positioning and (2) fMRI scanning. The order of functional scanning was as follows: spTMS to the precentral gyrus, BP task (if not obtained during the first session), spTMS to another TMS target (data not shown), and sham TMS (eAppendix). Each time the TMS coil was relocated, the subject was repositioned in the scanner. Following each scan with spTMS, a medium-resolution structural scan was obtained. All MRI sessions occurred at the same time of day (early afternoon).

spTMS Targeting. The Navigated Brain Stimulation system was used to coregister each subject to his or her own T1 (eFigure 1 and eAppendix). Stimulation intensity was determined by delivering spTMS at varying intensities (using a staircasing procedure62) to the hand area of the precentral gyrus until an intensity that evoked a contralateral motor response to 5 of 10 pulses was reached. The spTMS was delivered using a 70-mm figure-8 coil and biphasic stimulator (Magstim Rapid 2). To avoid evoking motor responses in the scanner, we used the Navigated Brain Stimulation system to move the coil along the precentral gyrus until a location that did not evoke a motor response was identified. Because the Navigated Brain Stimulation system is not MRI compatible, the exact position of the TMS coil was traced onto a cap worn by the subject, allowing stimulation to be delivered to the same location using an MRI-compatible TMS coil in the scanner. The subject was then escorted to the scanner.

fMRI Acquisition To minimize startle from the click associated with the TMS coil, subjects were fitted with Avotec pneumatic headphones through which white noise was played during the session. Volume was titrated to the maximum level that the subject could comfortably tolerate. Foam padding was used to minimize movement. An MRI-compatible TMS coil (Magstim and Jali Medical) was attached to a custom multijointed mount (eFigure 1 and eAppendix). An 8-foot radiofrequency-shielded cable, passed through a waveguide in the penetration panel, connected the TMS coil in the scanner to the stimulator in the control room.

The TMS coil was aligned to the coil tracing on the subject's cap. Single pulses were delivered to confirm that movements were not evoked. Subjects were instructed to remain calm, still, and awake with open eyes.

The first scan was a localizer image, followed by a higher-order shim (TE = 7.0 milliseconds; TR = 1558 milliseconds; FOV = 24 cm; slice thickness = 5.8 mm) and field map (TE = 7 and 10 milliseconds; TR = 710 milliseconds; FOV = 20 cm; matrix = 256 × 256; 25 × 1.0-mm slices). This was followed by two 20-pulse runs of spTMS to the precentral gyrus (110% motor threshold; intertrial interval = 16-24 seconds) and one 20-pulse run of the BP task. To minimize TMS artifacts, the pulse sequence for these echo-planar images (TR = 2000 milliseconds; TE = 25 milliseconds; FOV = 22.4 cm; matrix = 64 × 64; 35 × 3.0-mm slices [0.6-mm gap]; flip angle = 60°) was modified such that image acquisition occurred during the first 1770 milliseconds of the TR, thereby leaving a 230-millisecond silent gap during which spTMS could be delivered (eFigure 2). The same pulse sequence was used for the BP task, during which subjects were instructed to press a button with their right thumb as firmly and as quickly as possible following a 500-millisecond tone (Current Designs). Stimuli were controlled by E-Prime (Psychology Software Tools) and transistor-transistor logic pulses generated by the scanner. Finally, a medium-resolution structural scan (TR = 4.3 milliseconds; TE = 1.22 milliseconds; FOV = 28 cm; matrix = 256 × 256; 60 × 2.6-mm slices) was collected.

The subject was then slid out of the scanner and the TMS coil was configured for sham stimulation. The procedure was repeated with 2 runs of sham TMS replacing spTMS (for details of the sham TMS procedure, see eAppendix). One subject in each group discontinued participation in the experiment prior to collection of sham TMS data.

DATA PREPROCESSING

Except where otherwise noted, processing used AFNI (http://afni.nimh.nih.gov)63 and in-house software. Functional images were first reconstructed on the scanner. Images were corrected for slice time, motion, and field map using FSL software (http://www.fmrib.ox.ac.uk/fsl).64 Data were masked to exclude extracerebral voxels and converted to percent signal change. Functional images were aligned to the high-resolution T1 using the transformation matrix generated by aligning the medium- to the high-resolution T1 and then applying the transformation matrix to the functional data (6 df, least squares, sinc interpolation; resampled to 3 × 3 × 3.6 mm).

For each subject, the hemodynamic response was modeled using a generalized least-squares fit with restricted maximum likelihood estimation of temporal autocorrelation. Hemodynamic responses were modeled using a set of triangular (tent) functions (9 tents; 0-16 seconds). Similar to other basis functions (eg, finite impulse responses), this allowed the amplitude, peak latency, and width of the hemodynamic response to vary.

ANALYSIS

The aim of this investigation was to test whether individuals with schizophrenia show an attenuated thalamic response to cortical spTMS. To accomplish this, we used an a priori ROI-based strategy. This approach has 2 advantages. First, statistical power is maximized by eliminating the need to correct for thousands of voxelwise comparisons. Second, this strategy circumvents the assumption that the thalamus is anatomically similar in patients and control subjects. The ROIs were prescribed in the axial plane on the high-resolution T1, referring to a human brain atlas65 as needed (eTable 1 and eAppendix).

In addition to interrogating the stimulation site and the thalamus, we analyzed 2 other regions. The mSFG was selected for exploratory analyses after visual inspection of activation maps from the first 8 subjects enrolled in the study revealed that it was consistently and robustly activated by spTMS. When these analyses revealed abnormal thalamocortical coupling in schizophrenia, we assessed the generality of this finding by interrogating the insula, for which thalamic dysconnectivity in schizophrenia was recently reported.66 Importantly, for each subject, the nearest border of the mSFG and insula ROIs was always located several centimeters from the site targeted for spTMS. Because direct electromagnetic induction is limited to an area of approximately 2 cm2 and a depth of 2 cm,67,68 the responses observed in these regions (and the thalamus) were necessarily due to synaptic transmission.

For each ROI, a mask was created containing the upper fifth percentile of voxels responsive to spTMS (determined using the t statistic at the peak of each individual's hemodynamic response [4-6 seconds]). The hemodynamic response from these voxels was parameterized using the sum of 2 gamma functions (in units of percent signal change). The gamma functions were upsampled from 2000-millisecond (ie, the original sampling rate) to 10-millisecond resolution.69 This fit enabled us to extract model parameters corresponding to the amplitude, peak latency, and overall width (at approximately the full width at half maximum) of the hemodynamic response and then to compare them across groups.

For spTMS and sham TMS conditions, 1 of 2 runs was analyzed. Although a single 20-trial run is sufficient to produce a BP-evoked hemodynamic response,54 the technical challenges inherent in measuring the spTMS-evoked response with fMRI led us to collect a second spTMS run as a backup. For the analyses reported here, we selected the run in which the t statistic (corresponding to the greatest difference from baseline) was most similar to that of the BP run (see eAppendix for details about run selection and results from analyses of unselected runs). To control for nonspecific TMS effects, thalamic voxels responsive to spTMS were also compared with sham TMS.

When analyses of the spTMS-evoked responses in the mSFG and insula revealed group differences in amplitude in these regions, we assessed group differences in functional connectivity among ROIs. Specifically, time series were averaged across the upper fifth percentile of voxels within each ROI for each subject, demeaned, correlated, and then Z transformed using the Fisher technique.

HYPOTHESIS TESTING

Between-groups analyses of variance, t tests, Pearson correlations, and discriminant analyses were performed with SPSS Statistics version 20.0.0 software (SPSS Inc). Gamma fit parameters were also assessed with nonparametric statistics, which yielded similar conclusions (not reported). Owing to nonnormality of the connectivity metric, coefficients were rank transformed prior to testing.70,71 Hemodynamic response curves and their associated 95% CIs (computed using group means and standard errors at each time point) were plotted using in-house code written for R software (http://www.r-project.org). Effect size is reported as partial η2. The spTMS and BP task were not formally compared because we did not have theoretically motivated hypotheses involving this comparison.

CORTICAL RESPONSE TO spTMS, BUT NOT BP TASK, IS SIMILAR ACROSS GROUPS

The spTMS-evoked response did not differ between groups in the precentral gyrus (F1,26 = 0.52; P = .48; η2 = 0.02). However, during the BP task, patients with schizophrenia showed a wider hemodynamic response (F1,26 = 5.86; P = .02; η2 = 0.18) (Figure 1). There were no group differences in BP reaction time (F1,26 = 2.05; P = .16; η2 = 0.07).

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Figure 1. Group-averaged cortical response to single-pulse transcranial magnetic stimulation (spTMS) in the cortical region underlying the TMS coil (precentral gyrus) (A) and to a button-pressing (BP) task in the precentral gyrus (B) (n = 14 in each group). Shaded areas indicate 95% CIs. * P < .05. Insets, Single-subject representation of the region of interest (yellow) and the voxels most responsive to the condition (red). L indicates left; R, right.

THALAMIC RESPONSES TO spTMS AND BP TASK ARE ABNORMAL IN SCHIZOPHRENIA

In the spTMS condition, individuals with schizophrenia showed a smaller (F1,26 = 80.79; P = 1.86 × 10−9; η2 = 0.76) and earlier peaking (F1,26 = 4.39; P = .05; η2 = 0.14) thalamic response. Indeed, every patient showed a peak that was numerically smaller than the least responsive member of the control group (Figure 2C) (range of percent signal change, 0.26%-0.80% for patients vs 0.88%-1.67% for healthy subjects). A formal discriminant analysis indicated that this measure did an excellent job classifying members of the 2 groups (χ2 = 36.0; P = 1.95 × 10−9; leave-one-out cross-validation: sensitivity = 85.7%; specificity = 100.0%; overall classification accuracy = 92.9%). Peripheral consequences of spTMS stimulation could not account for this effect because, compared with spTMS, sham TMS produced a nonexistent response (patients: F1,12 = 16.33; P = .002; η2 = 0.58; healthy subjects: F1,12 = 135.50; P = 6.8 × 10−8; η2 = 0.92) that did not differ between groups (F1,24 = 3.0 × 10−5; P > .99; η2 = 1.0 × 10−6) (Figure 2). The BP task showed a similar, albeit weaker, pattern (F1,26 = 10.69; P = .003; η2 = 0.29) (Figure 2).

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Figure 2. Group-averaged response to single-pulse transcranial magnetic stimulation (spTMS) (A) and to a button-pressing (BP) task (B) in the thalamus (n = 14 in each group) as well as the sham TMS response in the same voxels (n = 13 in each group). Shaded areas indicate 95% CIs. * P < .05; † P = 1.86 × 10−9. Insets, Single-subject representation of the region of interest (yellow) and the voxels most responsive to the condition (red). L indicates left; R, right. Dot plots illustrate single-subject peak percent signal change (extracted 3-6.5 seconds following spTMS delivery) in response to spTMS (C) and the BP task (D) with the group means (horizontal lines) and SEMs (gray boxes) indicated. Because peak latency varied across subjects, the group means shown in C and D necessarily differ from the maxima of the average hemodynamic response function waveforms depicted in A and B. C and D represent data used for hypothesis testing.

mSFG AND INSULA RESPONSES TO PRECENTRAL GYRUS spTMS ARE DECREASED IN SCHIZOPHRENIA

The spTMS-evoked response was smaller in magnitude in the mSFG in patients with schizophrenia compared with healthy control subjects (F1,26 = 6.56; P = .02; η2 = 0.20) (Figure 3). To explore possible factors underlying this difference, we assessed functional connectivity between the precentral gyrus and mSFG, between the mSFG and thalamus, and between the precentral gyrus and thalamus (using time-series correlations). These analyses found no group differences in precentral gyrus–mSFG connectivity (F1,26 = 0.47; P = .31; η2 = 0.02) or in precentral gyrus–thalamus connectivity (F1,26 = 0.02; P = .61; η2 = 0.001) but did reveal that patients with schizophrenia had reduced coupling between the thalamus and mSFG relative to healthy control subjects (F1,26 = 32.00; P = 6.0 × 10−5; η2 = 0.55) (Table 2). Importantly, the lack of a group difference in coupling between the precentral gyrus and mSFG was not simply a function of low overall connectivity between these regions; actual magnitudes of the correlations reflected a relatively high level of functional connectivity in both groups (Table 2).

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Figure 3. Group-averaged medial superior frontal gyrus response to single-pulse transcranial magnetic stimulation (spTMS) of the precentral gyrus (n = 14 in each group). Shaded areas indicate 95% CIs. * P < .05. Inset, Single-subject representation of the region of interest (yellow) and the voxels most responsive to the condition (red). L indicates left; R, right.

Table Graphic Jump LocationTable 2. Group Mean Correlation Coefficient Between ROI Time Series

Variation in thalamocortical coupling also predicted the magnitude of the spTMS-evoked mSFG response. Across groups, subjects with lower thalamus-mSFG coupling showed a smaller evoked response in the mSFG (ρ26 = 0.37; P = .05). Results for the insula were complementary to those for the mSFG (eFigure 3, eTable 2, and eAppendix).

CONTROL ANALYSES

Disease chronicity and medication dosage, assessed using chlorpromazine equivalents,72 did not predict any of the brain measures (all P > .13). Across groups, variation in years of formal education did not predict any brain measure (all P > .15). Likewise, accounting for variation in education did not substantively alter the significance of any group difference. Because the majority of the patients with schizophrenia (n = 11) were diagnosed as having paranoid schizophrenia and the remaining 3 subjects were diagnosed as having residual, undifferentiated, or catatonic schizophrenia, it was not possible to meaningfully assess the effect of subtype. Nevertheless, analyses performed with these 3 individuals omitted did not alter any of our conclusions.

THALAMIC DEFICITS AND SYMPTOM SEVERITY

There was a trend for patients with smaller thalamic responses to spTMS to show more severe positive symptoms on the Positive and Negative Syndrome Scale (r12 = −0.49; P = .07). Relationships with negative symptoms were not significant (r12 = −0.17; P = .57).

Schizophrenia is a severe mental illness whose neurobiology remains unclear.13 There is considerable circumstantial evidence of a thalamic abnormality in schizophrenia as assessed structurally29,30 and functionally.32,33 Our results strengthen this hypothesis of thalamic dysfunction in schizophrenia with a procedure that supports causal inference: subjects with schizophrenia evinced a smaller spTMS-evoked response in the thalamus compared with healthy control subjects. Analysis of a sham stimulation condition indicated that these effects could not be attributed to secondary consequences of spTMS. Additionally, because no group differences were found in response to spTMS in the precentral gyrus, the results likely reflect local deficits in thalamic physiology, not downstream consequences of deficits in cortical function.

ABNORMAL THALAMIC FUNCTIONING IN SCHIZOPHRENIA IS CONFIRMED WITH spTMS-fMRI

The average thalamic spTMS-evoked response in patients with schizophrenia was less than half the magnitude of the average response in healthy subjects. Although this measure identified individuals from the 2 groups with 100% specificity, additional research is needed to determine whether the groups are better characterized as falling into 1 of 2 clusters or as falling along a continuum on which patients with schizophrenia tend to have lower values. In terms of pathophysiology, the difference might be due to 1 of 3 factors: (1) a physiological abnormality in the stimulated cortical tissue, (2) deficient corticothalamic signal propagation, or (3) a physiological abnormality in the thalamus. The first possibility is ruled out by the fact that the response in cortical tissue underlying spTMS did not differ across groups. The second seems unlikely because the connectivity between the thalamus and precentral gyrus, that is, the degree of corticothalamic coupling, did not differ across groups. The most likely interpretation, therefore, is that our results reflect aberrant functioning of the thalamus itself, a claim consistent with evidence of structural abnormalities2931,73,74 in the thalamus in subjects with schizophrenia.

mSFG AND INSULA SHOW DECREASED spTMS-EVOKED RESPONSE IN SCHIZOPHRENIA

Group differences in spTMS-evoked responses were also observed in the mSFG and insula, cortical regions distal to the site of spTMS delivery. Such findings could be attributed to (1) a functional deficit in the mSFG or insula, (2) a deficit in the region of stimulation (precentral gyrus) or its coupling with the mSFG or insula, or (3) an abnormality in a third area that is connected to both the precentral gyrus and the mSFG or insula (eg, the thalamus) or the coupling with this third area. Again, the results of the functional connectivity analysis support the third possibility, revealing reduced coupling between the thalamus and mSFG and the thalamus and insula in patients with schizophrenia but no difference in the degree of coupling between the precentral gyrus and these regions. (Note that in healthy control subjects, coupling between the mSFG and thalamus was significantly stronger than coupling between the precentral gyrus and thalamus [eAppendix]. Although this specific pattern does not alter the reasoning behind our interpretation of the group difference in overall patterns of functional connectivity, it is an intriguing observation that may merit future investigation.) Further consistent with the third scenario, when data from the groups were combined, the strength of the thalamus-mSFG coupling predicted the magnitude of the TMS-evoked responses in the mSFG and, likewise, the strength of the thalamus-insula coupling predicted the magnitude of the TMS-evoked responses in the insula. Taken together, these observations strongly suggest that the group difference in the magnitude of the mSFG and insula responses to spTMS reflects deficits centered on the thalamus or thalamocortical circuitry rather than local cortical deficits. Thus, although numerous studies have shown aberrant activation in cortical areas in response to various tasks in schizophrenia,37,75,76 our results suggest that such deficits could reflect underlying deficits in structures connected with the cortex such as the thalamus.77,78 The extent to which the abnormal coupling between the thalamus and mSFG and the thalamus and insula can be attributed to dysfunction in thalamic activity per se, compared with the integrity of structural connections between these regions, requires further investigation.79

CLINICAL SIGNIFICANCE

Numerically, there was no overlap in the amplitude of TMS-evoked thalamic response between patients with schizophrenia and healthy subjects. Additionally, the thalamic response amplitude in patients showed a trend toward predicting the severity of positive symptoms, a result in accord with similar relationships observed with sleep spindle data.26 Consequently, our results not only confirm the thalamic abnormality in schizophrenia but also show that it may be related to clinical symptoms.

FUTURE CHALLENGES

Several limitations of this investigation represent challenges for future research. First, although sleep spindle data suggest that thalamic deficits do not reflect a group difference in medication,26 it will be necessary to replicate our results while controlling for effects of medication. Additionally, further investigation with first-degree relatives will be necessary for understanding the potential genetic components of the abnormality in the thalamus. Investigating patients with first-episode schizophrenia will help discern whether the thalamic abnormality is present in early as well as later stages of the illness. Future studies will be required to assess the influence of potentially important demographic and diagnostic variables (eg, socioeconomic status, subtype).

A DEFICIT IN THE TRN?

The sleep spindle deficit in schizophrenia implicates a thalamic, and more specifically a TRN, abnormality in schizophrenia.26 Because the TRN, a structure that surrounds the dorsal and lateral portions of the thalamus, is very thin (approximately 1 mm in cross section80), it is not possible to resolve it with conventional fMRI techniques. There are 2 reasons, however, to believe that the activity we measured in the thalamus is heavily weighted by contributions of the TRN. First, the sole efferents from the TRN are inhibitory projections to the underlying thalamus. (Thus, the totality of the synaptic activity attributable to TRN output will be reflected in the blood oxygen level–dependent signal from the principal thalamic nuclei that receive these outputs.) Second, synaptic activity in the TRN is likely to be larger in magnitude than synaptic activity in principal thalamic nuclei. This is because there are 3.7 times more excitatory glutamatergic corticothalamic synapses onto the TRN than onto principal thalamic nuclei and because excitatory postsynaptic currents are 2.5 times larger in the TRN than in thalamocortical neurons.81 Consequently, it is plausible that the blood oxygen level–dependent signal we measured in the thalamus was heavily weighted by cortico-TRN-thalamic propagation of the spTMS-evoked response and that the decreased spTMS-evoked thalamic response in subjects with schizophrenia may reflect a more specific abnormality in the TRN.

Animal studies support the idea that the TRN is necessary for sensory gating and attention modulation,82,83 brain functions aberrant in schizophrenia.19,84,85 More evidence gleaned from animal models and higher-resolution imaging or postmortem studies in humans will be necessary to more fully test this hypothesis.

In summary, this study implicates an abnormality in the thalamus in the neurobiology of schizophrenia. This physiological abnormality cannot be attributed to differences in attention, compliance, or task performance that may exist between groups. Future studies will need to determine whether this deficit stems specifically from dysfunction of the TRN. More generally, this study underscores the value of concurrent spTMS-fMRI for probing the integrity of distributed neural circuits in psychiatric populations.

Correspondence: Yelena Guller, BS, Neuroscience Training Program, University of Wisconsin–Madison, 438E, W. J. Brogden Hall, 1202 W Johnson St, Madison, WI 53706 (guller@wisc.edu).

Submitted for Publication: October 27, 2011; final revision received December 13, 2011; accepted December 16, 2011.

Published Online: March 5, 2012. doi:10.1001/archgenpsychiatry.2012.23

Financial Disclosure: None reported.

Funding/Support: This work was supported by grants R01-MH064498 (Dr Postle), 20MH-077967-01A (Dr Tononi), RC1MH090912-12 (Dr Meyerand), and T31-GM007507 (Neuroscience Training Program) from the National Institutes of Health.

Previous Presentation: This paper was presented in part at the 66th Annual Meeting of the Society of Biological Psychiatry; May 14, 2011; San Francisco, California.

Additional Contributions: Daniel Acheson, PhD, Tom Johnstone, PhD, John Ollinger, PhD, and Adam Riggall assisted with programming; Eva Feredoes, PhD, and Andrew Fox gave advice; and Michael Anderle, BA, Rasmus Birn, PhD, Kristina Bolduc, BBA, Jenelle Fuller, BA, Marti Garcia, BS, Andy Mulder, and DJ Nephew, BS, provided technical assistance.

Nicholl D, Akhras KS, Diels J, Schadrack J. Burden of schizophrenia in recently diagnosed patients: healthcare utilisation and cost perspective.  Curr Med Res Opin. 2010;26(4):943-955
PubMed   |  Link to Article
Caqueo-Urízar A, Gutiérrez-Maldonado J, Miranda-Castillo C. Quality of life in caregivers of patients with schizophrenia: a literature review.  Health Qual Life Outcomes. 2009;7:84
PubMed   |  Link to Article
Corring DJ. Quality of life: perspectives of people with mental illnesses and family members.  Psychiatr Rehabil J. 2002;25(4):350-358
PubMed
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.  Arch Gen Psychiatry. 2005;62(6):593-602
PubMed   |  Link to Article
Osby U, Correia N, Brandt L, Ekbom A, Sparén P. Mortality and causes of death in schizophrenia in Stockholm county, Sweden.  Schizophr Res. 2000;45(1-2):21-28
PubMed   |  Link to Article
Meltzer HY, Baldessarini RJ. Reducing the risk for suicide in schizophrenia and affective disorders.  J Clin Psychiatry. 2003;64(9):1122-1129
PubMed   |  Link to Article
Schwarz E, Izmailov R, Spain M, Barnes A, Mapes JP, Guest PC, Rahmoune H, Pietsch S, Leweke FM, Rothermundt M, Steiner J, Koethe D, Kranaster L, Ohrmann P, Suslow T, Levin Y, Bogerts B, van Beveren NJ, McAllister G, Weber N, Niebuhr D, Cowan D, Yolken RH, Bahn S. Validation of a blood-based laboratory test to aid in the confirmation of a diagnosis of schizophrenia.  Biomark Insights. 2010;5:39-47
PubMed
Thaker GK. Schizophrenia endophenotypes as treatment targets.  Expert Opin Ther Targets. 2007;11(9):1189-1206
PubMed   |  Link to Article
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders4th ed, text revision. Washington, DC: American Psychiatric Association; 2000
Abbott A. Schizophrenia: the drug deadlock.  Nature. 2010;468(7321):158-159
PubMed   |  Link to Article
McCormick DA, Bal T. Sensory gating mechanisms of the thalamus.  Curr Opin Neurobiol. 1994;4(4):550-556
PubMed   |  Link to Article
Jones EG. The Thalamus. 2nd ed. Cambridge, England: Cambridge University Press; 2007
Sherman SM, Guillery RW. Exploring the Thalamus and Its Role in Cortical Function. 2nd ed. Cambridge, MA: MIT Press; 2006
Wolf R, Matzke K, Paelchen K, Dobrowolny H, Bogerts B, Schwegler H. Reduction of prepulse inhibition (PPI) after neonatal excitotoxic lesion of the ventral thalamus in pubertal and adult rats.  Pharmacopsychiatry. 2010;43(3):99-109
PubMed   |  Link to Article
Krause M, Hoffmann WE, Hajós M. Auditory sensory gating in hippocampus and reticular thalamic neurons in anesthetized rats.  Biol Psychiatry. 2003;53(3):244-253
PubMed   |  Link to Article
Potter D, Summerfelt A, Gold J, Buchanan RW. Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia.  Schizophr Bull. 2006;32(4):692-700
PubMed   |  Link to Article
Brockhaus-Dumke A, Schultze-Lutter F, Mueller R, Tendolkar I, Bechdolf A, Pukrop R, Klosterkoetter J, Ruhrmann S. Sensory gating in schizophrenia: P50 and N100 gating in antipsychotic-free subjects at risk, first-episode, and chronic patients.  Biol Psychiatry. 2008;64(5):376-384
PubMed   |  Link to Article
Kim DI, Mathalon DH, Ford JM, Mannell M, Turner JA, Brown GG, Belger A, Gollub R, Lauriello J, Wible C, O’Leary D, Lim K, Toga A, Potkin SG, Birn F, Calhoun VD. Auditory oddball deficits in schizophrenia: an independent component analysis of the fMRI multisite function BIRN study.  Schizophr Bull. 2009;35(1):67-81
PubMed   |  Link to Article
Salisbury DF, Shenton ME, Griggs CB, Bonner-Jackson A, McCarley RW. Mismatch negativity in chronic schizophrenia and first-episode schizophrenia.  Arch Gen Psychiatry. 2002;59(8):686-694
PubMed   |  Link to Article
Javitt DC. Intracortical mechanisms of mismatch negativity dysfunction in schizophrenia.  Audiol Neurootol. 2000;5(3-4):207-215
PubMed   |  Link to Article
Javitt DC, Doneshka P, Grochowski S, Ritter W. Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia.  Arch Gen Psychiatry. 1995;52(7):550-558
PubMed   |  Link to Article
Behrendt RP, Young C. Hallucinations in schizophrenia, sensory impairment, and brain disease: a unifying model.  Behav Brain Sci. 2004;27(6):771-830
PubMed
Behrendt RP. Dysregulation of thalamic sensory “transmission” in schizophrenia: neurochemical vulnerability to hallucinations.  J Psychopharmacol. 2006;20(3):356-372
PubMed   |  Link to Article
Fuentealba P, Steriade M. The reticular nucleus revisited: intrinsic and network properties of a thalamic pacemaker.  Prog Neurobiol. 2005;75(2):125-141
PubMed   |  Link to Article
Steriade M, Deschênes M, Domich L, Mulle C. Abolition of spindle oscillations in thalamic neurons disconnected from nucleus reticularis thalami.  J Neurophysiol. 1985;54(6):1473-1497
PubMed
Ferrarelli F, Peterson MJ, Sarasso S, Riedner BA, Murphy MJ, Benca RM, Bria P, Kalin NH, Tononi G. Thalamic dysfunction in schizophrenia suggested by whole-night deficits in slow and fast spindles.  Am J Psychiatry. 2010;167(11):1339-1348
PubMed   |  Link to Article
Ferrarelli F, Huber R, Peterson MJ, Massimini M, Murphy M, Riedner BA, Watson A, Bria P, Tononi G. Reduced sleep spindle activity in schizophrenia patients.  Am J Psychiatry. 2007;164(3):483-492
PubMed   |  Link to Article
Vukadinovic Z. Sleep abnormalities in schizophrenia may suggest impaired trans-thalamic cortico-cortical communication: towards a dynamic model of the illness.  Eur J Neurosci. 2011;34(7):1031-1039
PubMed   |  Link to Article
Ellison-Wright I, Bullmore E. Anatomy of bipolar disorder and schizophrenia: a meta-analysis.  Schizophr Res. 2010;117(1):1-12
PubMed   |  Link to Article
Glahn DC, Laird AR, Ellison-Wright I, Thelen SM, Robinson JL, Lancaster JL, Bullmore E, Fox PT. Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis.  Biol Psychiatry. 2008;64(9):774-781
PubMed   |  Link to Article
Adriano F, Spoletini I, Caltagirone C, Spalletta G. Updated meta-analyses reveal thalamus volume reduction in patients with first-episode and chronic schizophrenia.  Schizophr Res. 2010;123(1):1-14
PubMed   |  Link to Article
Tregellas JR, Davalos DB, Rojas DC, Waldo MC, Gibson L, Wylie K, Du YP, Freedman R. Increased hemodynamic response in the hippocampus, thalamus and prefrontal cortex during abnormal sensory gating in schizophrenia.  Schizophr Res. 2007;92(1-3):262-272
PubMed   |  Link to Article
Tregellas JR, Ellis J, Shatti S, Du YP, Rojas DC. Increased hippocampal, thalamic, and prefrontal hemodynamic response to an urban noise stimulus in schizophrenia.  Am J Psychiatry. 2009;166(3):354-360
PubMed   |  Link to Article
Bor J, Brunelin J, Sappey-Marinier D, Ibarrola D, d’Amato T, Suaud-Chagny MF, Saoud M. Thalamus abnormalities during working memory in schizophrenia: an fMRI study.  Schizophr Res. 2011;125(1):49-53
PubMed   |  Link to Article
Andrews J, Wang L, Csernansky JG, Gado MH, Barch DM. Abnormalities of thalamic activation and cognition in schizophrenia.  Am J Psychiatry. 2006;163(3):463-469
PubMed   |  Link to Article
Walter H, Vasic N, Höse A, Spitzer M, Wolf RC. Working memory dysfunction in schizophrenia compared to healthy controls and patients with depression: evidence from event-related fMRI.  Neuroimage. 2007;35(4):1551-1561
PubMed   |  Link to Article
Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC. Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia.  Arch Gen Psychiatry. 2009;66(8):811-822
PubMed   |  Link to Article
Barch DM. The relationships among cognition, motivation, and emotion in schizophrenia: how much and how little we know.  Schizophr Bull. 2005;31(4):875-881
PubMed   |  Link to Article
Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex.  Lancet. 1985;1(8437):1106-1107
PubMed   |  Link to Article
Strafella AP, Paus T. Cerebral blood-flow changes induced by paired-pulse transcranial magnetic stimulation of the primary motor cortex.  J Neurophysiol. 2001;85(6):2624-2629
PubMed
Ferrarelli F, Haraldsson HM, Barnhart TE, Roberts AD, Oakes TR, Massimini M, Stone CK, Kalin NH, Tononi G. A [17F]-fluoromethane PET/TMS study of effective connectivity.  Brain Res Bull. 2004;64(2):103-113
PubMed   |  Link to Article
Pascual-Leone A, Bartres-Faz D, Keenan JP. Transcranial magnetic stimulation: studying the brain-behaviour relationship by induction of “virtual lesions.”  Philos Trans R Soc Lond B Biol Sci. 1999;354(1387):1229-1238
PubMed   |  Link to Article
Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex.  Neuron. 2005;45(2):201-206
PubMed   |  Link to Article
Walsh V, Rushworth M. A primer of magnetic stimulation as a tool for neuropsychology.  Neuropsychologia. 1999;37(2):125-135
PubMed
Bohning DE, Shastri A, Wassermann EM, Ziemann U, Lorberbaum JP, Nahas Z, Lomarev MP, George MS. BOLD-f MRI response to single-pulse transcranial magnetic stimulation (TMS).  J Magn Reson Imaging. 2000;11(6):569-574
PubMed   |  Link to Article
Hanakawa T, Mima T, Matsumoto R, Abe M, Inouchi M, Urayama S, Anami K, Honda M, Fukuyama H. Stimulus-response profile during single-pulse transcranial magnetic stimulation to the primary motor cortex.  Cereb Cortex. 2009;19(11):2605-2615
PubMed   |  Link to Article
Ogawa S, Lee TM, Nayak AS, Glynn P. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields.  Magn Reson Med. 1990;14(1):68-78
PubMed   |  Link to Article
Heinen K, Ruff CC, Bjoertomt O, Schenkluhn B, Bestmann S, Blankenburg F, Driver J, Chambers CD. Concurrent TMS-fMRI reveals dynamic interhemispheric influences of the right parietal cortex during exogenously cued visuospatial attention.  Eur J Neurosci. 2011;33(5):991-1000
PubMed   |  Link to Article
Ruff CC, Blankenburg F, Bjoertomt O, Bestmann S, Freeman E, Haynes JD, Rees G, Josephs O, Deichmann R, Driver J. Concurrent TMS-fMRI and psychophysics reveal frontal influences on human retinotopic visual cortex.  Curr Biol. 2006;16(15):1479-1488
PubMed   |  Link to Article
McClintock SM, Freitas C, Oberman L, Lisanby SH, Pascual-Leone A. Transcranial magnetic stimulation: a neuroscientific probe of cortical function in schizophrenia.  Biol Psychiatry. 2011;70(1):19-27
PubMed   |  Link to Article
Carter CS, Barch DM, Bullmore E, Breiling J, Buchanan RW, Butler P, Cohen JD, Geyer M, Gollub R, Green MF, Jaeger J, Krystal JH, Moore H, Nuechterlein K, Robbins T, Silverstein S, Smith EE, Strauss M, Wykes T. Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia II: developing imaging biomarkers to enhance treatment development for schizophrenia and related disorders.  Biol Psychiatry. 2011;70(1):7-12
PubMed   |  Link to Article
First MB Sr, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Patient Edition. New York: New York State Psychiatric Institute; 2002
Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.  Schizophr Bull. 1987;13(2):261-276
PubMed
Aguirre GK, Zarahn E, D’esposito M. The variability of human, BOLD hemodynamic responses.  Neuroimage. 1998;8(4):360-369
PubMed   |  Link to Article
Ferrarelli F, Massimini M, Peterson MJ, Riedner BA, Lazar M, Murphy MJ, Huber R, Rosanova M, Alexander AL, Kalin N, Tononi G. Reduced evoked gamma oscillations in the frontal cortex in schizophrenia patients: a TMS/EEG study.  Am J Psychiatry. 2008;165(8):996-1005
PubMed   |  Link to Article
Pomarol-Clotet E, Canales-Rodríguez EJ, Salvador R, Sarró S, Gomar JJ, Vila F, Ortiz-Gil J, Iturria-Medina Y, Capdevila A, McKenna PJ. Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging.  Mol Psychiatry. 2010;15(8):823-830
PubMed   |  Link to Article
Shackman AJ, McMenamin BW, Slagter HA, Maxwell JS, Greischar LL, Davidson RJ. Electromyogenic artifacts and electroencephalographic inferences.  Brain Topogr. 2009;22(1):7-12
PubMed   |  Link to Article
Blankenburg F, Ruff CC, Bestmann S, Bjoertomt O, Eshel N, Josephs O, Weiskopf N, Driver J. Interhemispheric effect of parietal TMS on somatosensory response confirmed directly with concurrent TMS-fMRI.  J Neurosci. 2008;28(49):13202-13208
PubMed   |  Link to Article
Ferrarelli F, Tononi G. The thalamic reticular nucleus and schizophrenia.  Schizophr Bull. 2011;37(2):306-315
PubMed   |  Link to Article
Leichnetz GR. Afferent and efferent connections of the dorsolateral precentral gyrus (area 4, hand/arm region) in the macaque monkey, with comparisons to area 8.  J Comp Neurol. 1986;254(4):460-492
PubMed   |  Link to Article
Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, Buettner A, Winkler P. Localization of the motor hand area to a knob on the precentral gyrus: a new landmark.  Brain. 1997;120(pt 1):141-157
PubMed   |  Link to Article
Rothwell JC, Hallett M, Berardelli A, Eisen A, Rossini P, Paulus W.International Federation of Clinical Neurophysiology.  Magnetic stimulation: motor evoked potentials.  Electroencephalogr Clin Neurophysiol Suppl. 1999;52:97-103
PubMed
Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages.  Comput Biomed Res. 1996;29(3):162-173
PubMed   |  Link to Article
Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM. Advances in functional and structural MR image analysis and implementation as FSL.  Neuroimage. 2004;23:(suppl 1)  S208-S219
PubMed   |  Link to Article
Duvernoy HM, Bourgouin P. The Human Brain: Surface, Three-Dimensional Sectional Anatomy With MRI, and Blood Supply. 2nd ed. Vienna, Austria: Springer-Verlag; 1999
Corradi-Dell’acqua C, Tomelleri L, Bellani M, Rambaldelli G, Cerini R, Pozzi-Mucelli R, Balestrieri M, Tansella M, Brambilla P. Thalamic-insular dysconnectivity in schizophrenia: evidence from structural equation modeling [published online April 11, 2011].  Hum Brain Mapp
PubMed  |  Link to Article
Roth Y, Amir A, Levkovitz Y, Zangen A. Three-dimensional distribution of the electric field induced in the brain by transcranial magnetic stimulation using figure-8 and deep H-coils.  J Clin Neurophysiol. 2007;24(1):31-38
PubMed   |  Link to Article
Wagner T, Rushmore J, Eden U, Valero-Cabre A. Biophysical foundations underlying TMS: setting the stage for an effective use of neurostimulation in the cognitive neurosciences.  Cortex. 2009;45(9):1025-1034
PubMed   |  Link to Article
Handwerker DA, Ollinger JM, D’Esposito M. Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses.  Neuroimage. 2004;21(4):1639-1651
PubMed   |  Link to Article
Wager TD, Atlas LY, Leotti LA, Rilling JK. Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience.  J Neurosci. 2011;31(2):439-452
PubMed   |  Link to Article
Conover WJIR. Rank transformations as a bridge between parametric and nonparametric statistics.  Am Stat. 1981;35(3):124-129
Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho BC. Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs.  Biol Psychiatry. 2010;67(3):255-262
PubMed   |  Link to Article
Rose SE, Chalk JB, Janke AL, Strudwick MW, Windus LC, Hannah DE, McGrath JJ, Pantelis C, Wood SJ, Mowry BJ. Evidence of altered prefrontal-thalamic circuitry in schizophrenia: an optimized diffusion MRI study.  Neuroimage. 2006;32(1):16-22
PubMed   |  Link to Article
Agarwal N, Rambaldelli G, Perlini C, Dusi N, Kitis O, Bellani M, Cerini R, Isola M, Versace A, Balestrieri M, Gasparini A, Mucelli RP, Tansella M, Brambilla P. Microstructural thalamic changes in schizophrenia: a combined anatomic and diffusion weighted magnetic resonance imaging study.  J Psychiatry Neurosci. 2008;33(5):440-448
PubMed
Glahn DC, Ragland JD, Abramoff A, Barrett J, Laird AR, Bearden CE, Velligan DI. Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia.  Hum Brain Mapp. 2005;25(1):60-69
PubMed   |  Link to Article
Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia.  Nat Neurosci. 2002;5(3):267-271
PubMed   |  Link to Article
Barth DS, MacDonald KD. Thalamic modulation of high-frequency oscillating potentials in auditory cortex.  Nature. 1996;383(6595):78-81
PubMed   |  Link to Article
Rafal RD, Posner MI. Deficits in human visual spatial attention following thalamic lesions.  Proc Natl Acad Sci U S A. 1987;84(20):7349-7353
PubMed   |  Link to Article
Oh JS, Kubicki M, Rosenberger G, Bouix S, Levitt JJ, McCarley RW, Westin CF, Shenton ME. Thalamo-frontal white matter alterations in chronic schizophrenia: a quantitative diffusion tractography study.  Hum Brain Mapp. 2009;30(11):3812-3825
PubMed   |  Link to Article
Morel A, Magnin M, Jeanmonod D. Multiarchitectonic and stereotactic atlas of the human thalamus.  J Comp Neurol. 1997;387(4):588-630
PubMed   |  Link to Article
Golshani P, Liu XB, Jones EG. Differences in quantal amplitude reflect GluR4- subunit number at corticothalamic synapses on two populations of thalamic neurons.  Proc Natl Acad Sci U S A. 2001;98(7):4172-4177
PubMed   |  Link to Article
McAlonan K, Cavanaugh J, Wurtz RH. Attentional modulation of thalamic reticular neurons.  J Neurosci. 2006;26(16):4444-4450
PubMed   |  Link to Article
Zikopoulos B, Barbas H. Circuits for multisensory integration and attentional modulation through the prefrontal cortex and the thalamic reticular nucleus in primates.  Rev Neurosci. 2007;18(6):417-438
PubMed   |  Link to Article
Freedman R, Olincy A, Ross RG, Waldo MC, Stevens KE, Adler LE, Leonard S. The genetics of sensory gating deficits in schizophrenia.  Curr Psychiatry Rep. 2003;5(2):155-161
PubMed   |  Link to Article
Luck SJ, Gold JM. The construct of attention in schizophrenia.  Biol Psychiatry. 2008;64(1):34-39
PubMed   |  Link to Article

Figures

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Figure 1. Group-averaged cortical response to single-pulse transcranial magnetic stimulation (spTMS) in the cortical region underlying the TMS coil (precentral gyrus) (A) and to a button-pressing (BP) task in the precentral gyrus (B) (n = 14 in each group). Shaded areas indicate 95% CIs. * P < .05. Insets, Single-subject representation of the region of interest (yellow) and the voxels most responsive to the condition (red). L indicates left; R, right.

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Graphic Jump Location

Figure 2. Group-averaged response to single-pulse transcranial magnetic stimulation (spTMS) (A) and to a button-pressing (BP) task (B) in the thalamus (n = 14 in each group) as well as the sham TMS response in the same voxels (n = 13 in each group). Shaded areas indicate 95% CIs. * P < .05; † P = 1.86 × 10−9. Insets, Single-subject representation of the region of interest (yellow) and the voxels most responsive to the condition (red). L indicates left; R, right. Dot plots illustrate single-subject peak percent signal change (extracted 3-6.5 seconds following spTMS delivery) in response to spTMS (C) and the BP task (D) with the group means (horizontal lines) and SEMs (gray boxes) indicated. Because peak latency varied across subjects, the group means shown in C and D necessarily differ from the maxima of the average hemodynamic response function waveforms depicted in A and B. C and D represent data used for hypothesis testing.

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Figure 3. Group-averaged medial superior frontal gyrus response to single-pulse transcranial magnetic stimulation (spTMS) of the precentral gyrus (n = 14 in each group). Shaded areas indicate 95% CIs. * P < .05. Inset, Single-subject representation of the region of interest (yellow) and the voxels most responsive to the condition (red). L indicates left; R, right.

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Healthy Control Subjects and Patients With Schizophrenia
Table Graphic Jump LocationTable 2. Group Mean Correlation Coefficient Between ROI Time Series

References

Nicholl D, Akhras KS, Diels J, Schadrack J. Burden of schizophrenia in recently diagnosed patients: healthcare utilisation and cost perspective.  Curr Med Res Opin. 2010;26(4):943-955
PubMed   |  Link to Article
Caqueo-Urízar A, Gutiérrez-Maldonado J, Miranda-Castillo C. Quality of life in caregivers of patients with schizophrenia: a literature review.  Health Qual Life Outcomes. 2009;7:84
PubMed   |  Link to Article
Corring DJ. Quality of life: perspectives of people with mental illnesses and family members.  Psychiatr Rehabil J. 2002;25(4):350-358
PubMed
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.  Arch Gen Psychiatry. 2005;62(6):593-602
PubMed   |  Link to Article
Osby U, Correia N, Brandt L, Ekbom A, Sparén P. Mortality and causes of death in schizophrenia in Stockholm county, Sweden.  Schizophr Res. 2000;45(1-2):21-28
PubMed   |  Link to Article
Meltzer HY, Baldessarini RJ. Reducing the risk for suicide in schizophrenia and affective disorders.  J Clin Psychiatry. 2003;64(9):1122-1129
PubMed   |  Link to Article
Schwarz E, Izmailov R, Spain M, Barnes A, Mapes JP, Guest PC, Rahmoune H, Pietsch S, Leweke FM, Rothermundt M, Steiner J, Koethe D, Kranaster L, Ohrmann P, Suslow T, Levin Y, Bogerts B, van Beveren NJ, McAllister G, Weber N, Niebuhr D, Cowan D, Yolken RH, Bahn S. Validation of a blood-based laboratory test to aid in the confirmation of a diagnosis of schizophrenia.  Biomark Insights. 2010;5:39-47
PubMed
Thaker GK. Schizophrenia endophenotypes as treatment targets.  Expert Opin Ther Targets. 2007;11(9):1189-1206
PubMed   |  Link to Article
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders4th ed, text revision. Washington, DC: American Psychiatric Association; 2000
Abbott A. Schizophrenia: the drug deadlock.  Nature. 2010;468(7321):158-159
PubMed   |  Link to Article
McCormick DA, Bal T. Sensory gating mechanisms of the thalamus.  Curr Opin Neurobiol. 1994;4(4):550-556
PubMed   |  Link to Article
Jones EG. The Thalamus. 2nd ed. Cambridge, England: Cambridge University Press; 2007
Sherman SM, Guillery RW. Exploring the Thalamus and Its Role in Cortical Function. 2nd ed. Cambridge, MA: MIT Press; 2006
Wolf R, Matzke K, Paelchen K, Dobrowolny H, Bogerts B, Schwegler H. Reduction of prepulse inhibition (PPI) after neonatal excitotoxic lesion of the ventral thalamus in pubertal and adult rats.  Pharmacopsychiatry. 2010;43(3):99-109
PubMed   |  Link to Article
Krause M, Hoffmann WE, Hajós M. Auditory sensory gating in hippocampus and reticular thalamic neurons in anesthetized rats.  Biol Psychiatry. 2003;53(3):244-253
PubMed   |  Link to Article
Potter D, Summerfelt A, Gold J, Buchanan RW. Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia.  Schizophr Bull. 2006;32(4):692-700
PubMed   |  Link to Article
Brockhaus-Dumke A, Schultze-Lutter F, Mueller R, Tendolkar I, Bechdolf A, Pukrop R, Klosterkoetter J, Ruhrmann S. Sensory gating in schizophrenia: P50 and N100 gating in antipsychotic-free subjects at risk, first-episode, and chronic patients.  Biol Psychiatry. 2008;64(5):376-384
PubMed   |  Link to Article
Kim DI, Mathalon DH, Ford JM, Mannell M, Turner JA, Brown GG, Belger A, Gollub R, Lauriello J, Wible C, O’Leary D, Lim K, Toga A, Potkin SG, Birn F, Calhoun VD. Auditory oddball deficits in schizophrenia: an independent component analysis of the fMRI multisite function BIRN study.  Schizophr Bull. 2009;35(1):67-81
PubMed   |  Link to Article
Salisbury DF, Shenton ME, Griggs CB, Bonner-Jackson A, McCarley RW. Mismatch negativity in chronic schizophrenia and first-episode schizophrenia.  Arch Gen Psychiatry. 2002;59(8):686-694
PubMed   |  Link to Article
Javitt DC. Intracortical mechanisms of mismatch negativity dysfunction in schizophrenia.  Audiol Neurootol. 2000;5(3-4):207-215
PubMed   |  Link to Article
Javitt DC, Doneshka P, Grochowski S, Ritter W. Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia.  Arch Gen Psychiatry. 1995;52(7):550-558
PubMed   |  Link to Article
Behrendt RP, Young C. Hallucinations in schizophrenia, sensory impairment, and brain disease: a unifying model.  Behav Brain Sci. 2004;27(6):771-830
PubMed
Behrendt RP. Dysregulation of thalamic sensory “transmission” in schizophrenia: neurochemical vulnerability to hallucinations.  J Psychopharmacol. 2006;20(3):356-372
PubMed   |  Link to Article
Fuentealba P, Steriade M. The reticular nucleus revisited: intrinsic and network properties of a thalamic pacemaker.  Prog Neurobiol. 2005;75(2):125-141
PubMed   |  Link to Article
Steriade M, Deschênes M, Domich L, Mulle C. Abolition of spindle oscillations in thalamic neurons disconnected from nucleus reticularis thalami.  J Neurophysiol. 1985;54(6):1473-1497
PubMed
Ferrarelli F, Peterson MJ, Sarasso S, Riedner BA, Murphy MJ, Benca RM, Bria P, Kalin NH, Tononi G. Thalamic dysfunction in schizophrenia suggested by whole-night deficits in slow and fast spindles.  Am J Psychiatry. 2010;167(11):1339-1348
PubMed   |  Link to Article
Ferrarelli F, Huber R, Peterson MJ, Massimini M, Murphy M, Riedner BA, Watson A, Bria P, Tononi G. Reduced sleep spindle activity in schizophrenia patients.  Am J Psychiatry. 2007;164(3):483-492
PubMed   |  Link to Article
Vukadinovic Z. Sleep abnormalities in schizophrenia may suggest impaired trans-thalamic cortico-cortical communication: towards a dynamic model of the illness.  Eur J Neurosci. 2011;34(7):1031-1039
PubMed   |  Link to Article
Ellison-Wright I, Bullmore E. Anatomy of bipolar disorder and schizophrenia: a meta-analysis.  Schizophr Res. 2010;117(1):1-12
PubMed   |  Link to Article
Glahn DC, Laird AR, Ellison-Wright I, Thelen SM, Robinson JL, Lancaster JL, Bullmore E, Fox PT. Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis.  Biol Psychiatry. 2008;64(9):774-781
PubMed   |  Link to Article
Adriano F, Spoletini I, Caltagirone C, Spalletta G. Updated meta-analyses reveal thalamus volume reduction in patients with first-episode and chronic schizophrenia.  Schizophr Res. 2010;123(1):1-14
PubMed   |  Link to Article
Tregellas JR, Davalos DB, Rojas DC, Waldo MC, Gibson L, Wylie K, Du YP, Freedman R. Increased hemodynamic response in the hippocampus, thalamus and prefrontal cortex during abnormal sensory gating in schizophrenia.  Schizophr Res. 2007;92(1-3):262-272
PubMed   |  Link to Article
Tregellas JR, Ellis J, Shatti S, Du YP, Rojas DC. Increased hippocampal, thalamic, and prefrontal hemodynamic response to an urban noise stimulus in schizophrenia.  Am J Psychiatry. 2009;166(3):354-360
PubMed   |  Link to Article
Bor J, Brunelin J, Sappey-Marinier D, Ibarrola D, d’Amato T, Suaud-Chagny MF, Saoud M. Thalamus abnormalities during working memory in schizophrenia: an fMRI study.  Schizophr Res. 2011;125(1):49-53
PubMed   |  Link to Article
Andrews J, Wang L, Csernansky JG, Gado MH, Barch DM. Abnormalities of thalamic activation and cognition in schizophrenia.  Am J Psychiatry. 2006;163(3):463-469
PubMed   |  Link to Article
Walter H, Vasic N, Höse A, Spitzer M, Wolf RC. Working memory dysfunction in schizophrenia compared to healthy controls and patients with depression: evidence from event-related fMRI.  Neuroimage. 2007;35(4):1551-1561
PubMed   |  Link to Article
Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC. Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia.  Arch Gen Psychiatry. 2009;66(8):811-822
PubMed   |  Link to Article
Barch DM. The relationships among cognition, motivation, and emotion in schizophrenia: how much and how little we know.  Schizophr Bull. 2005;31(4):875-881
PubMed   |  Link to Article
Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex.  Lancet. 1985;1(8437):1106-1107
PubMed   |  Link to Article
Strafella AP, Paus T. Cerebral blood-flow changes induced by paired-pulse transcranial magnetic stimulation of the primary motor cortex.  J Neurophysiol. 2001;85(6):2624-2629
PubMed
Ferrarelli F, Haraldsson HM, Barnhart TE, Roberts AD, Oakes TR, Massimini M, Stone CK, Kalin NH, Tononi G. A [17F]-fluoromethane PET/TMS study of effective connectivity.  Brain Res Bull. 2004;64(2):103-113
PubMed   |  Link to Article
Pascual-Leone A, Bartres-Faz D, Keenan JP. Transcranial magnetic stimulation: studying the brain-behaviour relationship by induction of “virtual lesions.”  Philos Trans R Soc Lond B Biol Sci. 1999;354(1387):1229-1238
PubMed   |  Link to Article
Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex.  Neuron. 2005;45(2):201-206
PubMed   |  Link to Article
Walsh V, Rushworth M. A primer of magnetic stimulation as a tool for neuropsychology.  Neuropsychologia. 1999;37(2):125-135
PubMed
Bohning DE, Shastri A, Wassermann EM, Ziemann U, Lorberbaum JP, Nahas Z, Lomarev MP, George MS. BOLD-f MRI response to single-pulse transcranial magnetic stimulation (TMS).  J Magn Reson Imaging. 2000;11(6):569-574
PubMed   |  Link to Article
Hanakawa T, Mima T, Matsumoto R, Abe M, Inouchi M, Urayama S, Anami K, Honda M, Fukuyama H. Stimulus-response profile during single-pulse transcranial magnetic stimulation to the primary motor cortex.  Cereb Cortex. 2009;19(11):2605-2615
PubMed   |  Link to Article
Ogawa S, Lee TM, Nayak AS, Glynn P. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields.  Magn Reson Med. 1990;14(1):68-78
PubMed   |  Link to Article
Heinen K, Ruff CC, Bjoertomt O, Schenkluhn B, Bestmann S, Blankenburg F, Driver J, Chambers CD. Concurrent TMS-fMRI reveals dynamic interhemispheric influences of the right parietal cortex during exogenously cued visuospatial attention.  Eur J Neurosci. 2011;33(5):991-1000
PubMed   |  Link to Article
Ruff CC, Blankenburg F, Bjoertomt O, Bestmann S, Freeman E, Haynes JD, Rees G, Josephs O, Deichmann R, Driver J. Concurrent TMS-fMRI and psychophysics reveal frontal influences on human retinotopic visual cortex.  Curr Biol. 2006;16(15):1479-1488
PubMed   |  Link to Article
McClintock SM, Freitas C, Oberman L, Lisanby SH, Pascual-Leone A. Transcranial magnetic stimulation: a neuroscientific probe of cortical function in schizophrenia.  Biol Psychiatry. 2011;70(1):19-27
PubMed   |  Link to Article
Carter CS, Barch DM, Bullmore E, Breiling J, Buchanan RW, Butler P, Cohen JD, Geyer M, Gollub R, Green MF, Jaeger J, Krystal JH, Moore H, Nuechterlein K, Robbins T, Silverstein S, Smith EE, Strauss M, Wykes T. Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia II: developing imaging biomarkers to enhance treatment development for schizophrenia and related disorders.  Biol Psychiatry. 2011;70(1):7-12
PubMed   |  Link to Article
First MB Sr, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Patient Edition. New York: New York State Psychiatric Institute; 2002
Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.  Schizophr Bull. 1987;13(2):261-276
PubMed
Aguirre GK, Zarahn E, D’esposito M. The variability of human, BOLD hemodynamic responses.  Neuroimage. 1998;8(4):360-369
PubMed   |  Link to Article
Ferrarelli F, Massimini M, Peterson MJ, Riedner BA, Lazar M, Murphy MJ, Huber R, Rosanova M, Alexander AL, Kalin N, Tononi G. Reduced evoked gamma oscillations in the frontal cortex in schizophrenia patients: a TMS/EEG study.  Am J Psychiatry. 2008;165(8):996-1005
PubMed   |  Link to Article
Pomarol-Clotet E, Canales-Rodríguez EJ, Salvador R, Sarró S, Gomar JJ, Vila F, Ortiz-Gil J, Iturria-Medina Y, Capdevila A, McKenna PJ. Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging.  Mol Psychiatry. 2010;15(8):823-830
PubMed   |  Link to Article
Shackman AJ, McMenamin BW, Slagter HA, Maxwell JS, Greischar LL, Davidson RJ. Electromyogenic artifacts and electroencephalographic inferences.  Brain Topogr. 2009;22(1):7-12
PubMed   |  Link to Article
Blankenburg F, Ruff CC, Bestmann S, Bjoertomt O, Eshel N, Josephs O, Weiskopf N, Driver J. Interhemispheric effect of parietal TMS on somatosensory response confirmed directly with concurrent TMS-fMRI.  J Neurosci. 2008;28(49):13202-13208
PubMed   |  Link to Article
Ferrarelli F, Tononi G. The thalamic reticular nucleus and schizophrenia.  Schizophr Bull. 2011;37(2):306-315
PubMed   |  Link to Article
Leichnetz GR. Afferent and efferent connections of the dorsolateral precentral gyrus (area 4, hand/arm region) in the macaque monkey, with comparisons to area 8.  J Comp Neurol. 1986;254(4):460-492
PubMed   |  Link to Article
Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, Buettner A, Winkler P. Localization of the motor hand area to a knob on the precentral gyrus: a new landmark.  Brain. 1997;120(pt 1):141-157
PubMed   |  Link to Article
Rothwell JC, Hallett M, Berardelli A, Eisen A, Rossini P, Paulus W.International Federation of Clinical Neurophysiology.  Magnetic stimulation: motor evoked potentials.  Electroencephalogr Clin Neurophysiol Suppl. 1999;52:97-103
PubMed
Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages.  Comput Biomed Res. 1996;29(3):162-173
PubMed   |  Link to Article
Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM. Advances in functional and structural MR image analysis and implementation as FSL.  Neuroimage. 2004;23:(suppl 1)  S208-S219
PubMed   |  Link to Article
Duvernoy HM, Bourgouin P. The Human Brain: Surface, Three-Dimensional Sectional Anatomy With MRI, and Blood Supply. 2nd ed. Vienna, Austria: Springer-Verlag; 1999
Corradi-Dell’acqua C, Tomelleri L, Bellani M, Rambaldelli G, Cerini R, Pozzi-Mucelli R, Balestrieri M, Tansella M, Brambilla P. Thalamic-insular dysconnectivity in schizophrenia: evidence from structural equation modeling [published online April 11, 2011].  Hum Brain Mapp
PubMed  |  Link to Article
Roth Y, Amir A, Levkovitz Y, Zangen A. Three-dimensional distribution of the electric field induced in the brain by transcranial magnetic stimulation using figure-8 and deep H-coils.  J Clin Neurophysiol. 2007;24(1):31-38
PubMed   |  Link to Article
Wagner T, Rushmore J, Eden U, Valero-Cabre A. Biophysical foundations underlying TMS: setting the stage for an effective use of neurostimulation in the cognitive neurosciences.  Cortex. 2009;45(9):1025-1034
PubMed   |  Link to Article
Handwerker DA, Ollinger JM, D’Esposito M. Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses.  Neuroimage. 2004;21(4):1639-1651
PubMed   |  Link to Article
Wager TD, Atlas LY, Leotti LA, Rilling JK. Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience.  J Neurosci. 2011;31(2):439-452
PubMed   |  Link to Article
Conover WJIR. Rank transformations as a bridge between parametric and nonparametric statistics.  Am Stat. 1981;35(3):124-129
Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho BC. Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs.  Biol Psychiatry. 2010;67(3):255-262
PubMed   |  Link to Article
Rose SE, Chalk JB, Janke AL, Strudwick MW, Windus LC, Hannah DE, McGrath JJ, Pantelis C, Wood SJ, Mowry BJ. Evidence of altered prefrontal-thalamic circuitry in schizophrenia: an optimized diffusion MRI study.  Neuroimage. 2006;32(1):16-22
PubMed   |  Link to Article
Agarwal N, Rambaldelli G, Perlini C, Dusi N, Kitis O, Bellani M, Cerini R, Isola M, Versace A, Balestrieri M, Gasparini A, Mucelli RP, Tansella M, Brambilla P. Microstructural thalamic changes in schizophrenia: a combined anatomic and diffusion weighted magnetic resonance imaging study.  J Psychiatry Neurosci. 2008;33(5):440-448
PubMed
Glahn DC, Ragland JD, Abramoff A, Barrett J, Laird AR, Bearden CE, Velligan DI. Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia.  Hum Brain Mapp. 2005;25(1):60-69
PubMed   |  Link to Article
Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia.  Nat Neurosci. 2002;5(3):267-271
PubMed   |  Link to Article
Barth DS, MacDonald KD. Thalamic modulation of high-frequency oscillating potentials in auditory cortex.  Nature. 1996;383(6595):78-81
PubMed   |  Link to Article
Rafal RD, Posner MI. Deficits in human visual spatial attention following thalamic lesions.  Proc Natl Acad Sci U S A. 1987;84(20):7349-7353
PubMed   |  Link to Article
Oh JS, Kubicki M, Rosenberger G, Bouix S, Levitt JJ, McCarley RW, Westin CF, Shenton ME. Thalamo-frontal white matter alterations in chronic schizophrenia: a quantitative diffusion tractography study.  Hum Brain Mapp. 2009;30(11):3812-3825
PubMed   |  Link to Article
Morel A, Magnin M, Jeanmonod D. Multiarchitectonic and stereotactic atlas of the human thalamus.  J Comp Neurol. 1997;387(4):588-630
PubMed   |  Link to Article
Golshani P, Liu XB, Jones EG. Differences in quantal amplitude reflect GluR4- subunit number at corticothalamic synapses on two populations of thalamic neurons.  Proc Natl Acad Sci U S A. 2001;98(7):4172-4177
PubMed   |  Link to Article
McAlonan K, Cavanaugh J, Wurtz RH. Attentional modulation of thalamic reticular neurons.  J Neurosci. 2006;26(16):4444-4450
PubMed   |  Link to Article
Zikopoulos B, Barbas H. Circuits for multisensory integration and attentional modulation through the prefrontal cortex and the thalamic reticular nucleus in primates.  Rev Neurosci. 2007;18(6):417-438
PubMed   |  Link to Article
Freedman R, Olincy A, Ross RG, Waldo MC, Stevens KE, Adler LE, Leonard S. The genetics of sensory gating deficits in schizophrenia.  Curr Psychiatry Rep. 2003;5(2):155-161
PubMed   |  Link to Article
Luck SJ, Gold JM. The construct of attention in schizophrenia.  Biol Psychiatry. 2008;64(1):34-39
PubMed   |  Link to Article

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Supplemental Content

Guller Y, Ferrarelli F, Shackman AJ, Sarasso S, Peterson MJ, Langheim FJ, Meyerand ME, Tononi G, Postle BR. Probing thalamic integrity in schizophrenia using concurrent transcranial magnetic stimulation and functional magnetic resonance imaging. Arch Gen Psychiatry. Published online March 5, 2012. doi:10.1001/archgenpsychiatry.2012.23.

eAppendix. Supplemental methods, supplemental results, and supplemental references.

eFigure 1. Concurrent TMS-fMRI targeting and apparatus. (A) Frameless stereotaxy is used to align the subject to their T1 high-resolution structural image. (B, C) A custom plastic mount holds the TMS coil allowing it to rotate in all directions.

eFigure 2. Concurrent TMS-fMRI image acquisition timing. spTMS (and button press tone) stimuli occurred during a 230 ms gap in MRI acquisition (nominal TR: 2000ms; effective TR: 1170ms), ensuring that electromagnetic artifacts from discharge of the TMS coil did not corrupt acquisition of fMRI images.

eFigure 3. Group averaged spTMS-evoked response in insula. *P < .01, shaded areas: 95% CI. Inset: single-subject representation of ROI (yellow); voxels most responsive to condition (red). N=14 in each group.

eTable 1. Mean number of voxels (SEM) in each ROI.

eTable 2. Group mean correlation coefficient (r) between ROI time series.

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