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Brain Stimulation 04/2013; · 3.76 Impact Factor
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ABSTRACT: CONTEXT Converging lines of evidence implicate the glutamate and γ-aminobutyric acid neurotransmitter systems in the pathophysiology of major depressive disorder. Transcranial magnetic stimulation cortical excitability and inhibition paradigms have been used to assess cortical glutamatergic and γ-aminobutyric acid-mediated tone in adults with major depressive disorder, but not in children and adolescents. OBJECTIVE To compare measures of cortical excitability and inhibition with 4 different paradigms in a group of children and adolescents with major depressive disorder vs healthy controls. DESIGN Cross-sectional study examining medication-free children and adolescents (aged 9-17 years) with major depressive disorder compared with healthy controls. Cortical excitability was assessed with motor threshold and intracortical facilitation measures. Cortical inhibition was measured with cortical silent period and intracortical inhibition paradigms. SETTING University-based child and adolescent psychiatry clinic and neurostimulation laboratory. PATIENTS Twenty-four participants with major depressive disorder and 22 healthy controls matched for age and sex. Patients with major depressive disorder were medication naive and had moderate to severe symptoms based on an evaluation with a child and adolescent psychiatrist and scores on the Children's Depression Rating Scale-Revised. MAIN OUTCOME MEASURES Motor threshold, intracortical facilitation, cortical silent period, and intracortical inhibition. RESULTS Compared with healthy controls, depressed patients had significantly increased intracortical facilitation at interstimulus intervals of 10 and 15 milliseconds bilaterally. There were no significant group differences in cortical inhibition measures. CONCLUSIONS These findings suggest that major depressive disorder in children and adolescents is associated with increased intracortical facilitation and excessive glutamatergic activity.
JAMA psychiatry (Chicago, Ill.). 01/2013;
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ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is a technology that stimulates neurons with rapidly changing magnetic pulses with demonstrated therapeutic applications for various neuropsychiatric disorders. Functional near-infrared spectroscopy (fNIRS) is a suitable tool to assess rTMS-evoked brain responses without interference from the magnetic or electric fields generated by the TMS coil. We have previously reported a channel-wise study of combined rTMS/fNIRS on the motor and prefrontal cortices, showing a robust decrease of oxygenated hemoglobin concentration (Δ[HbO2]) at the sites of 1-Hz rTMS and the contralateral brain regions. However, the reliability of this putative clinical tool is unknown. In this study, we develop a rapid optical topography approach to spatially characterize the rTMS-evoked hemodynamic responses on a standard brain atlas. A hemispherical approximation of the brain is employed to convert the three-dimensional topography on the complex brain surface to a two-dimensional topography in the spherical coordinate system. The test-retest reliability of the combined rTMS/fNIRS is assessed using repeated measurements performed two to three days apart. The results demonstrate that the Δ[HbO2] amplitudes have moderate-to-high reliability at the group level; and the spatial patterns of the topographic images have high reproducibility in size and a moderate degree of overlap at the individual level.
Journal of Biomedical Optics 11/2012; 17(11):116020. · 3.16 Impact Factor
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ABSTRACT: Several research groups have initiated work to explore the neurobiology of deception using functional neuroimaging. The objective of this lesson is to review published research articles and present considerations in this developing field. Preliminary results in the laboratory setting demonstrate the potential of fMRI to detect deception with reasonable accuracy on the individual level. Additional work, however, is needed to establish validity for actual applications. This lesson also introduces the complex neuroanatomy associated with deceptive behavior. Although no studies in the literature currently include participants with psychiatric conditions, fMRI may prove to be a valuable tool for understanding, diagnosing, and treating certain disorders that have deception as a prominent component. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Directions in Psychiatry. 10/2012;
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ABSTRACT: IntroductionTranscranial magnetic stimulation (TMS) is a novel antidepressant therapy shown to be effective and safe in pharmacotherapy-resistant
major depression. The incremental cost-effectiveness and the direct cost burden compared with sham treatment were estimated,
and compared with the current standard of care.
MethodsHealthcare resource utilization data were collected during a multicenter study (n=301) and a decision analysis was used to stratify the 9-week treatment outcomes. A Markov model with an acute-outcome severity-based
risk of relapse was used to estimate the illness course over a full year of treatment follow-up. These model estimates were
also compared to best estimates of outcomes and costs of pharmacotherapy treatment, using the published STAR*D outcomes. The cost-effectiveness of TMS was described using an incremental cost-effectiveness ratio (ICER) per quality-adjusted
life year (QALY) gained and on a direct cost per patient basis across a varying range of assumptions. The model’s sensitivities
to costs due to losses in work productivity and to caregiver time were also examined.
ResultsCompared with sham treatment and at a cost of US300 per treatment session, TMS provides an ICER of US300 per treatment session, TMS provides an ICER of US34,999 per QALY, which
is less than the “willingness-to-pay’ standard of US50,000 per QALY for a new treatment for major depression. When productivity gains due to clinical recovery were included, the ICER was reduced to US50,000 per QALY for a new treatment for major depression. When productivity
gains due to clinical recovery were included, the ICER was reduced to US6667 per QALY. In open-label conditions, TMS provided
a net cost saving of US1123 per QALY when compared with the current standard of care. In the openlabel condition, cost savings increased further when the costs for productivity losses were included in the model (net savings of US1123 per QALY when compared with the current standard of care. In the openlabel condition, cost savings
increased further when the costs for productivity losses were included in the model (net savings of US7621). The overall
cost benefits of treating MD using TMS were greater in those patients at the earliest levels of treatment resistance in the
overall sample.
ConclusionTMS is a cost-effective treatment for patients who have failed to receive sufficient benefit from initial antidepressant pharmacotherapy.
When used at earlier levels of treatment resistance, significant cost savings may be expected relative to the current standard
of care.
Keywordsantidepressant-clinical trial-costeffectiveness-efficacy-health economics-major depression-TMS-transcranial magnetic stimulation
Advances in Therapy 04/2012; 26(3):346-368. · 2.11 Impact Factor
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ABSTRACT: To examine changes in motor cortical excitability in adolescent subjects receiving 30 sessions of high-frequency prefrontal repetitive transcranial magnetic stimulation (rTMS).
Eight adolescents with treatment-resistant major depressive disorder (MDD) enrolled in an open augmentation trial of 10 Hz rTMS. Resting motor thresholds were obtained by the visualization of movement method with a maximum likelihood threshold hunting computer algorithm at baseline and after every five sessions of rTMS. Motor threshold was recorded as the percentage of total machine output at each measurement.
Motor threshold data from baseline, weeks 2, 4, and 5 were included in a mixed model repeated measure analysis to examine a change in least square mean effect over time. The omnibus effect did not reach statistical significance (F=1.25, p=0.32). However, multiple comparisons from the overall model demonstrated a decrease in the least square mean motor threshold. The mean contrast from baseline to week 5 approached significance (p=0.07). Moreover, a post-hoc analysis with a Wilcoxon signed ranks test demonstrated a significant decrease at week 5 (p=0.03).
This suggests that high-frequency rTMS may increase cortical excitability in adolescents with treatment-resistant MDD.
Journal of child and adolescent psychopharmacology 02/2012; 22(1):56-64. · 2.59 Impact Factor
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ABSTRACT: Pain or discomfort at the site of stimulation is a common side effect of transcranial magnetic stimulation. Relevant physiology and predisposing factors have not been adequately described. Literature regarding work with minors is even more limited. The authors present two cases from a child and adolescent neurophysiology transcranial magnetic stimulation protocol and one case from a therapeutic study of repetitive transcranial magnetic stimulation in adolescents with treatment-resistant major depressive disorder. Relevant literature is reviewed. Potential subjects, parents, and study teams should be well aware of this potential side effect in child and adolescent populations. Subjects with anxiety disorders may be prone to pain during these procedures. Further work could assist in identifying predisposed individuals, refining the informed consent process, and implementing procedures to minimize discomfort.
Innovations in clinical neuroscience. 12/2011; 8(12):18-23.
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David S Bobb,
Bryon Adinoff,
Steven J Laken,
Shawn M McClintock,
Katya Rubia,
Hung-Wei Huang,
Mustafa M Husain,
Kimberly S Mapes,
Carol Tamminga,
C Munro Cullum,
Kaundinya Gopinath,
Madhukar H Trivedi, F Andrew Kozel
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ABSTRACT: OBJECTIVE:: Accumulating evidence implicates a strong association between abnormal frontostriatal-limbic brain circuits, executive dysfunction, and late-life depression (LLD). The stop signal task (SST) was designed by Rubia et al. for use with functional magnetic resonance imaging (fMRI) to identify the neural correlates of motor response inhibition, a well-characterized executive function. In this study, we compared brain activation between a group of unmedicated participants with LLD and an unmedicated healthy cohort during SST performance. METHODS:: Participants 55-85 years of age were screened, clinically evaluated, and entered into either the LLD (n = 15) or healthy comparison group (n = 13). Both groups underwent neuroimaging while performing the SST under similar conditions. The brain circuitry of successful motor inhibition was evaluated by contrasting the condition of correctly inhibiting responses with the condition of correctly responding to Go signals. Differential areas of brain activation between the LLD and comparison groups were determined with FMRIB Software Library. RESULTS:: Despite comparable SST performance measures, LLD participants demonstrated greater blood oxygen level dependent activation relative to the comparison group in predominantly left-lateralized frontostriatal-limbic circuitry that included the bilateral superior frontal cortices and left-hemispheric orbitofrontal gyri, insular cortex, cingulate cortex, caudate, and putamen. Conversely, the healthy comparison group did not exhibit any areas of greater activation than the LLD group. CONCLUSION:: Unmedicated participants with LLD activate additionalareas within frontostriatal-limbic brain circuitry when performing the SST at a level comparable to a healthy cohort.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 10/2011; · 3.35 Impact Factor
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ABSTRACT: Depression is often a serious and debilitating illness in adolescents. Unfortunately, a significant number of adolescents do not respond to antidepressant medications or psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment intervention shown to benefit depression in adults. This study considered rTMS as an adjunctive treatment in adolescents with major depressive disorder.
This prospective, open, multicenter trial of active adjunctive rTMS was conducted with 8 adolescents with DSM-IV-TR major depressive disorder (MDD) that had not responded sufficiently to 2 adequate antidepressant medication trials. All subjects were maintained on a stable dose of a selective serotonin reuptake inhibitor during the trial. Thirty daily rTMS treatments were given 5 days per week over 6 to 8 weeks. rTMS was applied to the left dorsolateral prefrontal cortex (120% of motor threshold; 10 Hz; 4-second trains; 26-second intertrain interval; 75 trains) for a total of 3,000 stimulations per treatment session.
Seven of 8 adolescents completed all 30 treatments. rTMS was well tolerated, and no significant safety issues were identified. Suicidal ideation was present at baseline in 3 of the adolescents, and it improved during treatment. The primary outcome measure was the Children's Depression Rating Scale-Revised (CDRS-R); results improved significantly from baseline (mean [SD]) (65.9 [6.6]) to treatment 10 (50.9 [12]), P < .02. The CDRS-R scores continued to improve through the rTMS treatment series at treatment 20 (40.1 [14]), P < .01; treatment 30 (32.6 [7.3]), P < .0001; and at 6-month follow-up (32.7 [3.8]), P < .0001.
This prospective open trial suggests that rTMS is a safe, feasible, and potentially effective adjunctive therapy for treatment-resistant MDD in adolescents.
clinicaltrials.gov Identifier: NCT00587639.
The Journal of Clinical Psychiatry 09/2011; 72(9):1263-9. · 5.80 Impact Factor
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F Andrew Kozel,
Kevin A Johnson,
Ziad Nahas,
Paul A Nakonezny,
Paul S Morgan,
Berry S Anderson,
Samet Kose,
Xingbao Li,
Kelvin O Lim,
Madhukar H Trivedi,
Mark S George
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ABSTRACT: As part of a sham controlled treatment trial using daily left repetitive transcranial magnetic stimulation (rTMS), brain changes associated with 4 to 6 weeks of treatment were examined using diffusion tensor imaging to noninvasively evaluate prefrontal white matter (WM) microstructure. A decrease in fractional anisotropy values of the left prefrontal WM could indicate damage to the region.
Diffusion tensor imaging was performed before and after 4 to 6 weeks of daily rTMS treatments. Mean fractional anisotropy levels associated with active rTMS and sham rTMS for the right and left prefrontal WM were assessed.
Adequate images were acquired for 8 participants (active n = 4, sham n = 4) before and after rTMS. A mean increase was found for the left prefrontal WM. The mixed model revealed a trend toward a significant treatment group × region interaction effect (P = 0.11). Furthermore, simple region effects (left prefrontal WM vs right prefrontal WM) were at a trend toward significance for difference after treatment within the active rTMS group (P = 0.07), but not within the sham rTMS group (P = 0.88).
Repetitive transcranial magnetic stimulation resulted in no evidence of damage to WM on the side of stimulation. Diffusion tensor imaging may offer a unique modality to increase our understanding of mechanisms of action for rTMS.
The journal of ECT 03/2011; 27(1):5-10. · 1.19 Impact Factor
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ABSTRACT: Identifying biosignatures to assess the probability of response to an antidepressant for patients with major depressive disorder (MDD) is critically needed. Functional connectivity MRI (fcMRI) offers the promise to provide such a measure. Previous work with fcMRI demonstrated that the correlation in signal from one region to another is a measure of functional connectivity. In this pilot work, a baseline non-task fcMRI was acquired in 14 adults with MDD who were free of all medications. Participants were then treated for 8 weeks with an antidepressant and then clinically re-evaluated. Probabilistic anatomic regions of interest (ROI) were defined for 16 brain regions (eight for each hemisphere) previously identified as being important in mood disorders. These ROIs were used to determine mean time courses for each individual's baseline non-task fcMRI. The correlations in time courses between 16 brain regions were calculated. These calculated correlations were considered to signify measures of functional connectivity. The degree of connectivity for each participant was correlated with treatment outcome. Among 13 participants with 8 weeks follow-up data, connectivity measures in several regions, especially the subcallosal cortex, were highly correlated with treatment outcome. These connectivity measures could provide a means to evaluate how likely a patient is to respond to an antidepressant treatment. Further work using larger samples is required to confirm these findings and to assess if measures of functional connectivity can be used to predict differential outcomes between antidepressant treatments.
Frontiers in psychiatry / Frontiers Research Foundation. 01/2011; 2:7.
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ABSTRACT: Transcranial magnetic stimulation (TMS) is a non-invasive method for stimulating the human cortex. Classical conditioning is a phenomenon of developed associations between stimuli. Our primary objective was to determine whether TMS effects could be conditioned. Prepulse inhibition represents another relationship between two stimuli, and a secondary assessment was performed to explore this relationship.
An auditory-visual conditioning stimulus (CS) was paired with the TMS unconditioned stimulus (US) over motor cortex producing a motor-evoked potential (MEP) unconditioned response (UR). Two versions of the CS-US pairing paradigms were tested, one with a short intertrial interval (ITI) and another with a long ITI. The short ITI paradigm had more CS-US pairings and shorter session duration than the long ITI paradigm. Tests for conditioned responses (CRs) were performed following CS-US pairing (CS+/US+), by presenting the CS alone (CS+/US-). Reverse testing was also performed after CS-US pairing (CS+/US+) in separate sessions, by presenting the US alone (CS-/US+).
Evidence for CRs was found only with the short ITI paradigm. The magnitudes of CRs were smaller than TMS-induced MEPs, and the CRs were found only in a percentage of tests. Prepulse inhibition was robustly evident for the long ITI paradigm, but not for the short ITI paradigm.
We have found evidence that classical conditioning principles can be applied to brain stimulation in humans. These findings provide a method for exploring brain and behavioral relationships in humans, as well as suggesting approaches to enhance therapeutic uses of TMS or other forms of brain stimulation.
Brain Stimulation 04/2010; 3(2):78-86. · 3.76 Impact Factor
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F Andrew Kozel
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ABSTRACT: Refinements in the methods of diagnosis for psychiatric disorders are critically needed. These new methods should be based on objectively measured brain characteristics that provide clinically useful information. Studying the brain with respect to psychiatric disorders, however, faces numerous challenges. Utilizing techniques learned in other areas of medicine to deal with symptoms that lead to complex disorders can provide insight into improving diagnostic models in psychiatry. Specifically, many areas of medicine use objective measures of an organ's function or characteristic to guide clinical management of particular subjective complaints. In psychiatry, an objectively measured brain characteristic that provides clinically useful information is proposed to be that person's "phronotype." Important requirements to developing phronotypes are discussed. Identifying phronotypes in psychiatry will require a specific investigative approach that must be grounded in rigorous scientific methodology. Successfully developing such markers will have a profound impact on clinical care, clinical research, basic science research, and most importantly the lives of those suffering from these illnesses.
Frontiers in psychiatry / Frontiers Research Foundation. 01/2010; 1:141.
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ABSTRACT: Deception involves complex neural processes and correlates in the brain. Functional brain imaging techniques have been used to study and understand brain mechanisms during deception. In this study, we utilized functional near-infrared spectroscopy (fNIRS) to investigate hemodynamic responses to deception in the prefrontal cortex (PFC) at the individual level. The protocol involved a mock theft scenario that was previously used in a functional MRI (fMRI) study of detecting deception. Subjects (N=11) were instructed to steal a ring or a watch and then conceal the item that they stole. Participants then responded to visually presented questions regarding which item they took. While the subjects were answering the questions, their PFC activity was measured using fNIRS. The brain activity associated with deceptive responses demonstrated significant changes in hemoglobin concentrations with respect to the baseline, while the response of truth telling was not statistically different from baseline. The regions of greater activation induced by deception identified by fNIRS were approximately consistent with those reported by the previous fMRI study using a similar protocol. This study demonstrates that fNIRS is a promising new technique to understand hemodynamic and neural correlates of deception and thus to detect deception with the added advantages of being compact, technically easier to implement, and inexpensive compared to functional MRI.
Brain research 09/2009; 1303:120-30. · 2.46 Impact Factor
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ABSTRACT: Simultaneously acquiring functional Near Infrared Spectroscopy (fNIRS) during Transcranial Magnetic Stimulation (rTMS) offers the possibility of directly investigating superficial cortical brain activation and connectivity. In addition, the effects of rTMS in distinct brain regions without quantifiable behavioral changes can be objectively measured.
Healthy, nonmedicated participants age 18-50 years were recruited from the local community. After written informed consent was obtained, the participants were screened to ensure that they met inclusion criteria. They underwent two visits of simultaneous rTMS/fNIRS separated by 2 to 3 days. In each visit, the motor cortex and subsequently the prefrontal cortex (5 cm anterior to the motor cortex) were stimulated (1 Hz, max 120% MT, 10 s on with 80 s off, for 15 trains) while simultaneous fNIRS data were acquired from the ipsilateral and contralateral brain regions.
Twelve healthy volunteers were enrolled with one excluded prior to stimulation. The 11 participants studied (9 male) had a mean age of 31.8 (s.d. 10.2, range 20-49) years. There was no significant difference in fNIRS between Visit 1 and Visit 2. Stimulation of both the motor and prefrontal cortices resulted in a significant decrease in oxygenated hemoglobin (HbO(2)) concentration in both the ipsilateral and contralateral cortices. The ipsilateral and contralateral changes showed high temporal consistency.
Simultaneous rTMS/fNIRS provides a reliable measure of regional cortical brain activation and connectivity that could be very useful in studying brain disorders as well as cortical changes induced by rTMS.
NeuroImage 06/2009; 47(4):1177-84. · 5.89 Impact Factor
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ABSTRACT: Functional magnetic resonance imaging (fMRI) is a technology used to detect brain activity. Patterns of brain activation have been utilized as biomarkers for various neuropsychiatric applications. Detecting deception based on the pattern of brain activation characterized with fMRI is getting attention - with machine learning algorithms being applied to this field in recent years. The high dimensionality of fMRI data makes it a difficult task to directly utilize the original data as input for classification algorithms in detecting deception. In this paper, we investigated the procedures of feature selection to enhance fMRI-based deception detection.
We used the t-statistic map derived from the statistical parametric mapping analysis of fMRI signals to construct features that reflect brain activation patterns. We subsequently investigated various feature selection methods including an ensemble method to identify discriminative features to detect deception. Using 124 features selected from a set of 65,166 original features as inputs for a support vector machine classifier, our results indicate that feature selection significantly enhanced the classification accuracy of the support vector machine in comparison to the models trained using all features and dimension reduction based models. Furthermore, the selected features are shown to form anatomic clusters within brain regions, which supports the hypothesis that specific brain regions may play a role during deception processes.
Feature selection not only enhances classification accuracy in fMRI-based deception detection but also provides support for the biological hypothesis that brain activities in certain regions of the brain are important for discrimination of deception.
BMC Bioinformatics 01/2009; 10 Suppl 9:S15. · 2.75 Impact Factor
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ABSTRACT: BACKGROUND: Several studies support the use of fMRI for detecting deception. There have been, however, no reported replications on different scanners or at different locations. In a previous study, deception was accurately detected in at least 90% of the participants in two independent cohorts. This study attempted to replicate those findings using a different scanner and location. METHODS: Healthy participants 18-50 years of age were recruited from the local community. After providing written informed consent, participants were screened to ensure that they were healthy, not taking any medications, and safe to have an MRI. For the testing paradigm, subjects chose one of two objects (ring or watch) to "steal" and placed it in their locker. Participants were then scanned while being visually presented with a series of questions. Functional MRI analysis was performed in the same manner as described in Kozel et al. 2005. A Chi-Squared test was used to test for a significant difference between the results in the previous study and in this replication study. RESULTS: Thirty subjects (20 women, mean age 29.0+/-6.5 years) were scanned with one subject being noncompliant with the protocol. Twenty-five of twenty-nine (86%) participants were correctly identified when being deceptive. There was no statistical difference between the accuracy rate obtained in this study (25/29) versus the previous study (28/31) (Chi-Squared, chi(2)=0.246, p=0.6197). CONCLUSIONS: Our methodology for detecting deception was successfully replicated at a different site suggesting that this methodology is robust and independent of both scanner and location.
The Open Forensic Science Journal 01/2009; 2:6-11.
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BMC Bioinformatics. 01/2009; 10:15.
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ABSTRACT: Observation of changes in autonomic arousal was one of the first methodologies used to detect deception. Electrodermal activity (EDA) is a peripheral measure of autonomic arousal and one of the primary channels used in polygraph exams. In an attempt to develop a more central measure to identify lies, the use of functional magnetic resonance imaging (fMRI) to detect deception is being investigated. We wondered if adding EDA to our fMRI analysis would improve our diagnostic ability. For our approach, however, adding EDA did not improve the accuracy in a laboratory-based deception task. In testing for brain regions that replicated as correlates of EDA, we did find significant associations in right orbitofrontal and bilateral anterior cingulate regions. Further work is required to test whether EDA improves accuracy in other testing formats or with higher levels of jeopardy.
Social neuroscience 01/2009; 4(6):510-7. · 3.17 Impact Factor
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ABSTRACT: Using Blood Oxygen Level Dependent (BOLD) functional MRI (fMRI) to detect deception is feasible in simple laboratory paradigms. A mock sabotage scenario was used to test whether this technology would also be effective in a scenario closer to a real-world situation. Healthy, nonmedicated adults were recruited from the community, screened, and randomized to either a Mock-crime group or a No-crime group. The Mock-crime group damaged and stole compact discs (CDs), which contained incriminating video footage, while the No-crime group did not perform a task. The Mock-crime group also picked up an envelope from a researcher, while the No-crime group did not perform this task. Both groups were instructed to report that they picked up an envelope, but did not sabotage any video evidence. Participants later went to the imaging center and were scanned while being asked questions regarding the mock crime. Participants also performed a simple laboratory based fMRI deception testing (Ring-Watch testing). The Ring-Watch testing consisted of "stealing" either a watch or a ring. The participants were instructed to report that they stole neither object. We correctly identified deception during the Ring-Watch testing in 25 of 36 participants (Validated Group). In this Validated Group for whom a determination was made, computer-based scoring correctly identified nine of nine Mock-crime participants (100% sensitivity) and five of 15 No-crime participants (33% specificity). BOLD fMRI presently can be used to detect deception concerning past events with high sensitivity, but low specificity.
Journal of Forensic Sciences 12/2008; 54(1):220-31. · 1.23 Impact Factor
