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Biomedical subjects

Mark S George

Publications and source records attributed to Mark S George.

At least 19 recordsLinked to original sources
PubMed2007

Serial vagus nerve stimulation functional MRI in treatment-resistant depression.

Vagus nerve stimulation (VNS) therapy has shown antidepressant effects in open acute and long-term studies of treatment-resistant major depression. Mechanisms of action are not fully understood, although clinical data suggest slower onset therapeutic benefit than conventional psychotropic interventions. We set out to map brain systems activated by VNS and to identify serial brain functional correlates of antidepressant treatment and symptomatic response. Nine adults, satisfying DSM-IV criteria for unipolar or bipolar disorder, severe depressed type, were implanted with adjunctive VNS therapy (MRI-compatible technique) and enrolled in a 3-month, double-blind, placebo-controlled, serial-interleaved VNS/functional MRI (fMRI) study and open 20-month follow-up. A multiple regression mixed model with blood oxygenation level dependent (BOLD) signal as the dependent variable revealed that over time, VNS therapy was associated with ventro-medial prefrontal cortex deactivation. Controlling for other variables, acute VNS produced greater right insula activation among the participants with a greater degree of depression. These results suggest that similar to other antidepressant treatments, BOLD deactivation in the ventro-medial prefrontal cortex correlates with the antidepressant response to VNS therapy. The increased acute VNS insula effects among actively depressed participants may also account for the lower dosing observed in VNS clinical trials of depression compared with epilepsy. Future interleaved VNS/fMRI studies to confirm these findings and further clarify the regional neurobiological effects of VNS.

Adult↗
PubMed2007

Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders.

Vagus nerve stimulation is an interesting new approach to treating neuropsychiatric diseases within the class of brain-stimulation devices sometimes labeled 'neuromodulators'. With vagus nerve stimulation, a battery-powered generator implanted in the chest wall connects to a wire wrapped around the vagus nerve in the neck, and sends intermittent pulses of electricity along the nerve directly into the brain. This mechanism takes advantage of the natural role of the vagus nerve in conveying information into the brain concerning homeostatic information (e.g., hunger, chest pain and respirations). Vagus nerve stimulation therapy is US FDA approved for the adjunctive treatment of epilepsy and has recently been FDA approved for the treatment of medication-resistant depression. Owing to its novel route into the brain, it has no drug-drug interactions or systemic side effects. This treatment also appears to have high long-term tolerability in patients, with low rates of patients relapsing on vagus nerve stimulation or becoming tolerant. However, alongside the excitement and enthusiasm for this new treatment, a lack of Class I evidence of efficacy in treating depression is currently slowing down adoption by psychiatrists. Much more research is needed regarding exactly how to refine and deliver the electrical pulses and how this differentially affects brain function in health and disease.

Cognition Disorders↗
PubMed2006

Vagus nerve stimulation acutely alters food craving in adults with depression.

Vagus nerve stimulation (VNS) is now available as a treatment for epilepsy and treatment-resistant depression. The vagus nerve plays a central role in satiety and short-term regulation of food intake and research suggests a relationship between VNS and weight loss. The underlying mechanisms of this relationship are unknown. The purpose of the current study was to determine whether acute cervical VNS might temporarily alter food cravings. Thirty-three participants were recruited for three groups; depression VNS, depression non-VNS, and healthy controls. Participants viewed 22 computerized images of foods twice in one session and completed ratings for food cravings after each image. The VNS participants' devices were turned on for one viewing of an image and off for the other (randomized order). Participants were blind to VNS condition (on versus off). Acute VNS device activation was associated with a significant change in cravings-ratings for sweet foods. A significant proportion of variability in VNS-related changes in cravings was accounted for by patients' clinical VNS device settings, acute level of depression, and body mass. Further studies are warranted addressing how acute or chronic VNS might modify eating behavior and weight.

Adult↗
PubMed2006

VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms.

Currently available therapeutic interventions for treatment-resistant depression, including switch, combination, and augmentation strategies, are less than ideal. Observations of mood elevation during vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy suggested a role for VNS therapy in refractory major depression and prompted clinical investigation of this neurostimulation modality. The VNS Therapy System has been available for treatment of pharmacoresistant epilepsy since 1997 and was approved by the US Food and Drug Administration for treatment-resistant depression in July, 2005. The physiology of the vagus nerve, mechanics of the VNS Therapy System, and efficacy and safety in pharmacoresistant epilepsy are reviewed. Promising results of VNS therapy for treatment-resistant depression have been forthcoming from both acute and long-term studies, evidenced in part by progressive improvements in depression rating scale scores during the 1st year of treatment with maintenance of response thereafter. VNS therapy is well tolerated in patients with either pharmacoresistant epilepsy or treatment-resistant depression. As in epilepsy, the mechanisms of VNS therapy of treatment-resistant depression are incompletely understood. However, evidence from neuroimaging and other studies suggests that VNS therapy acts via innervation of the nucleus tractus solitarius, with secondary projections to limbic and cortical structures that are involved in mood regulation, including brainstem regions that contain serotonergic (raphe nucleus) and noradrenergic (locus ceruleus) perikarya that project to the forebrain. Mechanisms that mediate the beneficial effects of VNS therapy for treatment-resistant depression remain obscure. Suggestions for future research directions are described.

Animals↗
PubMed2006

Cerebral blood flow changes during vagus nerve stimulation for depression.

Positron emission tomography (PET oxygen-15 labeled water or PET [15O]H2O) was used to identify changes in regional cerebral blood flow (rCBF) in response to acute vagus nerve stimulation (VNS) in four subjects with treatment-resistant major depression (TRMD). Four 90-s PET [15O]H2O scans were performed on each subject in an off-on sequence (2 VNS de-activated; 2 VNS activated). PET images were aligned, normalized for global uptake, and resampled to standard atlas space. Statistical t-images were used to evaluate change. VNS-induced increases in rCBF were found in the bilateral orbitofrontal cortex, bilateral anterior cingulate cortex, and right superior and medial frontal cortex. Decreases were found in the bilateral temporal cortex and right parietal area. Regions of change were consistent with brain structures associated with depression and the afferent pathways of the vagus nerve.

Adult↗
PubMed2006

Vagus nerve stimulation (VNS) for depression: what do we know now and what should be done next?

Vagus nerve stimulation (VNS) therapy is the first US Food and Drug Administration-approved somatic clinical intervention for treatment-resistant depression (TRD). Long-term open data suggest a sustainable antidepressant response over time. Here we review the clinical data that exist so far and their limitations. We also discuss guidelines that may inform the clinical utilization of this procedure. Further clinical studies, in addition to prospective cost utilization and health economic investigations, are needed to better understand VNS therapy and the impact it holds on TRD care.

Bipolar Disorder↗
PubMed2006

Acute and long-term VNS effects on pain perception in a case of treatment-resistant depression.

Vagus Nerve Stimulation (VNS) is approved by the FDA for treatment of both epilepsy and depression. Recent work has shown that VNS acutely affects pain perception in humans, actually increasing pain sensitivity momentarily while the device is firing. It is unclear how this acutely increased sensitivity might change over time with treatment and how it might relate to longer-term therapeutic effects of VNS on pain. We describe a patient with treatment-resistant depression and a history of severe lumbar degenerative disease with resultant chronic low back pain. His depression and pain symptoms both seemed to respond to VNS. He eventually stopped all medications and remained depression and pain free for 35 months with no change in his device settings. Sixty-six months after VNS implantation and 64 months after his initial clinical antidepressant response, under single-blind conditions, we performed quantitative sensory testing with laboratory thermal pain procedures during acute VNS-on and -off conditions. Interestingly, despite a significant and profound anti-nociceptive clinical response for the previous 35 months, he had significant increases in painfulness ratings while the VNS device was actively firing compared with device-off conditions. This case suggests that VNS-induced acute increases in pain sensitivity can coexist with a clinical anti-nociceptive response. If the acutely increased sensitivity sets the stage for the slower chronic anti-pain effects, the increased acute sensitivity does not disappear. Acute and chronic effects of VNS on pain perception merit further research.

Depression↗
PubMed2006

Postoperative left prefrontal repetitive transcranial magnetic stimulation reduces patient-controlled analgesia use.

BACKGROUND: Several recent studies suggest that repetitive transcranial magnetic stimulation can temporarily reduce pain perception in neuropathic pain patients and in healthy adults using laboratory pain models. No studies have investigated the effects of prefrontal cortex stimulation using transcranial magnetic stimulation on postoperative pain. METHODS: Twenty gastric bypass surgery patients were randomly assigned to receive 20 min of either active or sham left prefrontal repetitive transcranial magnetic stimulation immediately after surgery. Patient-controlled analgesia pump use was tracked, and patients also rated pain and mood twice per day using visual analog scales. RESULTS: Groups were similar at baseline in terms of body mass index, age, mood ratings, pain ratings, surgery duration, time under anesthesia, and surgical anesthesia methods. Significant effects were observed for surgery type (open vs. laparoscopic) and condition (active vs. sham transcranial magnetic stimulation) on the cumulative amount of patient-delivered morphine during the 44 h after surgery. Active prefrontal repetitive transcranial magnetic stimulation was associated with a 40% reduction in total morphine use compared with sham during the 44 h after surgery. The effect seemed to be most prominent during the first 24 h after cortical stimulation delivery. No effects were observed for repetitive transcranial magnetic stimulation on mood ratings. CONCLUSIONS: A single session of postoperative prefrontal repetitive transcranial magnetic stimulation was associated with a reduction in patient-controlled analgesia pump use in gastric bypass surgery patients. This is important because the risks associated with postoperative morphine use are high, especially among obese patients who frequently have obstructive sleep apnea, right ventricular dysfunction, and pulmonary hypertension. These preliminary findings suggest a potential new noninvasive method for managing postoperative morphine use.

Adult↗
PubMed2006

Tolerability and safety of high daily doses of repetitive transcranial magnetic stimulation in healthy young men.

Repetitive transcranial magnetic stimulation (rTMS) is an experimental technology that involves a powerful magnetic pulse applied to the scalp, which is sufficient to cause neuronal depolarization. Transcranial magnetic stimulation has been used in treatment studies for psychiatric disorders, primarily unipolar depression, and as a tool to map brain function. Although thousands of rTMS sessions have been given with few side effects, rTMS can produce serious adverse effects such as an unintended seizure. Safety guidelines for frequency, duration, and intensity of rTMS have aided in the prevention of such adverse side effects. However, the total dose (number of stimuli) able to be delivered safely to human subjects within a day or within a week has not been established. For example, previous rTMS studies as a treatment for depression consisted of delivering 800 to 3,000 magnetic pulses per day, with 8000 to 30,000 magnetic pulses over 2 to 3 weeks. This study examined whether high doses of rTMS within a day or over a week would produce significant side effects. As part of a study to examine rTMS effects in sleep deprivation, we exposed healthy men to 12,960 magnetic pulses a day for up to 3 days in 1 week. This equals 38,880 magnetic pulses over 1 week, which is likely one of the largest exposures of TMS to date. Despite this intense treatment regimen, we failed to produce significant side effects. Doses of up to 12,960 pulses per day appear safe and tolerable in healthy young men.

Adolescent↗
PubMed2006

Estimating resting motor thresholds in transcranial magnetic stimulation research and practice: a computer simulation evaluation of best methods.

OBJECTIVES: Resting motor threshold is the basic unit of dosing in transcranial magnetic stimulation (TMS) research and practice. There is little consensus on how best to estimate resting motor threshold with TMS, and only a few tools and resources are readily available to TMS researchers. The current study investigates the accuracy and efficiency of 5 different approaches to motor threshold assessment for TMS research and practice applications. METHODS: Computer simulation models are used to test the efficiency and accuracy of 5 different adaptive parameter estimation by sequential testing (PEST) procedures. For each approach, data are presented with respect to the mean number of TMS trials necessary to reach the motor threshold estimate as well as the mean accuracy of the estimates. RESULTS: A simple nonparametric PEST procedure appears to provide the most accurate motor threshold estimates, but takes slightly longer (on average, 3.48 trials) to complete than a popular parametric alternative (maximum likelihood PEST). Recommendations are made for the best starting values for each of the approaches to maximize both efficiency and accuracy. CONCLUSIONS: In light of the computer simulation data provided in this article, the authors review and suggest which techniques might best fit different TMS research and clinical situations. Lastly, a free user-friendly software package is described and made available on the world wide web that allows users to run all of the motor threshold estimation procedures discussed in this article for clinical and research applications.

Computer Simulation↗
PubMed2006

Reducing pain and unpleasantness during repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is associated with significant scalp discomfort under the coil for a high percentage of participants, especially with high stimulation intensities (100% of motor threshold or higher) or frequencies (1 Hz or greater). Some patients in rTMS clinical trials have been unable to tolerate the pain and have dropped out. There seem to be no published studies of strategies to reduce the localized pain and discomfort associated with rTMS. Thus, the authors conducted preliminary pilot trials of 4 different strategies for managing discomfort associated with left prefrontal rTMS. Healthy adults rated the painfulness and unpleasantness of left prefrontal rTMS (10 Hz; 5 seconds, on; 30 seconds, off; at 100% and 120% of resting motor threshold) before and after (1) topical application of a eutectic mixture of local anesthetics cream, (2) scalp injection of lidocaine, (3) scalp injection of lidocaine and epinephrine, and (4) with or without 3 x 3-in thin foam sheets between the coil and scalp. The discomfort produced by rTMS under these experimental conditions was compared with the discomfort produced by stimulation with the same parameters without the interventions. Localized anesthetic injections were associated with a significant decrease in pain intensity and unpleasantness, whereas the eutectic mixture of local anesthetics cream had no effect on rTMS-related discomfort. The use of foam sheets was associated with a slight but noticeable decrease in pain intensity and unpleasantness. More systematic research is needed on the effectiveness of different strategies for reducing rTMS-related pain and discomfort.

Administration, Topical↗
PubMed2005

Detecting deception using functional magnetic resonance imaging.

BACKGROUND: The ability to accurately detect deception is presently very limited. Detecting deception might be more accurately achieved by measuring the brain correlates of lying in an individual. In addition, a method to investigate the neurocircuitry of deception might provide a unique opportunity to test the neurocircuitry of persons in whom deception is a prominent component (i.e., conduct disorder, antisocial personality disorder, etc.). METHODS: In this study, we used functional magnetic resonance imaging (fMRI) to show that specific regions were reproducibly activated when subjects deceived. Subjects participated in a mock crime stealing either a ring or a watch. While undergoing an fMRI, the subjects denied taking either object, thus telling the truth with some responses, and lying with others. A Model-Building Group (MBG, n = 30) was used to develop the analysis methods, and the methods were subsequently applied to an independent Model-Testing Group (MTG, n = 31). RESULTS: We were able to correctly differentiate truthful from deceptive responses, correctly identifying the object stolen, for 93% of the subjects in the MBG and 90% of the subjects in the MTG. CONCLUSIONS: This is the first study to use fMRI to detect deception at the individual level. Further work is required to determine how well this technology will work in different settings and populations.

Adolescent↗
PubMed2005

Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study.

BACKGROUND: The need for effective, long-term treatment for recurrent or chronic, treatment-resistant depression is well established. METHODS: This naturalistic follow-up describes outpatients with nonpsychotic major depressive (n = 185) or bipolar (I or II) disorder, depressed phase (n = 20) who initially received 10 weeks of active (n = 110) or sham vagus nerve stimulation (VNS) (n = 95). The initial active group received another 9 months, while the initial sham group received 12 months of VNS. Participants received antidepressant treatments and VNS, both of which could be adjusted. RESULTS: The primary analysis (repeated measures linear regression) revealed a significant reduction in 24-item Hamilton Rating Scale for Depression (HRSD(24)) scores (average improvement, .45 points [SE = .05] per month (p < .001). At exit, HRSD(24) response rate was 27.2% (55/202); remission rate (HRSD(24) < or = 9) was 15.8% (32/202). Montgomery Asberg Depression Rating Scale (28.2% [57/202]) and Clinical Global Impression-Improvement (34.0% [68/200]) showed similar response rates. Voice alteration, dyspnea, and neck pain were the most frequently reported adverse events. CONCLUSIONS: These 1-year open trial data found VNS to be well tolerated, suggesting a potential long-term, growing benefit in treatment-resistant depression, albeit in the context of changes in depression treatments. Comparative long-term data are needed to determine whether these benefits can be attributed to VNS.

Adult↗
PubMed2005

Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.

BACKGROUND: Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS: This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS: At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS: This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

Adult↗
PubMed2005

A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression.

BACKGROUND: Previous reports have described the effects of vagus nerve stimulation plus treatment as usual (VNS+TAU) during open trials of patients with treatment-resistant depression (TRD). To better understand these effects on long-term outcome, we compared 12-month VNS+TAU outcomes with those of a comparable TRD group. METHODS: Admission criteria were similar for those receiving VNS+TAU (n = 205) or only TAU (n = 124). In the primary analysis, repeated-measures linear regression was used to compare the VNS+TAU group (monthly data) with the TAU group (quarterly data) according to scores of the 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR(30)). RESULTS: The two groups had similar baseline demographic data, psychiatric and treatment histories, and degrees of treatment resistance, except that more TAU participants had at least 10 prior major depressive episodes, and the VNS+TAU group had more electroconvulsive therapy before study entry. Vagus nerve stimulation plus treatment as usual was associated with greater improvement per month in IDS-SR(30) than TAU across 12 months (p < .001). Response rates according to the 24-item Hamilton Rating Scale for Depression (last observation carried forward) at 12 months were 27% for VNS+TAU and 13% for TAU (p < .011). Both groups received similar TAU (drugs and electroconvulsive therapy) during follow-up. CONCLUSIONS: This comparison of two similar but nonrandomized TRD groups showed that VNS+TAU was associated with a greater antidepressant benefit over 12 months.

Adolescent↗
PubMed2005

Cortical and subcortical brain effects of transcranial magnetic stimulation (TMS)-induced movement: an interleaved TMS/functional magnetic resonance imaging study.

BACKGROUND: To date, interleaved transcranial magnetic stimulation and functional magnetic resonance imaging (TMS/fMRI) studies of motor activation have not recorded whole brain patterns. We hypothesized that TMS would activate known motor circuitry with some additional regions plus some areas dropping out. METHODS: We used interleaved TMS/fMRI (11 subjects, three scans each) to elucidate whole brain activation patterns from 1-Hz TMS over left primary motor cortex. RESULTS: Both TMS (110% motor threshold) and volitional movement of the same muscles excited by TMS caused blood oxygen level-dependent (BOLD) patterns encompassing known motor circuitry. Additional activation was observed bilaterally in superior temporal auditory areas. Decreases in BOLD signal with unexpected post-task "rebounds" were observed for both tasks in the right motor area, right superior parietal lobe, and in occipital regions. Paired t test of parametric contrast maps failed to detect significant differences between TMS- and volition-induced effects. Differences were detectable, however, in primary data time-intensity profiles. CONCLUSIONS: Using this interleaved TMS/fMRI technique, TMS over primary motor cortex produces a whole brain pattern of BOLD activation similar to known motor circuitry, without detectable differences from mimicked volitional movement. Some differences may exist between time courses of BOLD intensity during TMS circuit activation and volitional circuit activation.

Adult↗
PubMed2005

Are individual differences in fatigue vulnerability related to baseline differences in cortical activation?

Recent evidence suggests that underlying patterns of cortical activation may partially account for individual differences in susceptibility to the effects of sleep deprivation. Here, functional magnetic resonance imaging (fMRI) was used to examine the activation of military pilots whose sleep-deprivation vulnerability previously was quantified. A Sternberg Working Memory Task (SWMT; S. Sternberg, 1966) was completed alternately with a control task during a 13-min blood oxygen level-dependent fMRI scan. Examination of the activated voxels in response to SWMT indicated that, as a group, the pilots were more similar to fatigue-resistant nonpilots than to fatigue-vulnerable nonpilots. Within the pilots, cortical activation was significantly related to fatigue vulnerability on simulator-flight performance. These preliminary data suggest that baseline fMRI scan activation during a working memory task may correlate with fatigue susceptibility.

Adolescent↗