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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
PubMed2003

Low CSF somatostatin associated with response to nimodipine in patents with affective illness.

BACKGROUND: In patients with depression, treatment with nimodipine has been shown to increase cerebrospinal fluid (CSF) somatostatin (SRIF) and ameliorate baseline global cerebral hypometabolism. This study was conducted to assess whether a low baseline level of CSF SRIF was associated with response to nimodipine treatment. METHODS: Twenty-one depressed patients underwent lumbar puncture for analysis of CSF somatostatin-like immunoreactivity (SRIF-LI) during a medication-free period and after at least 6 weeks of nimodipine monotherapy. Twenty-five healthy control subjects were utilized as a comparison group. Clinical improvement was assessed using the Clinical Global Impression Scale for Bipolar Illness. RESULTS: As predicted, baseline CSF SRIF-LI was significantly lower in eventual nimodipine responders (33.1 +/- 2.8 pg/mol) compared to eventual nonresponders [41.9 +/- 2.6 pg/mL; t(19) = 1.98, p =.03, one-tailed]. CONCLUSIONS: Low baseline CSF somatostatin in depression may be associated with response to nimodipine, which in turn may be related to the ability of nimodipine to increase CSF somatostatin.

Adult↗
PubMed2003

BOLD-fMRI response vs. transcranial magnetic stimulation (TMS) pulse-train length: testing for linearity.

PURPOSE: To measure motor and auditory cortex blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) response to impulse-like transcranial magnetic stimulation (TMS) pulses as a function of train length. MATERIALS AND METHODS: Interleaved with fMRI at 1.5 T, TMS pulses 0.3-msec long were applied at 1 Hz to the motor cortex area for thumb. Six subjects were studied in a TR = 1 second session administering trains of 1, 2, 4, 8, and 16 pulses, and a TR = 3 seconds session administering trains of 1, 2, 4, 8, 16, and 24 pulses. A simple hemodynamic model with finite recovery and saturation was used to quantitatively characterize the BOLD-fMRI response as a function of train length. RESULTS: In both the activations directly induced in motor cortex by TMS and the indirect activations in auditory cortex caused by the sound of the TMS coil firing, the BOLD-fMRI responses to multiple pulses were well described by a summation of single-pulse impulse functions. CONCLUSION: Up to 24 discrete pulses, BOLD-fMRI response to 1 Hz TMS in both motor cortex and auditory cortex were consistent with a linear increase in amplitude and length with train length, possibly suggesting that stimuli of 1 to 2 seconds may be too long to represent impulses.

Adult↗
PubMed2003

Transcranial magnetic stimulation.

TMS is a powerful new tool with extremely interesting research and therapeutic potentials. Further understanding of the ways by which TMS changes neuronal function, especially as a function of its use parameters, will improve its ability to answer neuroscience questions as well as to treat diseases. Because of its noninvasiveness, it does not readily fit under the umbrella of neurosurgery. Nevertheless, it is important for neurosurgeons to be aware of TMS, because findings from TMS studies will have implications for neurosurgical approaches like DBS and VNS. Indeed, it is possible to think of using TMS as a potential noninvasive initial screening tool to identify whether perturbation of a circuit has short-term clinical effects. In the example of chronic refractory depression or OCD, which is generally a chronic illness, it might then follow that rather than having daily or weekly TMS for the rest of their lives, patients would have DBS electrodes implanted in the same circuit. Whatever road the future takes, TMS is an important new tool that will likely be of interest to neurosurgeons over the next 20 years and perhaps even longer.

Brain↗
PubMed2003

Mechanisms and the current state of transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is unique among the current brain stimulation techniques because it is relatively non-invasive. TMS markedly differs from vagus nerve stimulation, deep brain stimulation and magnetic seizure therapy, all of which require either an implanted prosthesis or general anesthesia, or both. Since its rebirth in its modern form in 1985, TMS has already shown potential usefulness in at least three important domains-as a basic neuroscience research instrument, as a potential clinical diagnostic tool, and as a therapy for several different neuropsychiatric conditions. The TMS scientific literature has now expanded beyond what a single summary article can adequately cover. This review highlights several new developments in combining TMS with functional brain imaging, using TMS as a psychiatric therapy, potentially using TMS to enhance performance, and finally recent advances in the core technology of TMS. TMS' ability to non-invasively and focally stimulate the brain of an awake human is proving to be a most important development for neuroscience in general, and neuropsychiatry in particular.

Animals↗
PubMed2003

Vagus nerve stimulation (VNS): utility in neuropsychiatric disorders.

Early in the last century, neuroscientists initially speculated that it might be possible to influence brain activity and associated behaviours by stimulating the vagus nerve in the neck. Several animal studies pointed to this possibility. In the 1980s, Zabara discovered that vagus nerve stimulation (VNS) could reduce or eliminate seizures in dogs. His discovery led to enhanced methods of direct VNS and the development of an implantable device for human VNS. VNS is now an accepted long-term treatment for epilepsy, used by over 15000 patients worldwide. Many have wondered whether VNS could treat other neuropsychiatric disorders. This paper reviews the neurobiology involved in VNS, highlights the VNS clinical findings to date, and discusses potential VNS research opportunities for both clinical and basic investigators. Comments on the clinical utility of VNS in actual clinical practice are provided.

Animals↗
PubMed2003

Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been shown to improve depressive symptoms. We designed and carried out the following left prefrontal rTMS study to determine the safety, feasibility, and potential efficacy of using TMS to treat the depressive symptoms of bipolar affective disorder (BPAD). METHODS: We recruited and enrolled 23 depressed BPAD patients (12 BPI depressed state, nine BPII depressed state, two BPI mixed state). Patients were randomly assigned to receive either daily left prefrontal rTMS (5 Hz, 110% motor threshold, 8 sec on, 22 sec off, over 20 min) or placebo each weekday morning for 2 weeks. Motor threshold and subjective rating scales were obtained daily, and blinded Hamilton Rating Scale for Depression (HRSD) and Young Mania Rating Scales (YMRS) were obtained weekly. RESULTS: Stimulation was well tolerated with no significant adverse events and with no induction of mania. We failed to find a statistically significant difference between the two groups in the number of antidepressant responders (>50% decline in HRSD or HRSD <10 - 4 active and 4 sham) or the mean HRSD change from baseline over the 2 weeks (t = -0.22, p = 0.83). Active rTMS, compared with sham rTMS, produced a trend but not statistically significant greater improvement in daily subjective mood ratings post-treatment (t = 1.58, p = 0.13). The motor threshold did not significantly change after 2 weeks of active treatment (t = 1.11, p = 0.28). CONCLUSIONS: Daily left prefrontal rTMS appears safe in depressed BPAD subjects, and the risk of inducing mania in BPAD subjects on medications is small. We failed to find statistically significant TMS clinical antidepressant effects greater than sham. Further studies are needed to fully investigate the potential role, if any, of TMS in BPAD depression.

Adult↗
PubMed2003

Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study.

Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia.

Adult↗
PubMed2003

Prefrontal cortex transcranial magnetic stimulation does not change local diffusion: a magnetic resonance imaging study in patients with depression.

OBJECTIVE: To determine whether transcranial magnetic stimulation over the left dorsolateral prefrontal cortex produces pathologic changes or leakage of the blood-brain barrier in patients with depression by using apparent diffusion coefficient magnetic resonance imaging. BACKGROUND: Transcranial magnetic stimulation is a new technology for noninvasively stimulating the brain. It appears to be a relatively safe technique, with some important exceptions. Its neurobiologic mechanisms of action are poorly understood. One theory to explain its apparent antidepressant effects involves a potential change in local blood-brain barrier settings, allowing passage of peripheral substances directly into brain parenchyma. Knowing whether transcranial magnetic stimulation changes local brain diffusion is important as well from a safety perspective. To test whether transcranial magnetic stimulation changes local brain diffusion, we used apparent diffusion coefficient magnetic resonance imaging in depressed patients undergoing interleaved transcranial magnetic stimulation/functional magnetic resonance imaging over the left prefrontal cortex. METHODS: Within a 1.5 Tesla magnetic resonance imaging scanner, 14 depressed patients were stimulated with a figure-eight transcranial magnetic stimulation coil over the left prefrontal cortex. Apparent diffusion coefficient magnetic resonance imaging was acquired before, and immediately after, 1 Hertz transcranial magnetic stimulation (147 stimuli) intermittently delivered at a motor threshold of more than 7.35 minutes. Phase maps of the transcranial magnetic stimulation magnetic fields were used to guide region-of-interest placement. RESULTS: No significant qualitative apparent diffusion coefficient differences were observed before and after 1 Hertz transcranial magnetic stimulation underneath the coil. CONCLUSIONS: One Hertz transcranial magnetic stimulation over the left dorsolateral prefrontal cortex as applied in this study did not result in pathologic changes or leakage of the blood-brain barrier in patients with depression. If prefrontal transcranial magnetic stimulation at these usage parameters changes local diffusion, it is not an obvious or large effect.

Adolescent↗
PubMed2002

Left prefrontal-repetitive transcranial magnetic stimulation (rTMS) and regional cerebral glucose metabolism in normal volunteers.

Repetitive transcranial magnetic stimulation (rTMS) holds promise as a probe into the pathophysiology and possible treatment of neuropsychiatric disorders. To explore its regional effects, we combined rTMS with positron emission tomography (PET). Fourteen healthy volunteers participated in a baseline 18-fluorodeoxyglucose (FDG) PET scan. During a second FDG infusion on the same day, seven subjects received 30 min of 1 Hz rTMS at 80% of motor threshold to left prefrontal cortex, and seven other subjects received sham rTMS under identical conditions. Global and normalized regional cerebral glucose metabolic rates (rCMRglu) from the active and sham conditions were compared to baseline and then to each other. Sham, but not active 1 Hz rTMS, was associated with significantly increased global CMRglu. Compared to baseline, active rTMS induced normalized decreases in rCMRglu in right prefrontal cortex, bilateral anterior cingulate, basal ganglia (L>R), hypothalamus, midbrain, and cerebellum. Increases in rCMRglu were seen in bilateral posterior temporal and occipital cortices. Sham rTMS compared to baseline resulted in isolated normalized decreases in rCMRglu in left dorsal anterior cingulate and left basal ganglia, and increases in posterior association and occiptal regions. Differences between the 1 Hz active versus sham changes from baseline revealed that active rTMS induced relative decrements in rCMRglu in the left superior frontal gyrus and increases in the cuneus (L>R). One Hertz rTMS at 80% motor threshold over the left prefrontal cortex in healthy subjects compared to sham rTMS in another group (each compared to baseline) induced an area of decreased normalized left prefrontal rCMRglu not directly under the stimulation site, as well as increases in occipital cortex. While these results are in the predicted direction, further studies using other designs and higher intensities and frequencies of rTMS are indicated to better describe the local and distant changes induced by rTMS.

Adult↗
PubMed2002

Vagus nerve stimulation therapy: a research update.

Over the past 5 years, and especially within the last year, there has been a rapid expansion of vagus nerve stimulation (VNS)-related preclinical research, as well as clinical studies in indications other than epilepsy. The research advances in understanding VNS are occurring in the midst of a blossoming of other forms of therapeutic brain stimulation, such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS). In general, improved understanding of the neurobiological effects of VNS therapy as a function of the different use parameters (frequency, intensity, pulse width, duration, dose) is beginning to guide clinical use and help determine which diseases, in addition to epilepsy, VNS might treat.

Anxiety↗
PubMed2002

A potential role for thalamocingulate circuitry in human maternal behavior.

BACKGROUND: Little is known about the regional brain basis of human maternal behavior. To understand this better, we have been examining brain activity in mothers listening to infant cries. METHODS: We measured functional Magnetic Resonance Imaging brain activity in healthy, breastfeeding first-time mothers with young infants while they listened to infant cries, white noise control sounds, and a rest condition. Based on the thalamocingulate theory of maternal behavior and pilot work, we hypothesized that the cingulate, medial thalamus, medial prefrontal cortex, and right orbitofrontal cortex would display more activity with infant cries than with white noise (comparison 1) and would uniquely activate with the cries, meaning that these regions would display activity with cry minus rest but not with white noise minus rest (comparison 2). RESULTS: In hypothesized regions, the group displayed more activity in the medial thalamus, medial prefrontal and right orbitofrontal cortices with both comparisons. The anterior and posterior cingulate cortex displayed more activity only with comparison 1. In non-hypothesized brain regions, several other structures thought important in rodent maternal behavior displayed activity with both comparisons including the midbrain, hypothalamus, dorsal and ventral striatum, and vicinity of the lateral septal region. CONCLUSIONS: Our results partially support our hypotheses and are generally consistent with neuroanatomical studies of rodent maternal behavior.

Adult↗
PubMed2002

Vagus nerve stimulation (VNS) for major depressive episodes: one year outcomes.

BACKGROUND: Vagus nerve stimulation has shown promising results in an open, acute phase pilot study of adults in a treatment-resistant major depressive episode. This open, naturalistic follow-up study was conducted to determine whether the initial promising effects were sustained, and whether changes in function would be observed. METHODS: Thirty adult outpatients in a treatment-resistant, nonpsychotic major depressive episode received an additional 9 months of vagus nerve stimulation treatment following exit from the 3-month acute study. Changes in psychotropic medications and vagus nerve stimulation stimulus parameters were allowed during this longer-term follow-up study. A priori definitions were used to define response (> or = 50% reduction in baseline Hamilton Rating Scale for Depression total score) and remission (Hamilton Rating Scale for Depression < or = 10). RESULTS: The response rate was sustained [40% (12/30) to 46% (13/28); p =.317] and the remission rate significantly increased [17% (5/30) to 29% (8/28); p =.045] with an additional 9 months of long-term vagus nerve stimulation treatment after exit from the acute study (1 year total vagus nerve stimulation treatment). Significant improvements in function between acute study exit and the 1-year follow-up assessment as measured by the Medical Outcomes Study Short Form-36 were observed. CONCLUSIONS: Longer-term vagus nerve stimulation treatment was associated with sustained symptomatic benefit and sustained or enhanced functional status in this naturalistic follow-up study.

Adult↗
PubMed2002

Age, sex and laterality effects on cerebral glucose metabolism in healthy adults.

Normal cerebral glucose metabolism (CMRglc) was assessed with positron emission tomography in 66 healthy adults (28 women, 38 men; mean age 39, range 20--69 years) to determine effects of age, sex and laterality on CMRglc using statistical parametric mapping. Significant age-related decreases in global metabolism (gCMRglc) were noted in the entire sample and in both sexes, as well as widespread and bilateral decreases in cortical absolute regional metabolism (rCMRglc) and more focal anterior paralimbic normalized rCMRglc. However, significant positive correlations of age with normalized rCMRglc were observed in cerebellum, thalamus and occipital areas. Although the declines in gCMRglc and rCMRglc with age did not significantly differ between sexes, men compared with women had significantly lower gCMRglc and widespread decreased cortical and subcortical absolute rCMRglc. In the entire sample, and similarly in both sexes, left greater than right asymmetry was observed in medial frontal gyrus, posterior thalamus, lingual gyrus, cuneus and superior cingulate. The opposite laterality appeared in mesio-anterior cerebellum, and lateral frontal and temporal regions. Few regions showed significant interactions of metabolic laterality with either age or sex. These findings contribute toward a convergence in the literature, and the regression models of CMRglc vs. age serve as a normative database to which patients may be compared.

Adult↗
PubMed2002

Regional cerebral glucose utilization in patients with a range of severities of unipolar depression.

BACKGROUND: Patients with unipolar depression are most often reported to have decreased regional cerebral glucose metabolism (rCMRglu) in dorsal prefrontal and anterior cingulate cortices compared with healthy control subjects, often correlating inversely with severity of depression. METHODS: We measured rCMRglu with fluorine-18 deoxyglucose positron emission tomography (PET) in 38 medication-free patients with unipolar depression and 37 healthy control subjects performing an auditory continuous performance task to further investigate potential prefrontal and anterior paralimbic rCMRglu abnormalities in patients attending to this task. RESULTS: Compared with control subjects, the subgroup of patients with Hamilton depression scores of 22 or greater demonstrated decreased absolute rCMRglu in right prefrontal cortex and paralimbic/amygdala regions as well as bilaterally in the insula and temporoparietal cortex (right > left); they also exhibited increased normalized metabolic activity bilaterally in the cerebellum, lingula/cuneus, and brain stem. Severity of depression negatively correlated with absolute rCMRglu in almost the entire extent of the right cingulate cortex as well as bilaterally in prefrontal cortex, insula, basal ganglia, and temporoparietal cortex (right > left). CONCLUSIONS: Areas of frontal, cingulate, insula, and temporal cortex appear hypometabolic in association with different components of the severity and course of illness in treatment-resistant unipolar depression.

Adult↗
PubMed2002

Novel treatments of mood disorders based on brain circuitry (ECT, MST, TMS, VNS, DBS).

Advances in understanding the functional and structural anatomy of depression outlined in this issue set the stage for attempting to manipulate implicated brain regions as potential antidepressant therapies. On the one hand, these circuit- and device-based approaches to treating depression are not new. Electroconvulsive therapy (ECT) dates back to the beginning of modern biologic psychiatry with the discovery and rapid increase of first chemical (around 1910), and then later ECT. On the other hand, this area represents an important paradigm shift with treatments that are radical and different. A dizzying array of diverse technologies now allows researchers to stimulate the brain in undreamed of ways. However, the approaches described in this article are still considered experimental and are not approved for use in the United States by the Food and Drug Administration (FDA), except ECT, which predates the FDA. These device-based approaches to brain stimulation offer promise as potential acute and even longterm treatments. Additionally, the research determining whether and how these devices work to influence mood promises to help unravel the neurophysiology of mood regulation. These novel treatments are thus the translational tools to bridge from advances in brain imaging, into new treatments for depressed patients.

Brain↗
PubMed2002

Mechanisms and state of the art of transcranial magnetic stimulation.

In 1985, Barker et al. built a transcranial magnetic stimulation (TMS) device with enough power to stimulate dorsal roots in the spine. They quickly realized that this machine could likely also noninvasively stimulate the superficial cortex in humans. They waited a while before using their device over a human head, fearing that the TMS pulse might magnetically "erase the hard-drive" of the human brain. Almost 10 years later, in 1994, an editorial in this journal concerned whether TMS might evolve into a potential antidepressant treatment. In the intervening years, there has been an explosion of basic and clinical research with and about TMS. Studies are now uncovering the mechanisms by which TMS affects the brain. It does not "erase the hard-drive" of the brain, and it has many demonstrated research and clinical uses. This article reviews the major recent advances with this interesting noninvasive technique for stimulating the brain, critically reviewing the data on whether TMS has anticonvulsant effects or modulates cortical-limbic loops.

Animals↗