RESEARCH OVERVIEW 2005
Neuroimaging Center
Affective Disorders Laboratory
Michael Henry, M.D., Director
Researchers in the Affective Disorders Laboratory are studying how patterns of brain activity measured by the MRI scanner can be used to guide clinicians in decisions as to whether to continue or discontinue antidepressant therapy. The work is based on the earlier finding by this same group that symptoms associated with abrupt discontinuation of some antidepressants are associated with changes in the metabolic activity of the left frontal lobe and caudate nucleus. Research such as this may someday help doctors more effectively manage their patient medication regimens.
Behavioral Psychopharmacology Research Laboratory
Scott Lukas, Ph.D., Director
Researchers in the Behavioral Psychopharmacology Research Laboratory, in collaboration with researchers from the Bio-Organics and Natural Products Laboratory, have discovered that 1 week treatment with an extract of the Chinese herb, kudzu, significantly reduces alcohol drinking by heavy drinkers in a natural laboratory setting. The effect seems to be linked to an increased length of time waited by the subject between drinks (the 'latency period'). Kudzu may thus become an important treatment for alcohol abuse by allowing the body increased time to metabolize alcohol, thereby reducing the opportunity for blood alcohol levels to reach the level of intoxication.
Resources
Brain Imaging Center
Perry Renshaw, Ph.D., Director
Investigators at McLean's Brain Imaging Center have been workong on a number of ongoing studies, including the following:
- We discovered a mood effect produced by the magnetic fields in an MRI scanner. The technique, called "Low Field Magnetic Stimulation," is thought to be linked to the changing magnetic fields of the gradient coils in the MR system, and the corresponding induced electric fields in the brain. In this pilot but very exciting study, mood improvements were reported by 23 of 30 bipolar disorder subjects who received the scan. In a collaborative study with the Behavioral Genetics Laboratory, the effect was duplicated in animals using a small, head-sized coil outside of the MR system, in order to confirm the effect and demonstrate its independence from the static magnetic field of the MRI system. Further research is needed to confirm the findings, and a full scale clinical trial is being planned, but results may lead to a totally new treatment for depression.
- Our investigators used the Varian high field 4 Tesla magnet to investigate cerebral metabolism in the limbic region of children and adolescents (age 6 to 18 years old) with bipolar disorder. These children were shown to have an abnormal level of a neurotransmitter (GABA) in a part of the brain known as the anterior cingulate cortex, compared with healthy children. Although other studies have observed similar findings, this study was the first to measure the altered activity in children themselves, and the first to show that the dysfunction exists even in the early stages of bipolar illness. Findings such as this may give researchers better ways to identify illness earlier, and develop treatment programs for earlier intervention in the course of the illness.
- We identified abnormally low blood nitric oxide levels in cocaine-dependent men, when compared to women with similar cocaine abuse histories. NO has a number of biological functions but one of its most important actions is to relax blood vessels. Cocaine is a potent blood vessel constrictor and lower blood NO levels in cocaine-dependent men could lead to more severe blood flow disruptions than experienced by female cocaine users. This could in part explain why cocaine-dependent men have more brain and vascular dysfunction than their female counterparts, and suggest that increasing blood NO levels in cocaine-dependent men might be a useful adjunct treatment for cocaine dependence.
- In collaboration with scientists in the Behavioral Psychopharmacology Research Laboratory we have been using novel anatomic matching methods to better register functional magnetic resonance (fMRI) images with anatomical reference images for the study of substance abuse. fMRI images are distorted by magnetic field inconsistencies, causing a misalignment between these images and the high resolution anatomical images used to locate brain structures. These distortions can be especially severe in high field strength magnets and are most pronounced in the basal forebrain, a region of particular interest in the study of reward circuitry. Regions can be displaced by more than 10 mm, which can lead to the misinterpretation of fMRI scans. The new method 'warps' the high resolution images in the same manner as the fMRI images, so that brain structures identified in these images overlay the functional maps exactly and brain activations can be precisely located.
- Using phosphorus magnetic resonance spectroscopic imaging (31P-MRSI), we revealed for the first time that high energy phosphate levels are reduced in the frontal lobes of the brains of opiate-dependent patients after long-term methadone treatment compared to those patients just entering a methadone treatment program. These findings may reflect shifts in frontal lobe brain energy metabolism during early treatment that eventually normalize with prolonged treatment. It is theorized that this effect is seen because heroin is more potent than methadone in reducing blood oxygen levels, so the transition between heroin abuse and methadone substitution could be accompanied by brain oxygenation increases that alter the brain’s energy metabolism. Studies such as this could lead to better-designed treatment programs for drug abuse.
Cognitive Neuroimaging and Neuropsychology Laboratory
Deborah A. Yurgelun-Todd, Ph.D., Director
Staci Gruber, Ph.D., Associate Director
Key Personnel:
Piotr Bogorodzki, Ph.D.; Robert Irvin, M.D.; Gen Kanayama, M.D., Ph.D.; Srinivasan Pillay, M.D.; Jadwiga Rogowska, Ph.D.; Isabelle Rosso, Ph.D.; Marisa Silveri, Ph.D; Jennifer Tropp-Sneider, Ph.D.; Lisa Carabuena, B.S.; Ashley Cerny, B.S.; Donna Murray, BMT; Patricia Pimentel, B.S.; Margaret Riccuitti, B.A.; Ashley Young, A.B.
Research Initiative
The Cognitive Neuroimaging Laboratory is dedicated to the examination of cognitive and affective correlates of neural systems, which may mediate symptoms in psychiatric disorders. Techniques used in these investigations include studies of neuropsychological performance, neurological hard signs, and magnetic resonance imaging methods. The aim of these studies has been to identify brain abnormalities, particularly disruptions of the frontally mediated networks, which may represent risk factors for psychiatric illness or may be the site of pathology in these illnesses. Recent investigations have combined results from neuropsychological testing and brain imaging in healthy subjects and subjects with psychiatric disorders as a means of clarifying the possible dysfunctional neural network processes associated with these illnesses.
Research Highlights
To investigate hypotheses derived from neuropsychological studies of adult psychiatric patients, investigators in the Cognitive Neuroimaging Laboratory have successfully applied techniques in brain imaging, including structural morphometry, functional magnetic resonance imaging, and proton magnetic resonance spectroscopy to the study of schizophrenia and bipolar disorder. Most recently, the Cognitive Neuroimaging Laboratory has examined the potential etiologic bases of neural models of dysfunction in psychotic disorders by applying functional magnetic resonance techniques to examine cortical changes during development.
In a recent series of fMRI studies, patients with bipolar disorder and healthy control subjects were examined while performing a cognitive task of inhibition. Results indicate that relative to controls, bipolar patients demonstrated significantly reduced signal intensity within an area of the anterior cingulate which accompanied an increase in the prefrontal cortex during the task, suggesting differential processing strategies of bipolar patients and supporting the theory of altered frontal systems in these patients.
FMRI studies of stable schizophrenic patients during a sequential finger tapping task have demonstrated a significant reduction in contralateral and ipsilateral brain activity in both the primary motor cortex, (BA4) and the premotor and supplementary motor are (BA6) relative to control subjects. These findings suggest that motor system abnormalities are indeed present and identifiable on the basis of BOLD imaging in schizophrenic patients.
In an fMRI study designed to examine patterns of cortical activation underlying D-cycloserine’s therapeutic efficacy in schizophrenic patients, frontal and temporal lobe activity was measured during the performance of a verbal fluency test at baseline and after 8 weeks of supervised treatment. Patients who received D-cycloserine added to their dose of conventional neuroleptic demonstrated an increase in temporal lobe activity at the 8 week timepoint, which accompanied a decrease in negative symptoms relative to the patients who received placebo added to their dose of neuroleptic. These results suggest that the addition of D-cycloserine to conventional neuroleptics may improve negative symptoms through enhanced temporal lobe function.
BOLD fMRI data revealed that marijuana smokers, tested within 4 to 36 hours of discontinuation, exhibited significantly less activation than controls in the anterior cingulate bilaterally during right- and left-sided finger sequencing as compared to control subjects. These results suggest that recently abstinent chronic cannabis smokers produce reduced activation in motor cortical areas in response to finger sequencing compared to controls.
In a second important finding from this investigation, fMR imaging of recent heavy cannabis smokers during the performance of a working memory task who were tested within 6-36 hours of abstinence revealed increased activation of brain regions typically used for spatial working memory tasks, inlcluding the prefrontal cortex and anterior cingulate relative to control subjects. These findings suggest altered processing during the performance of working memory tasks in cannabis smoking subjects during early abstinence.
Sleep Research Laboratory
Cynthia Dorsey, Director
Researchers in the Sleep Research Laboratory continue to work in collaboration with investigators in the Brain Imaging Center to attempt to detect chemical changes in the brain that may be related to sleep disturbance associated with substance abuse and changes in sleep homeostasis. Such chemical changes in the brain are undetectable by more traditional means of assessment which measure only blood flow and glucose metabolism. Recent preliminary data obtained from control subjects studied in the 4-Tesla scanner replicated the investigators' previous findings using the 1.5 T of an increase in beta-NTP, a correlate of ATP, on the morning after a night of recovery sleep immediately following sleep deprivation. The 4T study results also showed a significant increase in beta-NTP on the morning after sleep deprivation, before recovery sleep. Methadone-maintained individuals are being studied using the same protocol. Continuing research on the effects of sleep deprivation on brain chemistry in those who are drug dependent may lead to a better understanding of changes in sleep as a function of substance abuse and withdrawal-related insomnia as an important contributor to relapse.