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Primary Psychiatry. 2010;17(9):34-37
This interview took place on June 10, 2010 and was conducted by Norman Sussman, MD.
Disclosure: Dr. Holt reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
If you would like to access this interview online, please visit www.primarypsychiatry.com.
Are we at a point where neuroimaging or neural biomarkers of psychiatric illness can help us identify and even start treating diseases early in their development?
One central goal in neuroimaging research in psychiatric illness is to define the neural correlates of particular psychiatric illnesses so that they can be used as biomarkers of the illness. The basic assumption is that at least some of the brain abnormalities found in people with an illness should also be seen in people who are at risk for that illness but not yet ill. These neural abnormalities could be used as biomarkers of risk; they could work just like stress tests, Papanicolaou smears, or other methods used for early risk detection by other fields of medicine. Then, these biomarkers would allow us to treat people at risk in a targeted, cost-effective way with preventive interventions.
Neuroimaging research in psychiatry is still a relatively young field. It started in the mid-1970s, with the development of computerised tomography scan. The high-resolution magnetic resonance imaging (MRI)-based methods that we use now have only been used since the mid- to late-90s. We have only been conducting this kind of research for the past 10–15 years. The spatial and temporal resolution of these methods are still improving. We have come a long way in identifying neural correlates of psychiatric illness, but we still have a way to go.
Does evaluating multiple aspects of illness in addition to neuroimaging provide a better prediction tool?
Yes. The key may be to use multiple methods in combination to develop a risk signature of psychiatric illnesses. However, it is challenging because a lot of the neural correlates of illness turn out to be somewhat nonspecific. They often overlap with what is seen in healthy people. Also, the different illnesses can show similar abnormalities. This may say more about our diagnostic and classification systems than the biology of the illnesses we study.
There has been a recent set of breakthroughs that will help push forward this line of research. There have been recent studies showing that certain treatments, like cognitive-behavioral therapy1,2 and fish oil,3 may actually prevent the development of certain major mental illnesses, such as schizophrenia and depression.
Can neural dysfunction predict who in combat might experience posttraumatic stress disorder (PTSD)?
PTSD has been associated with a set of abnormalities in brain function, including impaired function of the medial prefrontal cortex (PFC), exaggerated amygdala responses, and dysfunctional connections between the medial PFC and the amygdala. Risk for PTSD has been studied extensively by a group at Massachusetts General Hospital in Boston led by Roger K. Pitman, MD, using various neuroimaging methods including functional MRI (fMRI) as well as psychophysiologic techniques.4,5 They have measured skin conductance responses in response to emotional stimuli and during fear conditioning. They have used these methods to study brain function of combat veterans who do or do not have PTSD. The elegant aspect of their design is that each of the combat veterans they have studied also has an identical twin brother who has not been exposed to combat. The idea is that any abnormalities they find in the veterans with PTSD that they also find in those veterans’ twin brothers could be related to risk for PTSD.
They found several abnormalities in the veterans with PTSD and their twins, such as elevated dorsal anterior cingulate gyrus activity and an enlargement of a space in the middle of the brain called the cavum septum pellucidum. Now that they have found these abnormalities that could be related to risk, they can examine them prospectively in soldiers before they go into combat, to see if these actually are risk markers for PTSD.
Is it true that when patients with neuronal loss in areas like the hippocampus are effectively treated with an antidepressant, neuronal sprouting occurs because of an increase in brain-derived neurotropic factor?
The rat model of the effects of stress on the hippocampus differs from what we see in humans to some extent. Still, there is a lot of evidence for the effects of neurotrophic factors on brain regions affected in psychiatric illness and that antidepressants increase the release of these factors and possibly affect medial temporal lobe volume and neurogenesis. This is an active area of study right now, in research dedicated to developing novel treatments for depression and schizophrenia.
Addictive disorders are common. What do we know about reward circuitry responses?
There has been much research on the reward system of the brain, both in rats and monkeys as well as in humans. Research in humans has mostly been conducted using fMRI and positron emission tomography. There is a network of regions which includes the ventral striatum, orbital frontal cortex, dorsal lateral PFC, and dopaminergic cell groups of the midbrain, which are involved in the pursuit of reward and the experience, and anticipation of rewarding stimuli—all aspects of reward-related responses.
Addiction, major depressive disorder, and schizophrenia have each been associated with a different type of abnormality in the circuitry. For example, addiction may be most related to an impairment in what we call “top-down control” by the PFC of the function of subcortical reward circuitry. Schizophrenia, particularly the negative symptoms of the disorder, may be related to an impairment in the anticipation, or memory, of rewarding experiences, which may have a slightly different mechanism. We are still in the process of understanding what the specific neural correlates are of these behavioral abnormalities associated with the reward system. Luckily, this system has been very well-characterized in animal models.
If it really turns out to be the case that addiction is associated with a reduction in the top-down control of reward-related responses, there may be a way to augment the activity of the PFC and its modulation of subcortical activity in the striatum and other centers that may be dysregulated in these patients.
Have you done any work on understanding delusions of schizophrenia from a neural point of view?
Yes. Our model comes from several lines of converging evidence that suggest that delusions result from an abnormality in emotional learning and memory.
The idea is that we have a somewhat flexible neural system that tells us whether something in the environment is important, dangerous, or relevant to us in some way. It actually appears that we have two interacting systems that evaluate the emotional meaning of information in the environment. There is a fast, sometimes inaccurate system, and then a slow but more detail-oriented and precise system. Sometimes the fast system misfires, even in healthy non-delusional people. Then, the second more accurate system kicks in to correct these errors.
When people develop delusional ideas, the system misfires frequently, telling the person that something in his or her environment is important, relevant, or dangerous. Yet, there is no mechanism that comes in to correct these misperceptions.
Our lab, among others, has found neuroimaging evidence to support this hypothesis. We have found that delusions are associated with misfiring of certain regions of the brain, such as the cingulate gyrus, in response to information that is not personally relevant or emotionally significant for most people.6-8
Is there a correlation between treatment, elimination of delusions, and changes in these areas?
Neuroimaging studies that conduct this type of within-subject comparison represent the best approach to testing this model of delusions, but it is difficult to do this kind of study well. If you are not careful, there will be several things that are changing at the same time, like doses of medication and symptom severity. We are conducting a study like this right now to see if we can tease out the effects of treatment on delusions and the associated changes in brain function.
Is quantitative electroencephalogram (EEG) valuable in your work?
I have done some event-related potential (ERP) work and I think it is extremely valuable. It can be a very good companion to fMRI because it has very good temporal resolution. However, the spatial resolution is not very good, while fMRI has the opposite set of strengths.
fMRI essentially measures blood flow by taking advantage of the fact that the deoxygenated hemoglobin (deoxyhemoglobin) is paramagnetic. Because deoxyhemoglobin is paramagnetic, we can measure where it is going in the brain because it disrupts the MRI signal in a predictable way.
EEG measures electrical activity of pyramidal neurons. Because it is directly measuring neuronal activity, the electrical discharge of neurons, it is very accurate temporally, on the order of milliseconds. However, because it can only measure activity that is near the surface of the scalp, it can only measure activity of neurons that are near the cortical surface; it cannot provide the sort of spatial resolution that we have with MRI-based methods.
Has there been work on the circuits involved with anxiety disorders?
This brings up a current question in psychiatric neuroimaging research that many are grappling with, which is whether to continue to use the Diagnostic and Statistical Manual of Mental Disorders classification schemes in our research, since these classifications may not reflect unique biologic or neurophysiologic characteristics. For example, social anxiety disorder may be difficult to distinguish neurophysiologically from generalized anxiety disorder or other types of phobias.
Obsessive-compulsive disorder (OCD), however, appears to have a neural signature that is somewhat distinct in comparison to other anxiety disorders. It seems to be associated with more prominent orbital frontal-striatal abnormalities. This is interesting because it is consistent with the impression of many clinicians, that the clinical features of OCD are somewhat distinct from the clinical features of other anxiety disorders. This is in the line with the general idea that the DSM-IV-TR may have it right in some cases but not in others.
What is the major message for our clinical audience at this point?
I believe that we are slowly moving closer to being able to use neuroimaging as a clinical tool to identify people at risk and to measure effects of treatment. A large benefit of neuroimaging research that we have already seen clinically is that it has contributed to the reduction of the stigma associated with psychiatric disorders. It is really helpful for patients to understand that we have identified abnormalities of the brain associated with these disorders. These are medical disorders, which you can see evidence of, in research studies, on an MRI scan.
Have there been any major findings related to the PFC?
The frontal lobe is the part of the cerebral cortex that is most relevant for psychiatric illness. It is the control center of the brain. The dorsal and lateral PFC are involved in decision-making, planning, and task switching—any process that involves conscious choice. The medial and ventral portions of the PFC are involved in emotional perception, introspective activity, and integrating internal states with incoming sensory information. Many psychiatric disorders appear to be associated with abnormalities of the PFC, including schizophrenia, bipolar disorder, major depression, and PTSD.
Are there other brain areas of interest that you would like to comment on?
Neuroimaging researchers are very interested currently in understanding what the midline cortical network does and whether there are abnormalities in the functioning of this network in psychiatric disorders. This network includes the medial PFC and posterior cingulate gyrus. These regions show elevated activity during what people call “stimulus-independent thought,” which you have during times when you are not really engaged in thinking about anything going on in your surrounding environment. Instead, you may be daydreaming or thinking about the past or future. This network is of interest to psychiatric researchers because certain psychiatric disorders are associated with abnormal introspective thinking—either too much or too little of it. So far, it has been shown that this network functions abnormally in schizophrenia and depression.
What have we learned from the research on the neuropsychology of epilepsy?
It is interesting that medial temporal lobe epilepsy is sometimes associated with psychotic symptoms. Abnormalities in the medial temporal lobe are likely involved in the psychosis associated with schizophrenia too.9 A lot of evidence now supports this possibility. There has been some recent evidence showing abnormally elevated activity in a part of the hippocampus, which is within the medial temporal lobe, in people who have schizophrenia, as well as in people who are at risk for schizophrenia and later develop it.10
Epilepsy is an interesting model in that in some cases it has a very specific neuroanatomical correlate associated with psychiatric symptoms. It suggests that we are on the right track and that, at some point, we will understand psychiatric illnesses just as well as neurologists understand epilepsy. PP
References
1. Morrison AP, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004;185:291-297.
2. Garber J, Clarke GN, Weersing VR, et al. Prevention of depression in at-risk adolescents: a randomized controlled trial. JAMA. 2009;301(21):2215-2224.
3. Amminger GP, Schafer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154.
4. Pitman RK, Gilbertson MW, Gurvits TV, et al. Clarifying the origin of biological abnormalities in PTSD through the study of identical twins discordant for combat exposure. Ann N Y Acad Sci. 2006;1071:242-254.
5. Shin LM, Lasko NB, Macklin ML, et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch Gen Psychiatry. 2009;66(10):1099-1107.
6. Holt DJ, Titone D, Long LS, et al. The misattribution of salience in delusional patients with schizophrenia. Schizophr Res. 2006;83(2-3):247-256.
7. Holt DJ, Lebron-Milad K, Milad MR, et al. Extinction memory is impaired in schizophrenia. Biol Psychiatry. 2009;65(6):455-463.
8. Holt DJ, Lakshmanan B, Freudenreich O, Goff DC, Rauch SL, Kuperberg GR. Dysfunction of a cortical midline network during emotional appraisals in schizophrenia. Schizophr Bull. In press.
9. Holt DJ, Phillips ML. The human amygdala in schizophrenia. In: Phelps EA, Whalen PJ, eds. The Human Amygdala. New York, NY: Guilford; 2009:344-361.
10. Schobel SA, Lewandowski NM, Corcoran CM, et al. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch Gen Psychiatry. 2009;66(9):938-946.
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