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NEURO – IMAGING IN PSYCHIATRY

Dr Himadri Sikhor Das

In psychiatry Neuroimaging is primarily used to aid in differential diagnosis. The clinical value of neuroimaging is used to demonstrate underlying organic brain pathology as a possible cause of disturbed mental status. Pathognomonic image profiles indicative of specific psychiatric disorders have not yet been fully identified; thus for the time being neuroimaging studies are finding only limited utility in identification of specific primary psychiatric diseases. In the future, however neuroimaging techniques may be used to make or confirm psychiatric diagnoses and neuroimaging profiles may be incorporated into the diagnostic criteria of certain psychiatric disorders. However in the future, imaging data may be valualable for predicting natural courses of illness as well as monitoring response to treatment.

MRI IMAGING IN PSYCHIATRIC ILLNESSES: -

Although specific clinical decisions must be mode on a case-to-case basis, tentative guidelines regarding the indications for structural neuroimaging in psychiatry have been suggested. These should be considered for patients who meet any of the four following criteria: -

1. Acute mental status change (including those of affect, behaviors or personality), plus any of:
- Age > 50 years
- Abnormal neurological examination.
- History of significant head trauma (i.e. Head trauma resulting in loss of consciousness or neurological sequelae)

2. New onset psychosis
3. New onset delirium or dementia of unknown etiology.
4. Prior to an initial course of ECT.

In addition to the above which focus on acute presentation; neuroimaging should also be considered when a patient’s distorted metal status proves refractory. Following these criteria a very low proportions of brain lesion associated with treatable general medical conditions could be missed. Move specifically, older age groups, psychiatric inpatients and patients with co-morbid medical illness likely will present the highest rate of positive findings. Finally an even higher percentage of patients may benefit from negative findings in a more subtle fashion i.e., as a consequence of the reassurance attained from having gross structural pathology ruled out and the primary psychiatric diagnoses solidified.

ROLE OF MRI IN CLINICAL NEUROSCIENCE: -

MRI is seen to play an important role in clinical neuroscience research in psychiatry. In general studies are done with two aims: -

- First images from large cohorts of patients and comparison subjects are reserved in order to identity pathological change that occurs in ill individuals.
- Second general research approach in to ask focused questions about the volume or shape of specific brain tissue types or structure to provide evidence regarding the involvement of these structures in the pathophysiology of specific conditions.

RECENT IMAGING MODALITIES: Recent advances in NMR and nuclear medicine techniques are finding more and more importance in pursuing active research work in Psychiatric diseases as well providing new insights into the human brain. With the advent of functional imaging, processes like memory, emotion, thought etc are being researched by scientists all over the world.

I. NUCLEAR MEDICINE (PET/SPECT):

Nuclear medicine procedures used for diagnosis and research of psychiatric conditions generally utilize PET and SPECT scans. These methods show blood flow by imaging trace amounts of radioisotopes. PET however can measure metabolism revealing how well the body is functioning. Use of radioactive tracers is well suited to studies of epilepsy, schizophrenia, Parkinson’s disease and stroke. Both PET and SPECT depict the distribution of blood into tissues, but PET does so with greater accuracy.

PET scanners watch the way the tissue cells (eg. brain cells) consume substances such as sugar (glucose). The substance is tagged with a radioisotope and brewed in a small, low energy cyclotron. The isotope has a small half-life meaning it loses half of its radioactivity only within minutes or hours of being created. Injected into the body the radioactive solution emits positrons wherever it flows. The positrons collide with electrons and the two annihilate each other releasing a burst of energy in the form of two gamma rays. These rays shoot in opposite directions and strike crystals in a ring of detectors around the patient’s head causing the crystals to light up. A computer records the location of each flash and plots the source of radiation, translating the data into an image. By tracing the radioactive substance a doctor can pinpoint areas of abnormal brain activity or determine the health of cells. Unlike PET, which specially requires a cyclotron on site, SPECT uses commercially available radioisotopes greatly reducing the cost of operation.

II. FUNCTIONAL MAGNETIC RESONANCE IMAGING (FMRI) IN PSYCHIATRY.

First, the most commonly used fMRI technique called BOLD-fMRI (Blood-Oxygen-Level-dependent fMRI) potentially offers imaging with a temporal resolution on the order of 100 milliseconds and a spatial resolution of 1-2 millimeters, which is much greater than that of PET and SPECT scanning. This means that transient cognitive events can potentially be imaged and small structures like the amygdala can be more readily resolved. Most fMRI techniques are noninvasive and do not involve the injection of radioactive materials so that a person can be imaged repeatedly. This allows imaging of a patient repeatedly through different disease states (i.e. imaging a bipolar patient through manic, depressive, and euthymic states) or developmental changes (ie. Learning cognitive stages of development, stages of grief recovery). Third, with fMRI, one can easily make statistical statements in comparing different mental states within an individual in a single session. Thus, fMRI may be of important use in understanding how a given individual’s brain functions and perhaps, in the future, making psychiatric diagnoses and treatment recommendations. It is in fact already starting to being used in presurgical planning to map vital areas like languages, motor function, and memory.

The four main applications of MRI yielding functional information in psychiatry can be categorized as: -
1. BOLD-fMRI that measures regional differences in oxygenated blood.
2. Perfusion fMRI, which measures regional cerebral blood flow.
3. Diffusion-weighted fMRI which measures random movement of water molecules and
4. MRI spectroscopy, which can measure certain cerebral metabolites noninvasively.

1. BOLD-fMRI (BLOOD-OXYGEN-LEVEL-DEPENDENT FMRI):

BOLD-fMRI is currently the most common fMRI technique. With this technique, it is assumed that an area is relatively more active when it has more oxygenated blood compared to another point in time. This is based on the principle that when a brain region is being used, arterial oxygenated blood will redistribute and increase to this area. BOLD fMRI is a relative technique in that it must compare images taken during one mental state to another to create a meaningful picture. As images are acquired very rapidly (ie. a set of 15 coronal brain slices every 3 seconds is commonly) one can acquire enough images to measure the relative differences between two states to perform a statistical analysis within a single individual. Ideally, these states would differ in only one aspect so that everything is controlled for except the behavior in question.

BOLD fMRI paradigms generally have several periods of rest alternating with several periods of activation. Images are then compared over the entire activation to the rest periods. BOLD fMRI is best used for studying processes that can be rapidly turned on and off like language, vision, movement, hearing and memory.
BOLD fMRI is very sensitive to movement so that tasks are limited to those without head movement, including speaking. BOLD fMRI is also limited in that artifacts are often present in brain regions that are close to air (ie. sinuses). Thus there are some problems in observing important emotional regions at the base of the brain like the orbitofrontal and medial temporal cortices. Another problem is that sometimes observed areas of activation may be located more in areas near large draining veins rather than directly at a capillary bed near the site of neuronal activation.

Currently, there are no indications for BOLD fMRI in clinical psychiatry, although this technique holds considerable promise for unraveling the neuroanatomic basis of psychiatric disease. It may be of potential help in sorting out diagnostic heterogeneity and treatment planning in the future. Neurologists and neurosurgeons are beginning to use this technique clinically to noninvasively map language, motor and memory function in patients undergoing neurosurgery.

2. PERFUSION fMRI:

Two fMRI methods have been developed for measuring cerebral blood flow. The first method, called intravenous bolus tracking, relies on the intravenous (iv) injection of a magnetic compound such as a gadolinium-containing contrast agent and measuring its T2 weighted signal as it perfuses through the brain over a short time period of time.

Areas perfused with the magnetic compound show less signal intensity as the compound creates a magnetic inhomogeneity that decreases the T2 signal. The magnetic compound may be injected once during the control and once during the activation task and relative differences in blood flow between the two states may be determined to develop a perfusion image. Alternatively one can measure changes in blood few over time over time after a single injection to generate a perfusion map.

This technique also only generates a map of relative cerebral blood flow, not absolute flow as in the text technique. Arterial spin labeling is a T1 weighted noninvasive technique where intrinsic hydrogen atoms in arterial water outside of the slice of interest are magnetically tagged (“flipped”) as they course through the blood and are then imaged as they enter the slice of interest.

Arterial spin labelling is noninvasive, does not involve an IV bolus injection, and can, thus, be repeatedly performed in individual subjects. Also, absolute regional blood flow can be measured which cannot be easily measured with SPECT or BOLD fMRI and requires an arterial line with PET. As absolute information is obtained, cerebral blood flow can be serially measured over separate imaging sessions such as measuring blood flow in bipolar subjects as they course through different disease states. Absolute blood flow information may be important in imaging such processes as anxiety, which may be hard to turn on and off. For instance, in social phobics, a relaxation task may be imaged on one day and anticipating making a speech may be imaged on the next day. Comparing these separate tasks in different imaging sessions would not be possible with BOLD fMRI. Arterial spin labelling has some limitations in that it takes several minutes to acquire information on a single slice of interest. Therefore, one must have a specific brain region that one is interested in examining. Also, as it currently takes several minutes to acquire a single slice, it would be tedious obtaining enough images on this slice within a single session to make a statistical statement on a given subject.

3. DIFFUSION-WEIGHTED IMAGING (DWI)

Diffusion-weighted imaging is very sensitive to the random movement of 1 H in water molecules (Brownian movement). The amount of water diffusion for a given pixel can be calculated and is called the apparent diffusion coefficient (ADC). Areas with low ADC value (ie. low diffusion) appear more intense. ADC values are direction sensitive. While it is currently unclear now diffusion-weighted imaging will be useful in studying psychiatric disorders, it hold great promise for changing the clinical management of acute ischaemic stroke by potentially refining the criteria for patients most likely to benefit from thrombolytic therapy.

4. MRI SPECTROSCOPY (MRS):

MRI spectroscopy (MRS) offers the capability of using MRI to noninvasively study tissue biochemistry. In the conventional and functional MRI techniques listed. The hydrogen atom in water is the main one that is flipped (resonated). In MRS, either 1H atoms in other molecules or other atoms such as 31P, 23Na, K, 19F or Li are flipped. Within a given brain region called a voxel, information on these molecules is usually presented as a spectrograph with precession frequency on the x-axis revealing the identity of a compound and intensity on the y-axis, which helps quantify the amount of a substance. The quantity of a substance is related is related to the area under its spectrographic peak; the larger the area, the more of a substance that is present.

The two most widely used MRS techniques involve either viewing 1H atoms in molecules other than water or 31P-containing molecules. In 1H MRS, the water signal must first be suppressed as it is much greater than the signal from other 1H-containing compounds and has overlapping spectroscopic peaks with compounds.

Compounds that can be resolved with 1H-MRS include:

a) N-acetylaspartate (NAA) which is though to be a neuronal marker that decreases in processes where neurons die;
b) Lactate which is a product of anaerobic metabolism and may indicate hypoxia;
c) Excitatory neurotransmitters glutamate and aspartate;
d) The inhibitory neurotransmitter gamma-amino butyric acid (GABA);
e) Cytosolic choline which includes primarily mobile molecules involved in phospholipid membrane metabolism but also small amounts of the neurotransmitter acetylcholine and its precursor choline;

1. Myolinositol which is important in phospholipoid metabolism and intracellular second messenger systems; and
2. Creatine molecules such as creatine and phosphocreatine, which usually have relatively constant concentrations throughout the brain and are often used as relative reference molecules (ie. one may see NAA concentration reported as the ratio NAA/creatine in the literature).

Phosphorus (31P) MRS allows the quantification of ATP metabolism, intracellular pH, and phospholipid metabolism. Mobile phospholipid, including phosphomonoesters (PME - putative cell membrane building blocks) and phosphodiesters (PDE – putative cell membrane breakdown products) can also be measured, supplying information on phospholipid membrane metabolism.

MRS can be used to identify regional biochemical abnormalities. For example, P-MRS studies of euthymic bipolar patients have revealed decreased frontal lobe PMEs (cell membrane building blocks) compared with healthy controls. However, when bipolar patients become either manic or depressed, their PMEs increase.

These findings appear to be unrelated to medication treatment. The finding of decreased frontal PMEs in euthymic bipolars has also been demonstrated in schizophrenia and speculatively accounts for the finding of decreased frontal lobe metabolism in both of these disorders. The schizophrenia finding also appears to be medication-independent.

MRS may also be of future help in the differential diagnosis of certain psychiatric diseases such as dementia. In normal aging, there is a decrease in PMEs and increase in PDEs. In early Alzheimer’s Dementia compared with healthy controls. Some believe that a decrease in NAA coupled with an increased myoinositol lever helps in differentiating probable Alzheimer’s Dementia from healthy age-matched controls as well as other dementias (usually decreased NAA but normal myoinositol levels).

With MRS, changes in metabolic activity can be measured over time within an individual scanning session. MRS can also be used to measure changes in metabolic activity between sessions, such as before and after medication treatment. For example, Satlin et al. (1997) used 1H MRS to measure midparietal lobe cytosolic choline levels in 12 Alzheimer’s subjects before and after treatment with Xanomeline, an M1 selective cholinergic agonist, or placebo. Additionally, MRS can be used to measure drug levels of certain psychotropic drugs. The magnetic elements Li and F do not naturally occur in the human body but they are fund in psychotropic drugs; lithum for Li and fluoxetine and stelazine for F. For example, studies have consistently found that the brain concentrations of lithium are about 0.5 that of serum Li levels and correlate with treatment response.

For psychiatry, MRS is a research to be used in the characterization of tumor, stroke and epileptogenic tissue and in presurgical planning.

LIMITATIONS:

MRS is restricted to studying mobile magnetic compounds. As neurochemical receptors are noted usually mobile, they cannot be measured with MRS. Thus, receptor-ligand studies are still the domain of SPECT and PET. Another problem with MRS is that due to the low concentrations of many of the imaged substances, larger areas than with water are needed to obtain detectable signals. Larger volume units imaged over longer periods are thus used with this technique, limiting both temporal and spatial resolution compared with conventional MRI and BOLD-fMRI. However, stronger magnetic fields which can spread out precession frequencies over a wider range may improve this resolution.

A brief view of recent findings are outlined.

PSYCHOTIC DISORDERS:

Research studies have identified a large number of pathologies in at last some subjects of schizophrenia for eg, the main regions sharing consistent abnormalities in schizophrenia have been frontal & temporal lobe structures. Volume decreases have been found in 62% of 37 studies of the whole temporal lobe, in 81% of 16 studies of the superior temporal gyrus and in 77% of 30 studies of the medial temporal lobe. Temporal lobe volume reduction may be uni or bilateral with deficits observed more commonly in left temporal lobe. Frontal lobe volume reductions have been reported in 55% of all published studies. Regional volume reductions have been reported in thalamus and corpus callosum. Interestingly, basal ganglia volumes may increase during treatment with typical, but not atypical neuroleptic agents. Recently studies in children have also shown findings consistent with the adult findings.

MOOD DISORDERS:

Major Depression

The spectrum of affective illness is very broad, ranging from single episodes of depressed mood, which are self-limited to life-long, treatment-refractory despondency with recurrent suicidality. Proposed that both primary and secondary mood disorders may involve abnormalities in specific frontosubcortical circuits that regulate mood. Depression is observed frequently in persons with degenerative diseases of the basal ganglia, such as Huntington’s disease, Parkinson’s disease, Wilson’s disease.

In older adults, frontal lobe atrophy and an increasing burden of T2 weighted, high signal intensity lesions have been correlated with late-life depression. Evidence suggests that depression may be seen following focal damage to critical brain regions as well as in response to diffuse brain injury. As the amygdala plays a key role in the brain’s integration of emotional meaning with perception and experience, volumetric studies of this brain structure currently are being reported. Sheline et al. have observed decreased amygdalar core nuclei volumes in depressed subjects increased amygdalar volumes in depressed patients. Mervaala et al. have noted significant amygdalar asymmetry (right smaller than left) in severely depressed subjects.

Strokes and tumors located in left sided frontal regions have been associated with new onset depression and less commonly; right-sided lesions may lead to manic symptoms. Subcortical lesions, especially of the caudate and thalamus, also can lead to mood dysregulation, with right sided lesions again being more commonly associated with mania. 30 MR studies with most consistent finding observed in 10 of 12 studies is a three-fold increase in the presence of WMH. The etiology of these WMH in bipolar patients is not clear, rates of alcohol and substance abuse, smoking cardiovascular risk factors contribute. As in schizophrenia some patients with bipolar disorder have increased lateral and third ventricular volume. Brain regions with volume deficits in bipolar include the cerebellum, especially in patients who are older or how have had multiple episodes of mania toxic effects of alcohol abuse lithium treatment.

Reduced volume and altered activity of subgenual prefrontal cortex in familial bipolar disorder has been reported. Subgenual cingulate cortex volume more recently increased amygdalar volumes have been seen in persons with bipolar disorder. Limited available data suggest that panic attacks may arise, in a minority of cases, as a consequence of ictal activity and that brain MR may identify a reasonably high yield of septo-hippocampal abnormalities in the subpopulation of panic patients who also have electroencephalogram abnormalities. Emission tomography studies generally have observed increased orbitofrontal and cingulate blood flow and glucose utilization, with decreased caudate perfusion. Hippocampal volume reductions on the order of 5% to 12% have been reported, which are of a lesser magnitude than those observed in AD or temporal-lobe epilepsy.

Neuroimaging studies of Dementing illness constitute a very active area of ongoing research. A great deal of attention has been paid to the hippocampus, as progressive atrophy has been reported to correlate with memory loss in a number of studies of both healthy adults and individuals with dementing illnesses. Recently have suggested that other regions of interest (e.g. entorhinal cortex, anterior cingulate and the banks of the superior temporal sulcus) may show larger rates of change in structural volume, over the for the hippocampal formation. Assessment of the medial occipitemporal, inferior and middle temporal gyri in demented elderly also has been suggested as a means to predict progression to AD. Alternatively, measurement of global cerebral volume also has been proposed as a means to assess disease progression. In healthy older adults, ventricular volume has been shown to increase by approximately 1.5 cm / year, suggesting that brain tissue loss is relatively slow in the absence of degenerative disorders. Frontotemporal dementia (FTD) may be distinguished from AD on the basis of anterior hippocampal atrophy (AD).

Decreases in the area of the body and posterior subregions of the corpus callosum have been reported in autistic individuals. Anorexia nervosa has been strongly associated with cerebral ventricular enlargement as well as gray and white matter deficits. Refeeding is associated with some improvement in ventricular and white matter volumes but gray matter volume deficits tend to persist, as do some neurocognitive impairments. Anorexia and bulimia may be associated with hyponatremia, which can lead to the development of central pontine myelinolysis.

Substance Use Disorders.

Alcohol-induced ventricular and sulcal enlargement have been observed by many. Regional atrophy of the corpus callosum and the hippocampus also have been reported. The cerebellum appears to be particularly sensitive to alcohol-induced damage. In addition to atrophic changes, diffuse white matter hyperintensities, suggestive of demyelination have been observed in T2 weighted examination of asymptomatic alcoholics. Signal intensity changes within the globus pallidus also have been observed in persons with cirrhosis, which may improve following liver transplantation.

Wernicke korsakoff syndrome results from nutritional deficiencies and may be precipitated by glucose administration to thiamine deficient alcoholics. The neuroanatomic change most closely associated with Wernicke Korsakoff syndrome in mamillary body atrophy although regional changes in the thalamus, orbitofrontal cortex and mesial temporal lobe also have been reported. Central pontine myelinolysis often is detected in alcoholics and presumably arises from rapid correction of electrolyte imbalance in severe hyponatremia. Extrapontine lesions also may be observed in CPM patient, affecting the cerebellar peduncles, basal ganglia and the thalamus. Marchiafava Bignami disease is a rare hemispheric disconnection syndrome typically associated with chronic alcoholism. MBD often is associated with hypointense T1 weighted or hyperintense T2 weighted lesions of the corpus callosum, suggestive of demyelination. Alcohol discontinuation and nutritional supplementation may contribute to recovery from MBD.

Stimulant Dependence.

Cocaine dependence recently has been associated with an increased incidence of WMH on T2 weighted imaging studies an incidence rate for asymptomatic stroke of approximately 3% in abstinent former cocaine users. Abuse of amphetamine and methampetamine also have been associated with cerebral ischaemia.

Other Drugs

Lipophilic adulterants present in preparations of vaporized heroin may produce signs of a toxic leukoencephalopathy. Chronic use of combined heroin and cocaine has been associated with increased pituitary volume as well as reduced prefrontal and temporal cortex volume. Solvent abuse has been linked to loss of gray white matter tissue differentiation, increased perivascular white-matter signal hyperintensities and cerebral atrophy.

CONCLUSIONS:

While there are currently no clinical indications for ordering any of these fMRI techniques, they hold considerable promise for unraveling the neurocircuitry and metabolic pathways of psychiatric disorders in the immediate future and in further helping in psychiatric diagnosis and treatment planning.

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NEURO – IMAGING IN PSYCHIATRY

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