Positron Emission Tomography Studies

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The most common findings of PET studies of patients with depression are caudate and prefrontal hypome-tabolism. One study examined brain metabolic activity in three types of depressive disorder: UP depression, BP depression, and obsessive/compulsive disorder with secondary major depression. This study demonstrated a decreased glucose metabolic activity in the anterior lateral prefrontal cortex in all three groups of patients compared to controls. There was also a significant correlation between left frontal cortical metabolic rate and Hamilton Depression Score. A study examining regional cerebral blood flow in patients with primary depression and controls found significantly reduced cerebral blood flow in the left anterior cingulate and left dorsal lateral prefrontal cortex. In addition to confirming the frontal and basal ganglia findings, another recent study reported hypo-metabolism in prefrontal cortex ventral to the genu of the corpus callosum in both familial BP and familial UP depression.

Studies of primary mood disorders have also identified regional brain abnormalities associated with disorders of both mental state (i.e., current clinical disorder) and trait (i.e., abnormalities that persist beyond the current clinical disorder). For example, a trait abnormality of increased blood flow in the left amygdala has been reported in patients with primary UP familial depression. On the other hand, treatment with antidepressants has been found to reverse a state of abnormality by returning blood flow in the left prefrontal cortex to control levels. A fluorodeoxyglu-cose study has also demonstrated a significant increase in the metabolic rate of the basal ganglia associated with treatment of depressive disorder. Another recent study of patients with UP depression demonstrated that rostral anterior cingulate hypometabolism uniquely differentiated depressed patients who did and did not respond to treatment.

Although receptor studies examining the pathophy-siology of primary mood disorders have rarely been conducted, one study found an increase in mu opiate receptor binding in paralimbic areas in patients with UP depression.

Although secondary depressions have not been extensively studied using functional imaging techniques, PET studies have been conducted in patients with depression associated with stroke, Parkinson's disease, or Huntington's disease. A study of metabolic activity in patients with basal ganglia stroke demonstrated that patients with basal ganglia lesions not involving motor pathways (i.e., lesions of the head of the caudate, anterior internal capsule, or anterior or dorsal medial thalamus) had focal ipsilateral hypome-tabolism involving regions of frontal, temporal, or cingulate cortex. In contrast, patients with lesions of the motor pathways (putamen and posterior internal capsule) had widespread ipsilateral hypometabolism. When these patients with subcortical lesions were classified as having no mood disturbance, mania, or depression, patients with either depression or mania demonstrated hypometabolism in the temporal lobe. Patients with mania showed temporal hypometabo-lism in the right hemisphere, whereas those with depression showed bilateral temporal hypometabo-lism as well as cingulate hypometabolism.

Biochemical studies of patients with secondary depression have also been carried out using imaging of serotonin receptor binding. Serotonin S2 receptor binding was examined in patients with unilateral stroke using 11C-N-methylspiperone. This study found that patients with right hemisphere stroke had significantly greater ipsilateral to contralateral S2 serotonin receptor binding in the temporal and parietal cortex than age-matched healthy controls or patients with left hemisphere stroke. However, there were no significant differences in the amount of S2 receptor binding in the frontal cortex among patients with right or left hemisphere stroke or normal controls.

Another important finding from this study was that among patients with left hemisphere stroke, the amount of serotonin S2 binding in the left temporal cortex was highly correlated with the Zung Depression Score (Fig. 6). This finding suggested that lower concentrations of S2 receptor binding in the left temporal cortex were associated with higher depression scores. This only held true, however, for patients with left hemisphere stroke. There was no significant correlation between depression scores and S2 receptor binding in the frontal, temporal, or parietal cortex following right hemisphere stroke.

This was the first study to demonstrate a lateralized biochemical response to brain injury in humans. It was also consistent with a previous finding in rats that ischemic lesions of the right but not left hemisphere produced significant depletions of norepinephrine in

NMSP binding in Left Temporal Cortex

NMSP binding in Left Temporal Cortex

Left to Right Hemisphere Ratio

Figure 6 Relationship between Zung depression score and positron emission tomography measures of 11C-N-methylspiperone binding to S2 serotonin receptors in the temporal cortex following a left hemisphere stroke (N = 8). The binding is expressed on the horizontal axis as a ratio of binding in the left temporal cortex to binding in an identical region of the right temporal cortex. Lower numbers indicate less S2 serotonin receptor binding. Lower numbers of S2 receptors were associated with higher depression scores. The triangles indicate receptor changes in one patient who had spontaneous remission of a major depression. As the depression score fell from 55 to 25, the amount of serotonin S2 receptor binding increased from 0.86 to 1.15. This patient, with a small left basal ganglia infarct, demonstrated that S2 receptor binding may be a state marker for poststroke depression (data from Mayberg et al., 1988, with permission of Cambridge University Press).

Left to Right Hemisphere Ratio

Figure 6 Relationship between Zung depression score and positron emission tomography measures of 11C-N-methylspiperone binding to S2 serotonin receptors in the temporal cortex following a left hemisphere stroke (N = 8). The binding is expressed on the horizontal axis as a ratio of binding in the left temporal cortex to binding in an identical region of the right temporal cortex. Lower numbers indicate less S2 serotonin receptor binding. Lower numbers of S2 receptors were associated with higher depression scores. The triangles indicate receptor changes in one patient who had spontaneous remission of a major depression. As the depression score fell from 55 to 25, the amount of serotonin S2 receptor binding increased from 0.86 to 1.15. This patient, with a small left basal ganglia infarct, demonstrated that S2 receptor binding may be a state marker for poststroke depression (data from Mayberg et al., 1988, with permission of Cambridge University Press).

brain regions both ipsilateral and contralateral to the site of the lesion. Combining these findings from both human and animal studies, it has been hypothesized that left frontal cortical injury or left basal ganglia injury may produce mild to moderate depletions of both norepinephrine and serotonin (and perhaps dopamine). Depletions of serotonin resulting from left hemisphere injury may lead to serotonergic dysfunction in several uninjured brain regions including the temporal lobe. Temporal lobe dysfunction could then initiate changes in limbic circuitry (Fig. 1) through connections from the amygdala to the basal ganglia, thalamus, or orbital frontal cortex, and this could ultimately lead to the manifestations of depression. Right hemisphere lesions, in contrast, may initially produce even greater depletions of norepinephrine and serotonin compared with left hemisphere lesions. The combination of serotonin and norepinephrine depletion has been shown in rats to lead to greater upregulation of serotonin receptors than depletion of serotonin alone. Thus, large depletions of both nor-epinephrine and serotonin may lead to compensatory upregulation of S2 receptors in the temporal and parietal cortex. This upregulation in uninjured cortex could lead to enhanced serotonergic function in the right temporal and parietal cortex and therefore block the development of depression.

In summary, functional imaging studies using patients with either primary or secondary mood disorders have, with a moderate degree of consistently, found abnormal activity in the frontal cortex (particularly in the left ventral inferior frontal cortical region) and basal ganglia. In addition, abnormalities have been reported in the cingulate, subgenual cortex, inferior temporal cortex, amygdala, and dorsal medial thalamus. These studies, as well as the structural imaging studies, are consistent with the previously stated hypothesis that frontal-striatal-substantia ni-gra-dorsal medial thalamus-prefrontal circuits form the anatomical substrate for mood disorders and that hypometabolic effects in the cortex produced by basal ganglia lesions disrupt the function of noradrenergic, serotonergic, and dopaminergic transmissions in the cortex, ultimately leading to either primary or secondary depression.

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Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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