Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding.

Tourette syndrome, a chronic tic disorder with autosomal dominant inheritance, exhibits considerable phenotypic variability even within monozygotic twin pairs. The origins of this variability remain unclear. Recent findings have implicated the caudate nucleus as a locus of pathology, and pharmacological evidence supports dopaminergic involvement. Within monozygotic twins discordant for Tourette syndrome severity, differences in D2 dopamine receptor binding in the head of the caudate nucleus predicted differences in phenotypic severity (r = 0.99); this relation was not observed in putamen. These data may link Tourette syndrome with a spectrum of neuropsychiatric disorders that involve associative striatal circuitry.

Schizophrenia as a developmental disorder of the cerebral cortex.

The hypothesis that schizophrenia results from a developmental, as opposed to a degenerative, process affecting the cerebral cortex has become popular in current thinking about the disorder. While many of the data gathered in support of this hypothesis do not in themselves represent conclusive proof, an intriguing picture is emerging from a variety of research approaches. These approaches include the observation of minor physical anomalies, premorbid neuropsychological and social deficits, obstetrical complications, and exposure to adverse intrauterine events. Morphometric brain measurement techniques and neuropathological studies have perhaps provided more substantial support.

A postmortem study of frontal cortical dopamine D1 receptors in schizophrenics, psychiatric controls, and normal controls.

We tested the hypothesis that aberrant dopaminergic innervation in frontal and cingulate cortices of schizophrenic patients might be revealed by examining dopamine D1 receptor density in these brain regions. A quantitative autoradiographic assay with [3H]-SCH 23390 was performed with samples from schizophrenic patients, normal controls, neuroleptic-treated controls, and suicides. There was a significant elevation in specific binding of [3H]-SCH 23390 in the intermediate layer of the prefrontal cortex from neuroleptic-treated controls (p = .05). Elevated [3H]-SCH 23390 binding in several layers from prefrontal and cingulate cortex was observed in schizophrenic subjects, although these results did not reach statistical significance. When data from subjects who had received neuroleptics (schizophrenics and neuroleptic controls) were compared to subjects who had not received neuroleptics (normal controls and suicides), there was a significant elevation in receptor density in both the prefrontal (p = .05) and cingulate cortices (p = .03). These data suggest that elevated [3H]-SCH 23390 binding in human prefrontal and cingulate cortices may occur with chronic neuroleptic treatment, although increased receptor density that may exist as a feature of psychotic illnesses cannot be excluded.

Quantitative autoradiography of dopamine-D1 receptors, D2 receptors, and dopamine uptake sites in postmortem striatal specimens from schizophrenic patients.

A number of previously published homogenate receptor binding studies have postulated that dopaminergic dysfunction in schizophrenia may be related to abnormalities in dopamine receptors. In this study, postmortem striatal specimens from patients with schizophrenia, normal controls, and psychiatric controls that had received neuroleptics were studied with quantitative autoradiography for dopamine receptors. Autoradiography with single concentrations of [3H]-SCH 23390 for D1 receptors, [3H]-raclopride for D2 receptors, and [3H]-CFT for dopamine uptake sites failed to define significant differences between the study groups. [3H]-CFT bound in a patchy distribution in the striatum that is believed to correspond to striosomal and matrix striatal compartments. There were no differences between groups when [3H]-CFT binding density was examined in the striosomal and matrix compartments. There were also no differences between groups in the percentage of striatal area occupied by striosomal or matrix compartments as defined by [3H]-CFT binding. We conclude that abnormalities of these dopamine receptor subtypes are probably not primary features of the schizophrenic syndrome in the brain collection examined. Previous reports of elevated D2 receptor binding in schizophrenia may have been related to drug treatment effects. Alternatively, the relatively high affinity of ligands used in previous studies for D4 receptors may explain the discrepancy in our findings. Unchanged [3H]-CFT binding in the schizophrenic group also suggests that the density of mesostriatal neuronal terminals is not altered in schizophrenia.

The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia.

BACKGROUND: Pathology of dorsolateral prefrontal cortex and dysregulation of dopaminergic neurons have been associated with the pathophysiology of schizophrenia, but how these phenomena relate to each other in patients has not been known. It has been hypothesized that prefrontal cortical pathology might induce both diminished steady-state and exaggerated responses of dopaminergic neurons to certain stimuli (e.g., stress). We examined the relationship between a measure of prefrontal neuronal pathology and striatal dopamine activity in patients with schizophrenia and in a nonhuman primate model of abnormal prefrontal cortical development. METHODS: In the patients, we studied in vivo markers of cortical neuronal pathology with NMR spectroscopic imaging and of steady-state striatal dopamine activity with radioreceptor imaging. In the monkeys, we used the same NMR technique and in vivo microdialysis. RESULTS: Measures of N-acetyl-aspartate concentrations (NAA) in dorsolateral prefrontal cortex strongly and selectively predicted D2 receptor availability in the striatum (n = 14, rho = -.64, p < .01), suggesting that the greater the apparent dorsolateral prefrontal cortex pathology, the less the steady-state dopamine activity in these patients. A similar relationship between NAA measures in dorsolateral prefrontal cortex and steady-state dopamine concentrations in the striatum was found in the monkeys (n = 5, rho = .70, p < .05). We then tested in the same monkeys the relationship of prefrontal NAA and striatal dopamine overflow following amphetamine infusion into dorsolateral prefrontal cortex. Under these conditions, the relationship was inverted, i.e., the greater the apparent dorsolateral prefrontal cortex pathology, the greater the dopamine release. CONCLUSIONS: These data demonstrate direct relationships between putative neuronal pathology in dorsolateral prefrontal cortex and striatal dopamine activity in human and nonhuman primates and implicate a mechanism for dopamine dysregulation in schizophrenia.

Individual variation in D2 dopamine receptor occupancy in clozapine-treated patients.

OBJECTIVE: The objectives of this study were 1) to pursue the question of clozapine's striatal D2 occupancy in relation to its clinical effectiveness; 2) to investigate the relation between schizophrenic symptoms, clozapine blood levels, and estimated D2 occupancy during clinically stable and unstable conditions; and 3) to examine long-term stability in D2 occupancy. METHOD: Specific binding of the D2 radioligand [123I]benzamide ([123I]IBZM) was studied with single photon emission computed tomography in 13 patients with schizophrenia when they were clinically stable during chronic clozapine treatment, after clozapine dose reduction of > or = 50%, and in a subgroup (N = 7) after restabilization on clozapine regimens. Clozapine's estimated D2 occupancy was based on comparison with values from drug-free normal subjects. RESULTS: A wide range of estimated D2 occupancies (18% to > or = 80%) were associated with sustained, favorable response to clozapine without correlation with residual symptoms. Clozapine blood levels were negatively related to [123I]IBZM specific binding. Acute dose reduction was associated with predicted worsening in positive and negative symptoms and increases in [123I]IBZM specific binding. Independent of clozapine blood level, patients with more symptoms showed lower [123I]IBZM specific binding, consistent with competition of endogenous dopamine for D2 binding sites in patients with greater symptoms. Restabilization on clozapine regimens produced D2 occupancies closely correlated with baseline values. CONCLUSIONS: There was no evidence for a critical degree of D2 occupancy required to sustain clozapine's therapeutic effects across subjects. Simple linear regression was the best-fit model for clozapine's D2 occupancy. Longitudinal follow-up suggests stability over time of D2 occupancy in relation to dose and clinical response within individual patients.

Reduced central serotonin transporters in alcoholism.

OBJECTIVE: Dysfunction of monoamine uptake mechanisms has been implicated in the pathogenesis of alcohol dependence. The authors explored whether serotonergic dysfunction is associated with anxiety and depression, which increase the risk of relapse in alcoholics. METHOD: The availability of serotonin and dopamine transporters in 22 male alcoholics and 13 healthy male volunteers was measured with the use of [123I] beta-CIT and single photon emission computed tomography, and psychopathological correlates were assessed. RESULTS: A significant reduction (a mean of about 30%) in the availability of brainstem serotonin transporters was found in the alcoholics, which was significantly correlated with lifetime alcohol consumption and with ratings of depression and anxiety during withdrawal. CONCLUSIONS: The findings support the hypothesis of serotonergic dysfunction in alcoholism and in withdrawal-emergent depressive symptoms.

Tourette's syndrome: [I-123]beta-CIT SPECT correlates of vocal tic severity.

OBJECTIVE: To examine in vivo the density of brain monoaminergic transporters in Tourette's syndrome (TS). BACKGROUND: TS is a heritable neuropsychiatric disorder characterized by chronic vocal and motor tics and is often associated with obsessive-compulsive symptoms. Hyperstimulation of dopamine receptors and dysfunction of serotonergic transmission have been implicated in its pathogenesis, but direct evidence of involvement of these neurochemical systems has been limited. METHODS: Symptom severity and the availability of presynaptic monoaminergic transporters in the basal ganglia, midbrain, and thalamus were measured using SPECT and the radioligand [I-123]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([I-123]beta-CIT) in 10 patients with TS and in 10 age- and sex-matched normal volunteers. RESULTS: A significant negative correlation was found between a measure of overall tic severity and beta-CIT binding in the midbrain (r = -0.73, p = 0.02) and the thalamus (r = -0.82, p < 0.01). When examined post hoc, these correlations were determined largely by vocal tic severity. No other significant correlations were found between symptom severity and beta-CIT binding in the striatum or cortex. CONCLUSIONS: These findings indicate that serotonergic neurotransmission in the midbrain and serotonergic or noradrenergic neurotransmission in the thalamus may be important factors in the expression of TS and may suggest novel targets for treatment.

In vivo olanzapine occupancy of muscarinic acetylcholine receptors in patients with schizophrenia.

Olanzapine is an atypical antipsychotic with potent antimuscarinic properties in vitro (K(i) = 2-25 nM). We studied in vivo muscarinic receptor occupancy by olanzapine at both low dose (5 mg/dy) and high dose (20 mg/dy) in several regions of cortex, striatum, thalamus and pons by analyzing [I-123]IQNB SPECT images of seven schizophrenia patients. Both low-dose and high-dose olanzapine studies revealed significantly lower [I-123]IQNB binding than that of drug-free schizophrenia patients (N = 12) in all regions except striatum. [I-123]IQNB binding was significantly lower at high-dose than low-dose in the same regions. Muscarinic occupancy by olanzapine ranged from 13% to 57% at 5 mg/dy and 26% to 79% at 20 mg/dy with an anatomical pattern indicating M(2) subtype selectivity. The [I-123]IQNB data indicate that olanzapine is a potent and subtype-selective muscarinic antagonist in vivo, perhaps explaining its low extrapyramidal side effect profile and low incidence of anticholinergic side effects.

Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia.

Functional magnetic resonance imaging (fMRI) is a potential paradigm shift in psychiatric neuroimaging. The technique provides individual, rather than group-averaged, functional neuroimaging data, but subtle methodological confounds represent unique challenges for psychiatric research. As an exemplar of the unique potential and problems of fMRI, we present a study of 10 inpatients with schizophrenia and 10 controls performing a novel "n back" working memory (WM) task. We emphasize two key design steps: (1) the use of an internal activation standard (i.e., a physiological control region) to address activation validity, and (2) the assessment of signal stability to control for "activation" artifacts arising from unequal signal variance across groups. In the initial analysis, all but one of the patients failed to activate dorsolateral prefrontal cortex (DLPFC) during the working memory task. However, some patients (and one control) also tended to show sparse control region activation in spite of normal motor performance, a result that raises doubts about the validity of the initial analysis and concerns about unequal subject motion. Subjects were then matched for signal variance (voxel stability), producing a subset of six patients and six controls. In this comparison, the internal activation standard (i.e., motor activation) was similar in both groups, and five of six patients, including two whom were neuroleptic-naive, failed to activate DLPFC. In addition, a tendency for overactivation of parietal cortex was seen. These results illustrate some of the promise and pitfalls of fMRI. Although fMRI generates individual brain maps, a specialized survey of the data is necessary to avoid spurious or unreliable findings, related to artifacts such as motion, which are likely to be frequent in psychiatric patients.

Lateralized differences in iodine-123-IBZM uptake in the basal ganglia in asymmetric Parkinson's disease.

UNLABELLED: We used equilibrium analysis of SPECT data from patients with asymmetric Parkinson's disease to determine if lateralized differences in the striatal uptake of [123I]IBZM correlate with asymmetry in clinical findings and, by inference, with lateralized differences in the concentration of extracellular dopamine. METHODS: Twelve patients with asymmetric clinical signs of idiopathic Parkinson's disease were injected with a bolus of [123I]IBZM, and multiple SPECT scans recorded the time course of radioligand uptake. The time integral method was used to estimate peak specific binding, so that a ratio of specific-to-nonspecific binding in the left and right striatum of each subject at equilibrium could be determined. Nine patients also had 99mTc-HMPAO SPECT scans which were examined for evidence of blood flow asymmetries. RESULTS: Paired t-tests comparing [123I]IBZM uptake revealed significantly greater (mean = 7.3%) availability of dopamine-D2 receptors in the basal ganglia contralateral to maximal clinical signs. Differences in receptor availability correlated significantly with differences in every measure of the clinical assessment. No significant differences in regional cerebral blood flow between the two sides were observed with 99mTc-HMPAO. CONCLUSION: These results demonstrate the ability of [123I]IBZM SPECT to reveal clinically meaningful variations in striatal dopamine receptor availability in patients with asymmetric Parkinson's disease. The equilibrium analysis technique used to determine these findings is a simple and robust method of measuring relative receptor availability and may be useful in studying other illnesses where dysfunction of dopaminergic neurotransmission is suspected.

An improved method for rapid and efficient radioiodination of iodine-123-IQNB.

UNLABELLED: The SPECT radioligand, 3-quinuclidinyl-4-[123I]iodobenzilate ([123I]IQNB), binds to muscarinic receptors and has generated interest as a potential agent for clinical SPECT. Unfortunately, cumbersome and inefficient radioiodination procedures have limited the practicality of [123I]IQNB SPECT imaging. METHODS: We report a rapid (5 min) and simple radioiodination procedure for preparing [123I]IQNB from a tri-n-butylstannyl precursor in a no-carrier-added reaction that yields high specific activity with radiochemical yield exceeding 60%. The radiochemical purity of the final product exceeds 95%. RESULTS: We have used this procedure to radioiodinate the four stereoisomers of [123I]IQNB. The procedure is highly reliable and reproducible. SPECT studies on a healthy human volunteer at 1, 2, 6 and 24 hr after injection of each of the four stereoisomers reveal expected differences in the kinetic and binding characteristics of the four stereoisomers. (R,S)-[123I]IQNB appears to be the SPECT agent of choice. CONCLUSION: Radioiodination of [123I]IQNB from our tri-n-butylstannyl precursor is simpler, more efficient and less expensive than previous techniques. The potential exists for a "kit" which would be practical in a typical clinical setting.

Limbic-prefrontal connectivity and clozapine.

The mechanisms of the antipsychotic efficacy and side effect profile of clozapine are incompletely understood. In vivo pharmacologic studies suggest that while clozapine does produce D2 receptor blockade, its unusual clinical profile may relate to activity at other receptor sites and to anatomical areas outside the striatum. Rodent studies indicate that acute administration of clinical doses of antipsychotic drugs, including clozapine, induces Fos (the protein product of the immediate early gene, c-fos) in the nucleus accumbens. However, unlike typical antipsychotic drugs, clozapine does not induce Fos in the dorsal striatum and does induce Fos in medial portions of the prefrontal cortex. Clozapine seems to produce a unique signature effect on long-term neuronal metabolism in its induction of Fos in the shell of the nucleus accumbens and in the medial prefrontal cortex. Future in vivo studies of cerebral blood flow and glucose metabolism in human patients may help to elucidate the specificity and reproducibility of the effects of clozapine in the ventral striatum and prefrontal cortex.

Dopamine D2 receptor imaging and neuroleptic drug response.

Studies with positron emission tomography and single photon emission computed tomography have yielded important findings concerning the relationship between dopamine D2 receptor occupancy and neuroleptic dose, plasma neuroleptic levels, and clinical response. For "typical" neuroleptics, therapeutic response is associated with occupancy levels as low as 60%-70%, which can be achieved at lower doses than are routinely used. For these drugs, extrapyramidal side effects increase, and therapeutic response remains unchanged with higher occupancy levels. Although the mechanisms responsible for the improved clinical efficacy and tolerability of atypical neuroleptics are still poorly understood, antipsychotic efficacy has been observed at lower D2 receptor occupancy rates than with typical neuroleptics. It is unclear whether the lower incidence of extrapyramidal side effects observed with the atypical neuroleptic clozapine can be attributed to its lower D2 occupancy, its relatively specific effects on the ventral striatum, or its nondopaminergic effects. There are a number of additional unresolved issues, including the high interindividual variation in scan outcome measurements, possible effects of concomitant medication, possible effects of endogenous dopamine, and assumptions in various strategies used to model receptor densities and occupancy rates.

Schizophrenia and bipolar disorder: findings from studies of the Stanley Foundation Brain Collection.

The Stanley Foundation Brain Collection contains a matched set of specimens from patients diagnosed with schizophrenia, bipolar disorder, non-psychotic depression and normal controls. Specimens have been shipped to investigators in more than 50 laboratories around the world. To date, results obtained from studies with this collection indicate that schizophrenia and bipolar disorder may both be characterized by abnormalities in frontal cortical interneurons, although different subpopulations of these neurons may be specifically affected in the two disorders. In samples from patients with familial bipolar disorder and major depression, there are alterations in glial density in cingulate cortex. Specific effects of antidepressant drugs on the transcription factor cAMP regulatory element binding protein and brain-derived neurotrophic factor have also been observed.

Psychomotor slowing, negative symptoms and dopamine receptor availability--an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients.

Anhedonia and psychomotor slowing in schizophrenia have been attributed to a dysfunction of dopaminergic neurotransmission. To differentiate between disease and drug-induced negative symptoms, we examined eight drug-free and eight neuroleptic-treated schizophrenic patients. Positive and negative symptoms and extrapyramidal side effects were assessed using standardized rating scales (PSAS, AMDP, SANS). 'Reaction time' and 'motor speed' were measured using a computer-aided system and striatal dopamine D2/D3 receptor availability was assessed using [I-123]IBZM SPECT. Psychomotor reaction time, parkinsonism, affective flattening and avolition were increased in treated patients relative to the untreated cohort and were negatively correlated with dopamine D2/D3 receptor availability. Significant positive correlations were found between parkinsonism and affective flattening and between psychomotor slowing and avolition. Positive symptoms were not significantly associated with striatal IBZM binding. These findings support the hypothesis that neuroleptic-induced dopamine D2/D3 blockade in the striatum can mimic certain negative symptoms, such as affective flattening and avolition, and indicates that psychomotor testing may be helpful in differentiating between disease and drug-induced negative symptoms.

The subnuclear distribution of 5-HT3 receptors in the human nucleus of the solitary tract and other structures of the caudal medulla.

The distribution of 5-HT3 receptors was examined in the human medulla using [3H]LY278584, a highly selective 5-HT3 receptor antagonist. The highest density of 5-HT3 receptors was found in the substantia gelatinosus subnucleus of nucleus of the solitary tract (NTS) throughout its rostrocaudal extent, followed by the dorsal subnucleus, the area postrema (AP), the commissural subnucleus, the medial subnucleus, and in an arc corresponding to the pars gelatinosus of the spinal trigeminal nucleus (nSp5). The distribution of 5-HT3 receptors in the brain may help explain some of the reported CNS activities of 5-HT3-selective drugs. The anti-emetic and antinociceptive activities of 5-HT3 antagonists may be mediated by receptors in sensory areas of the brainstem.

Quantitative autoradiography of striatal dopamine D1, D2 and re-uptake sites in rats with vacuous chewing movements.

Rats treated with haloperidol that developed vacuous chewing movements (VCM), a possible animal model of tardive dyskinesia, were studied with quantitative autoradiography for dopamine type-1 (D1) and type-2 (D2) receptors as well as dopamine re-uptake sites. Haloperidol increased striatal D2 receptors, but did not affect D1 receptors or the dopamine re-uptake site. D2 receptor increases occurred in rats with and without VCMs. In so far as VCM is a model for tardive dyskinesia, haloperidol induced increases in striatal D2 receptors do not appear to be etiologic for these abnormal movements.

Reduced tyrosine kinase receptor C mRNA levels in the frontal cortex of patients with schizophrenia.

Using a quantitative RNA-PCR approach tyrosine kinase receptor (trk) C mRNA levels were determined in brain material from the frontal cortex (BA10), temporal cortex (BA20) and cerebellum of control specimen and patients with schizophrenia, bipolar disorder or non-psychotic depression (15 subjects each). In the frontal cortex of schizophrenics there was a 5.8-fold reduction of trk C mRNA levels, which reached statistical significance (P < 0.05). Trk C levels in the cerebellum were positively correlated with lifetime fluphenazine equivalents (r = 0.54), suggesting that neuroleptics influence TRK C gene activity in the cerebellum. Moreover, the distinct medication-independent reduction of trk C mRNA may point to a disturbed neurotrophic gene activity in the frontal cortex of schizophrenic patients.

Antidepressant drug exposure is associated with mRNA levels of tyrosine receptor kinase B in major depressive disorder.

1. Recent studies have provided support for the notion that the high affinity neurotrophin receptor tyrosine receptor kinase B (trk B) may be involved in the treatment of depression. 2. Using a quantitative RT-PCR approach trk B mRNA levels were determined in brain material from cerebellum, temporal cortex, and frontal cortex of control specimen and patients with major depressive disorder, schizophrenia and bipolar disorder (15 subjects each). 3. Interestingly, elevated trk B mRNA levels were found in cerebellum (3.6-fold) in patients with major depressive disorder, reaching statistical significance (p=0.03). 4. The major depressive disorder-on drugs group differed from controls (p=0.006) in the cerebellum. 5. Since only patients with major depressive disorder received antidepressants, elevated trk B mRNA levels are possibly related to drug treatment.