Localization of serotonin 5-HT1A receptor mRNA in neurons of the human brainstem.
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Adult↗
Biomedical subjects
M C Austin
Publications and source records attributed to M C Austin.
Ictal postictal and interictal single-photon emission tomography in the lateralization of temporal lobe epilepsy.
Single-photon emission tomography (SPET) using radioligands that are fixed on first pass through the cerebral circulation shows distinctive and rapidly changing blood flow patterns accompanying temporal lobe seizures. We sought to determine the optimal time to perform SPET studies for clinical seizure lateralization in temporal lobe epilepsy. Interictal, ictal and postictal SPET scans of 73 consecutively studied patients with unilateral temporal lobe epilepsy were read by three blinded observers to assess the accuracy of lateralization in each condition. The blinded observers correctly identified the side of focus in 97% of ictal studies, 72% of postictal studies and 50% of interictal studies. No incorrect scores were made in the ictal studies, whilst 5% of postictal and 12% of interictal studies were lateralized to the wrong side. Inter-observer agreement was best with the ictal studies. The dramatic perfusion changes of ictal SPET provide consistent, reliable and easily interpretable information that is superior to that provided by interictal and postictal studies. Injection of ligand during seizures is therefore the method of choice for SPET to aid the non-invasive lateralization of temporal seizure foci.
Adult↗
Dopaminergic and peptidergic mRNA levels in juvenile rat brain after prenatal cocaine treatment.
The effects of prenatal cocaine treatment on gene expression in dopaminergic pathways of juvenile rats were investigated by in situ hybridization histochemistry. Pregnant rats from gestational day 8 to 20 were administered one of the following treatments: (A) 40 mg/kg cocaine hydrochloride/3 ml/day s.c.; (B) 0.9% saline/3 ml/day s.c. and pair fed to cocaine-exposed dams; (C) 0.9% saline/3 ml/day s.c. and placement on cellulose-diluted diet to match the caloric intake of the cocaine-treated group without explicit food restriction; (D) no injection and lab chow diet. Levels of mRNA for the dopamine transporter, tyrosine hydroxylase, cholecystokinin, D1 and D2 dopamine receptors and enkephalin were quantitated in relevant dopaminergic regions of forebrain and midbrain of offspring that were sacrificed on postnatal day 21. Quantitative analysis revealed no significant changes in mRNA levels in any of the brain regions examined. In the present animal model, cocaine exposure in utero had no significant effect on mRNA levels of the dopamine transporter, D1 or D2 dopamine receptors, enkephalin, tyrosine hydroxylase, or cholecystokinin in juvenile rats.
Animals↗
Expression of serotonin transporter messenger RNA in the human brain.
The characterization and cellular localization of human brain mRNA encoding the serotonin transporter were investigated using northern blot analysis and in situ hybridization histochemistry. In contrast to results from rodent studies, in which single hybridizing mRNAs are detected in brain and periphery, northern analysis of human midbrain raphe tissue revealed the presence of three mRNA species absent from samples prepared from substantia nigra/ventral tegmental area. In situ hybridization studies revealed dense hybridization signal corresponding to serotonin transporter mRNA highly localized to neurons of the dorsal and median raphe nuclei and the caudal linear nucleus. No hybridization signal was observed in neurons of the substantia nigra or locus ceruleus. These findings demonstrate the first anatomical visualization of human brain serotonin transporter gene expression and reveal heterogeneity associated with serotonin transporter transcripts, similar to, but distinct from the pattern of expression visualized in human peripheral tissues.
Adult↗
Reperfusion after thrombolytic therapy in ischemic stroke measured by single-photon emission computed tomography.
BACKGROUND AND PURPOSE: We used 99mTc-hexamethylpropyleneamine oxime single-photon emission computed tomography (SPECT) to study cerebral perfusion in patients treated with streptokinase for acute ischemic stroke in an open and prospective study. Our primary aims were (1) to compare the extent of reperfusion between patients who had received thrombolytic therapy and a control group studied during the same period who were ineligible to receive such therapy and (2) to determine if, among all patients, reperfusion led to improved outcome. METHODS: Fifty-seven patients (22 treated with streptokinase) had two SPECT studies performed, the first before streptokinase administration and the second 24 hours later. RESULTS: On the first SPECT study hyperfusion was present in the middle cerebral artery or anterior cerebral artery territories in 40 patients (17 treated with streptokinase). Patients in the treatment and control groups with initial hypoperfusion on SPECT were well matched for the volume of the perfusion defect and the severity of neurological deficit. A greater number of patients who received streptokinase developed at least partial reperfusion (streptokinase, 65%; control, 52%) on the second study but not significantly so (P = .43). Similarly, the proportion of each hypoperfused region that reperfused (P = .74) and the reduction in the size of the perfusion defect (P = .06) were higher in the streptokinase group but did not reach statistical significance. When all patients were considered, those who did not reperfuse had higher mortality rates (P = .008), less neurological improvement (P = .016), and more functional disability (P < .001) than patients who had reperfusion or normal perfusion initially. CONCLUSIONS: These findings suggest that at least some reperfusion during the first 48 hours of ischemic stroke is a common natural occurrence and is of prognostic significance. The observed trend toward better reperfusion indexes among patients treated with streptokinase is encouraging, but larger controlled trials are required to answer this definitively.
Aged↗
Parietal lobe epilepsy: clinical features and seizure localization by ictal SPECT.
We studied clinical and ictal single-photon emission computed tomography (SPECT) features in 14 patients with parietal lobe epilepsy, nine of whom had structural parietal lobe lesions. Thirteen patients had simple partial seizures of somatosensory (eight), psychic (four), and motor (nine) types. Complex partial seizures (CPS) occurred in seven patients; six were psychoparetic (prominent staring, relative immobility) and one had hyperkinetic activity. Seizures lasted 7 to 110 seconds; 99mTc-HMPAO (hexamethylpropylene amine oxime) was injected ictally, 7 to 89 seconds from seizure onset and 0 to 74 seconds (mean, 21.0 +/- 24.4 seconds) before seizure termination. Ictal SPECT demonstrated focal areas of parietal hyperperfusion in all 14 cases and corresponded with sites of the structural lesions. Parietal hyperperfusion was anterior in eight, posterior in four, and diffuse in two. Quantitative analysis revealed increases in parietal side-to-side perfusion ratios on ictal compared with interictal scans of 11 to 51% (mean, 25.5 +/- 14.4%). Ictal SPECT localization correlated with two main clinical seizure patterns: an anterior syndrome characterized by sensorimotor manifestations and a posterior syndrome characterized by CPS of the psychoparetic type. Ictal SPECT is helpful for localization of parietal seizures. Parietal hyperperfusion is discrete and short-lived, demanding true ictal injections for diagnostic studies.
Adolescent↗
Electroconvulsive shock increases tyrosine hydroxylase and neuropeptide Y gene expression in the locus coeruleus.
Electroconvulsive seizures (ECS) increase tyrosine hydroxylase (TH) activity in the locus coeruleus (LC) but not in the substantia nigra (SN). To determine whether new enzyme synthesis contributes to the increase in TH activity, we carried out in situ hybridization histochemistry to determine the effect of ECS on TH mRNA levels in the LC and SN. The effect of ECS on neuropeptide Y (NPY) mRNA levels in the LC was also studied because NPY coexists with norepinephrine in the LC neurons and has been implicated in depressive disorders. A significant increase was observed in TH mRNA and NPY mRNA levels in LC neurons in the ECS group. There was no difference between TH or NPY mRNA levels in the left and right LC. No change was observed in TH mRNA expression in the SN compacta or SN reticulata. We conclude that the regionally selective increase in TH activity after ECS is at least partly due to increased gene expression and that NPY gene expression is regulated in a similar fashion following ECS.
Animals↗
Ictal SPECT using technetium-99m-HMPAO: methods for rapid preparation and optimal deployment of tracer during spontaneous seizures.
Ictal SPECT provides unique information for the clinician treating patients with refractory epilepsy and reveals insights into the pathophysiology of seizures. We describe our methods for the routine attainment of ictal images using 99mTc-HMPAO. We have devised and implemented techniques for rapid reconstitution of 99mTc-HMPAO adjacent to the video-EEG monitoring suite such that the tracer can be rapidly injected into patients when spontaneous seizures occur. Our quality assurance data show that this can be done safely outside a nuclear medicine department. The clinical results in patients with temporal lobe epilepsy show that ictal injections (97% correct lateralization of focus, 0% incorrect) are more sensitive and accurate compared to interictal studies (48% correct, 10% incorrect), demonstrating that the implementation of these techniques is worthwhile.
Brain↗
Dopamine and endogenous opioid regulation of picrotoxin-induced locomotion in the ventral pallidum after dopamine depletion in the nucleus accumbens.
Microinjection of picrotoxin or the mu-opioid agonist, Tyr-D-Ala-Gly-NmePhe-Gly-OH (DAMGO), into the ventral pallidum (VP) produces an increase in locomotor activity that is antagonized by dopamine receptor blockade. To investigate the regulation of VP-induced locomotion by the dopaminergic innervation of the nucleus accumbens (NA) and the role of opioid receptors in this regulation, dopamine innervation of the NA was bilaterally lesioned with 6-hydroxydopamine (6-OHDA). The lesions resulted in an 89-97% depletion of tissue dopamine levels in the nucleus accumbens compared with sham-lesioned rats. Dopamine depletion in the NA failed to significantly antagonize picrotoxin or DAMGO injected into the VP. However, the dopamine receptor antagonist, haloperidol (0.1 mg/kg, IP), blocked the picrotoxin-initiated increase in horizontal photocell counts in both sham- and 6-OHDA-lesioned rats. The opioid receptor antagonist, naloxone (1.0 mg/kg, SC), also blocked the picrotoxin-induced locomotion in 6-OHDA-lesioned rats but did not block locomotion in the sham-lesioned rats. At a higher dose (3.0 mg/kg, SC), naloxone blocked picrotoxin-induced locomotion in both sham- and 6-OHDA-lesioned rats. These results indicate that although dopamine depletion in the NA does not affect the permissive role of dopamine transmission on locomotion elicited from the VP, it results in an increased sensitivity to enkephalinergic transmission.
Animals↗
Expression of tyrosine hydroxylase in cerebellar Purkinje neurons of the mutant tottering and leaner mouse.
In situ hybridization histochemistry, Northern blot analysis and immunohistochemistry were used to examine tyrosine hydroxylase (TH) mRNA concentrations and immunoreactivity in the locus coeruleus and cerebellum of the tottering (tg/tg), leaner (tgla/tgla), compound heterozygous (tg/tgla) and wild type control (+/+) mice, bred on a C57BL/6J background. Cerebellar Purkinje neurons, long considered to be GABAergic, showed high levels of TH mRNA in the caudal vermis and the lateral hemispheres of the cerebellum of tg/tg, tg/tgla, and tgla/tgla mice. Analysis of grain density over individual Purkinje cells showed significantly greater concentrations of TH mRNA in tg/tg, tg/tgla, and tgla/tgla mice as compared to +/+ wild type control mice. Comparison of adult (greater than or equal to 2 months) and young, pre-seizure (less than or equal to 3 weeks) mutant mice showed Purkinje cells densely labelled for TH mRNA at both ages, suggesting that TH gene expression in Purkinje cells is independent of the onset of seizures. Northern blot analysis confirmed the findings from the in situ hybridization studies, demonstrating a single band identical to TH mRNA. Immunohistochemistry confirmed the presence of TH protein in Purkinje cells of the caudal vermis and the lateral hemispheres of the cerebellum in both control and mutant mice. Quantitation of mRNA for TH and the coexisting neuropeptide, galanin, in the locus coeruleus detected no significant differences between adult tg/tg, tg/tgla and +/+ control mice. The present findings demonstrate that the classically GABAergic Purkinje cells in the cerebellum express low levels of TH, and that the mutant tottering and leaner strains of mice express extremely high levels of mRNA and protein for TH.
Animals↗
Postictal switch in blood flow distribution and temporal lobe seizures.
The ictal increase of regional cerebral blood flow has yet to be fully utilised in the investigation of focal seizures. Although single photon emission tomography (SPECT) is being increasingly used in the localisation of epileptic foci, the evolution and time courses of the peri-ictal perfusion changes have yet to be clarified. We performed serial SPECT studies in the interictal, ictal and immediate postictal states in 12 patients with refractory temporal lobe epilepsy to define the patterns and duration of peri-ictal cerebral blood flow changes. Visual analysis showed a constant pattern of unilateral global increases in temporal lobe perfusion during seizures which suddenly switched to a pattern of relative mesial temporal (hippocampal) hyperperfusion and lateral temporal hypoperfusion in the immediate postictal period. Quantitative analysis confirmed the visual assessment. Lateral temporal cortex ictal/normal side to side ratios were increased by mean 35.1% (95% confidence interval 21.8% to 48.4%) more in the ictal studies than in the interictal studies and mesial temporal cortex ratios increased by mean 30.8% (22.4% to 39.2%). In the postictal state, however, lateral temporal ratios were reduced by mean 7.7% (-15.8% to 0.4%) compared with interictal values, whereas mesial temporal perfusion was maintained compared with the interictal studies. These observations provide critical information for interpreting scans which can be used in the localisation of epileptic foci. This postictal switch in blood flow patterns may reflect the underlying metabolic processes of neuronal activation and recovery and have implications for understanding the neurobiology of human epileptic seizures.
Basal Ganglia↗
Dystonia, clinical lateralization, and regional blood flow changes in temporal lobe seizures.
We analyzed the lateralizing value of ictal dystonia and head-turning in temporal lobe epilepsy, and sought the biologic basis of these clinical signs by studying the regional changes in perfusion with ictal single-photon emission computed tomography (SPECT). We identified unilateral temporal lobe epilepsy in 40 of 42 patients undergoing evaluation for temporal lobe surgery, and with ictal SPECT all 40 showed striking hyperperfusion of the epileptogenic temporal lobe. Twenty-five of the 40 patients showed unilateral or predominantly unilateral upper limb dystonia, which was opposite the epileptic temporal lobe in all cases. Analysis of regional count ratios in cases with ictal dystonia, compared with those without, showed significant changes only in the basal ganglia. Specifically, we found that ictal dystonia was associated with a relative increase in perfusion of the basal ganglia opposite the dystonic limb. Although we found 26 cases with head-turning, the sign was of no lateralizing value, even when only those with major or "tonic" versions (n = 11) were analyzed. Slight increases in cortical blood flow on the side opposite the direction of version were associated with head-turning, irrespective of the side of seizure focus. In clinical practice, ictal SPECT is a highly accurate aid in the lateralization of temporal lobe foci, in addition to providing a new method to investigate the pathophysiology of clinical signs in focal seizures.
Adolescent↗
Dopaminergic involvement in locomotion elicited from the ventral pallidum/substantia innominata.
Microinjection of the indirect GABAA antagonist, picrotoxin, or the mu opioid agonist, Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO), into the ventral pallidum and substantia innominata (VP/SI) increases locomotor activity in rats. The VP/SI has direct and indirect projections to the region of the ventral mesencephalon containing dopamine perikarya, and to certain dopamine terminal fields, including the nucleus accumbens. Thus, it is possible that modulation of the mesocorticolimbic dopamine system by pharmacological stimulation in the VP/SI may play a role in the locomotor stimulant response. It was shown that pretreatment with dopamine receptor antagonists, either peripherally or microinjected into the nucleus accumbens significantly attenuated the motor stimulant effect of DAGO or picrotoxin injection into the VP/SI. Injection of either picrotoxin or DAGO into the VP/SI increased the levels of dopamine metabolites in the nucleus accumbens and prefrontal cortex. Thus, the motor stimulant response following pharmacological stimulation of the VP/SI appears to be mediated by increased dopamine neurotransmission via feedback mechanisms to the mesocorticolimbic dopamine system.
Animals↗
GABAA receptors containing alpha 1 and beta 2 subunits are mainly localized on neurons in the ventral pallidum.
The gamma-aminobutyric acid (GABA) projection from the nucleus accumbens to the ventral pallidum (VP) is important in the regulation of locomotion. Thus, stimulation and inhibition of GABAA receptors in the VP can alter locomotor activity. To determine whether the GABAA receptors are located presynaptically on accumbens efferents to the VP or postsynaptically on neurons intrinsic to the VP two experiments were performed. In the first, quinolinic acid lesions of the nucleus accumbens did not alter [3H]muscimol binding in the VP, while lesions in the VP significantly reduced (60-80%) binding as measured by light microscopic receptor autoradiography. In the second experiment, in situ hybridization with oligonucleotide probes for mRNAs of the alpha 1 and beta 2 subunits of the GABAA receptor was examined in the nucleus accumbens and VP. No mRNA for either subunit was observed in the nucleus accumbens, although many positively labeled neurons were present within the VP. By contrast, a moderate to high density of cells in both the nucleus accumbens and VP contained mRNA for glutamic acid decarboxylase. These data argue that the majority of GABAA receptors in the VP are not located presynaptically on axonal terminals originating from neurons in the nucleus accumbens.
Animals↗
GABAergic and enkephalinergic regulation of locomotion in the ventral pallidum: involvement of the mesolimbic dopamine system.
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Animals↗
Repeated administration of desmethylimipramine blocks the reserpine-induced increase in tyrosine hydroxylase mRNA in locus coeruleus neurons of the rat.
The levels of tyrosine hydroxylase and galanin mRNA were measured by in situ hybridization histochemistry in the rat locus coeruleus after repeated (21 days) administration of desmethylimipramine (10 mg/kg/day), of reserpine (0.25 mg/kg/day), of coadministered desmethylimipramine and reserpine, or of vehicle. Reserpine administration resulted in increased levels of both tyrosine hydroxylase and galanin mRNAs in locus coeruleus neurons as compared to vehicle-treated controls. Administration of desmethylimipramine alone failed to alter either the tyrosine hydroxylase or galanin mRNA. However, coadministration of desmethylimipramine with reserpine blocked the elevation in tyrosine hydroxylase mRNA induced by reserpine alone.
Animals↗
Patterns of postictal cerebral blood flow in temporal lobe epilepsy: qualitative and quantitative analysis.
We used single-photon emission computed tomography (SPECT) to study postictal cerebral blood flow (CBF) in 51 patients with temporal lobe epilepsy. There were 78 seizures studied, 77 by early postictal injection of Tc-99m HMPAO (delay from seizure onset = 4.3 +/- 4.5 min) and one by ictal injection. Increased focal temporal lobe uptake, predominantly confined to the anteromesial region, was present in 83% and declined rapidly over 5 minutes. Reduced activity in the lateral temporal lobe accompanied the mesial increase in 80% of studies, extending over much of the ipsilateral hemisphere and closely associated with the degree and extent of postictal EEG slow waves. These patterns enabled correct seizure localization by blinded analysis in 69% (31/45) of the patients with a unilateral EEG focus. The remainder showed bilateral or no changes. One of six patients with bitemporal EEG foci had unilateral perfusion changes. The positive predictive value for the correct localization of a unilateral focus by postictal SPECT was 97% (31/32). Postictal CBF imaging with SPECT can be used to support noninvasive electrographic localization and may decrease the need for invasive electrode studies.
Adult↗
Visual and quantitative analysis of interictal SPECT with technetium-99m-HMPAO in temporal lobe epilepsy.
Interictal 99mTc-HMPAO SPECT images were compared to ictal EEG localization in 51 patients with intractable temporal lobe epilepsy to determine their usefulness for preoperative seizure focus localization. Both quantified temporal lobe asymmetry and blinded visual detection of temporal lobe hypoperfusion were employed. Visual analysis detected ipsilateral hypoperfusion in 18 (39%) of the 46 patients with a unilateral focus and contralateral hypoperfusion in 3. None of the five patients with bitemporal foci had unilateral hypoperfusion. The positive predictive value of unilateral temporal lobe hypoperfusion was 86% (18/21). Quantified anterior temporal lobe asymmetry, greater than a previously derived normal range, correctly identified the focus in 22 (48%) but gave the wrong side in 5, resulting in a predictive value of 81%. The degree of asymmetry correlated inversely with age of seizure onset, but not with other clinical parameters, histology, or verbal and nonverbal memory. The usefulness of interictal 99mTc-HMPAO SPECT for pre-operative seizure focus localization is limited by low sensitivity when performed with a conventional rotating gamma camera. This suggests that ictal or immediate postictal imaging may be necessary for this purpose.
Adult↗