Changes in regional energy metabolism after cortical cold lesion in the rat brain

In the present investigation, regional ATP, glucose, and lactate contents were examined in the cortical and subcortical structures after cold lesion in rats. Bioluminescence imaging of ATP, glucose, and lactate was performed in serial tissue sections at 4 h (n=4), 12 h (n=4) and 24 h (n=4) after cold injury or sham surgery. Bioluminescence images were analyzed by computer-assisted densitometry, at the lesion site, in cortical areas, in the hippocampus, and in the thalamus. ATP and glucose content were significantly decreased at the lesion site as well as on the contralateral side after 4, 12, and 24 h postinjury. Lactate content increased significantly in the hippocampal area on the ipsilateral side at 12 h. Cortical lactate was bilaterally unchanged. The cold lesion injury led to a characteristic ischemic profile in the hippocampus signaled by low ATP and glucose content paralleled by high lactate levels. The otherwise global depletion of glucose and ATP suggests that other factors besides cerebral blood flow may contribute to the impairment of energy metabolism.     

Changes in cortical and subcortical energy metabolism after repetitive and single controlled cortical impact injury in the mouse

In the present investigation we examined regional ATP, glucose, and lactate content in the cortical and subcortical region, in a mouse model of controlled cortcal impact (CCI) injury. In serial tissue sections, bioluminescence imaging of ATP, glucose, and lactate was performed 1 h after a single CCI injury or sham surgery and 15 min, 1, 24, and 48 h after the induction of a second CCI injury 24 h later or sham surgery. Bioluminescence images were analyzed by computer-assisted densitometry at the lesion site, at the contralateral site, and in a subcortical region. After repetitive CCI injury, the cortical ATP content decreased bilaterally at 15 min and 1 h, and reached a significant minimum at 24 h, as compared with sham. At 48 h the ATP content bilaterally reached base level again. No significant changes in ATP were found in the subcortical region. After repetitive CCI injury, the lactate content increased bilaterally, reached a significant level at 15 min at the trauma site, and bilaterally reached a significant maximum at 1 h. Thereafter, lactate content decreased below base level without reaching significance and reached baseline again at 48 h. In the ipsilateral subcortical region, lactate content increased transiently above the baseline at 1 h and decreased to a significant minimum at 24 and 48 h. No significant changes were found in the contralateral subcortical area. No significant differences between glucose content in sham animals and the cortical and subcortical area could be measured over time; the subcortical glucose content was bilaterally lower than cortical content at all time points and reached a significant minimum bilaterally at 48 h after repetitive CCI injury compared with cortical glucose content. Single CCI injury did not affect ATP, glucose, and lactate contents at any time point. Repetitive CCI injury caused a more severe depression in cerebral metabolism at early time points after trauma compared with a single CCI injury and indicates that lactate might be an early indicator of post-traumatic metabolic disruption.     

Positron emission tomography and subcortical glucose metabolism in schizophrenia

Our previous observation of a disturbed subcortical-to-cortical gradient of activity in schizophrenia was further elucidated by examining glucose metabolism in three subcortical structures: lenticular nucleus, caudate nucleus, and thalamus. Local cerebral glucose metabolism was determined with 18F-fluorodeoxyglucose using positron emission tomography (PET) in a sample of 20 unmedicated schizophrenics and 18 normal volunteers. Repeated evaluations were performed for 12 schizophrenics following treatment with psychotropic medications and for 11 controls. Unmedicated schizophrenics had lower cortical and caudate absolute metabolic rates. Subcortical-to-cortical ratios for the lenticular nucleus and thalamus were increased in schizophrenics compared with controls, reflecting a preservation of activity in these structures relative to decreased cortical metabolism. When patients were grouped by length of medication-free period before the initial study, there was a trend for patients who had been medication free less than 6 months to have higher subcortical ratios. However, there were no consistent effects of medication in the subsample of patients whose PET studies were repeated following treatment. The results demonstrate relative hypermetabolism in structures implicated in dopamine pathways. An understanding of the physiological significance of this finding awaits the combined measurement of metabolic activity and neuroreceptors in schizophrenics.     

Cerebral hypometabolism in progressive supranuclear palsy studied with positron emission tomography

Progressive supranuclear palsy (PSP) is characterized by supranuclear palsy of gaze, axial dystonia, bradykinesia, rigidity, and a progressive dementia. Pathological changes in this disorder are generally restricted to subcortical structures, yet the type and range of cognitive deficits suggest the involvement of many cerebral regions. We examined the extent of functional impairment to cerebral cortical and subcortical structures as measured by the level of glucose metabolic activity at rest. Fourteen patients with PSP were compared to 21 normal volunteers of similar age using 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography. Glucose metabolism was reduced in the caudate nucleus, putamen, thalamus, pons, and cerebral cortex, but not in the cerebellum in the patients with PSP as compared to the normal subjects. Analysis of individual brain regions revealed significant declines in cerebral glucose utilization in most regions throughout the cerebral cortex, particularly those in the superior half of the frontal lobe. Declines in the most affected regions of cerebral cortex were greater than those in any single subcortical structure. Although using conventional neuropathological techniques the cerebral cortex appears to be unaffected in PSP, significant and pervasive functional impairments in both cortical and subcortical structures are present. These observations help to account for the constellation of cognitive symptoms in individual patients with PSP and the difficulty encountered in identifying a characteristic psychometric profile for this group of patients.     

Local cerebral glucose metabolism in newborn dogs: Effects of hypoxia and halothane anesthesia

Local cerebral glucose utilization (LCGU) was measured in 36 neuroanatomical structures of normal awake, halothane-anesthetized, and hypoxic newborn puppies by the autoradiographic 2-[¹⁴C]deoxyglucose method. In normal animals, LCGU was highest in the vestibular nucleus and in other gray matter nuclei of the brainstem and declined in a caudal-to-rostral progression through the neuraxis (i.e., LCGU of cerebellum > thalamus ? caudateputamen > cerebral cortex). Lowest rates of glucose metabolism were detected in white matter structures. Halothane anesthesia (1.5% inspired) caused few changes in local glucose metabolism, the most notable being decreased LCGU among structures of the auditory system (cochlear nucleus, lateral lemniscus, inferior colliculus) and increased LCGU in the interpeduncular nucleus. Acute systemic hypoxia (arterial oxygen tension of approximately 12 mm Hg) produced markedly heterogeneous effects on local glucose metabolism: LCGU was increased in some gray matter structures, decreased in the thalamus, and substantially increased in the subcortical white matter and corpus callosum. In puppies whose brains were frozen in situ after 55 minutes of hypoxia, the concentration of lactate was increased ten- to elevenfold in cortical gray and subcortical white matter, but the concentrations of glucose, adenosine triphosphate, and phosphocreatine declined to a greater extent in the white matter. The results suggest that during hypoxia the high rate of glycolysis in white matter exceeded substrate supply so that glucose availability became the limiting factor for local energy production. Such a mechanism may contribute to the white matter injury that often develops following hypoxic-ischemic insults in the perinatal period.     

Effect of lesions of the ventromedial nucleus of the thalamus on cerebral metabolism: experimental study in the rat using the 14C-deoxyglucose method

Local cerebral glucose utilization (LCGU) was studied quantitatively in awake rats one week and one month following unilateral electrolytic lesion of the ventromedial thalamic nucleus (VM). Significant decrease in LCGU were observed in the ipsilateral cortex as well as in some contralateral cortical areas and bilateral subcortical structures. The modifications by the VM lesion, of the metabolic activations induced by electrical stimulation of substantia nigra pars reticulata (SNR, main afference of the VM) were investigated also. Results suggest that VM is an important relay nucleus on the pathways directed from one SNR towards ipsilateral corticostriatal system and contralateral thalamus and basal ganglia. Finally, one month following the VM lesion a recovery of metabolic activations induced by SNR stimulation was observed whereas basal glucose consumption remained decreased.     

Six-month test-retest reliability of MRI-defined PET measures of regional cerebral glucose metabolic rate in selected subcortical structures

Test-retest reliability of resting regional cerebral metabolic rate of glucose (rCMR) was examined in selected subcortical structures: the amygdala, hippocampus, thalamus, and anterior caudate nucleus. Findings from previous studies examining reliability of rCMR suggest that rCMR in small subcortical structures may be more variable than in larger cortical regions. We chose to study these subcortical regions because of their particular interest to our laboratory in its investigations of the neurocircuitry of emotion and depression. Twelve normal subjects (seven female, mean age = 32.42 years, range 21-48 years) underwent two FDG-PET scans separated by approximately 6 months (mean = 25 weeks, range 17-35 weeks). A region-of-interest approach with PET-MRI coregistration was used for analysis of rCMR reliability. Good test-retest reliability was found in the left amygdala, right and left hippocampus, right and left thalamus, and right and left anterior caudate nucleus. However, rCMR in the right amygdala did not show good test-retest reliability. The implications of these data and their import for studies that include a repeat-test design are considered.     

A case of aphasia with speech disorders by infarction of the left caudate nucleus and putamen

An infarction involving the left putamen, caudate nucleus and the anterior limb of the internal capsule, resulted in aphasia with semantic paraphasias, verbal incoherence and verbal memory impairment. Cerebral blood flow (CBF) studies with 133Xe inhalation at 20 days post onset showed, on one hand, a bilateral lowering of cortical blood flow and on the other hand a left frontal-parietal hypoperfusion area. Spontaneous recovery occurred within 2 months. While the mean CBF became normal at 14 months post onset, a relative hypoperfusion area persisted on the anterior left hemispheric cortex. On the basis of these findings and current CBF and metabolic studies carried out in patients with subcortical lesions, the authors discuss the role of cortical and subcortical structures in subcortical aphasic syndromes. The importance of reciprocal connections between cortex, striatum and thalamus is stressed.     

Spreading depression in the cortex and subcortical structures of the brain of the rat induced by exposure to focused ultrasound

Steady potential shifts produced by focused ultrasound were recorded in the cerebral cortex, hippocampus, thalamus and caudate nucleus of the rat. Impulses of 50-100 ms duration were presented with frequency 5 and 10 Hz. Negative slow potential shifts gradually increased up to 3-7 mV during 10-30 s and were often followed by the spreading depression (SD) waves. In every analyzed structure the SD amplitude reached 20-30 mV; the SD duration in the cortex, caudate nucleus and thalamus was 30-40 s while in the hippocampus it was 80-120 s. Seizures initiated by the ultrasound influence proceded in some cases the SD. Threshold ultrasound doses were not effective for 5-7 min after every the SD wave but at the end of the refractory period they became effective again. So, local influence of the focused ultrasound may result in functional blockade of the brain structures due to the cortical and subcortical spreading depression.     

Photochemically induced cortical infarction in the rat. 2. Acute and subacute alterations in local glucose utilization

Local CMRglu (LCMRglu) values were measured by [14C]2-deoxyglucose autoradiography in the rat at 4 h and 5 days following photochemically induced cortical infarction, and these data were compared with neuropathological findings in adjacent serial sections. At both time periods, LCMRglu was markedly reduced within the lesion center, and irregular regions of moderate-to-marked glucose hypermetabolism were noted within the marginal zone of the developing infarct. At 4 h, the hypermetabolic zones were shown by pathological examination to be characterized by normal-sized, moderately hyperchromatic neurons scattered among occasional dark, shrunken neurons within preserved neuropil. In contrast, the hypermetabolic zones at 5 days coincided with foci of intense macrophage infiltration, with dissolution of the neuropil. Significant decreases in glucose utilization were also demonstrated at 4 h within brain structures remote from the site of focal injury. These structures included the lateral and auditory cortices ipsilaterally, the striatum and thalamus ipsilaterally, and the hippocampus bilaterally. In addition to these remote metabolic effects, depressed metabolism occurred within the homologous cortical region contralateral to the site of infarction. By 5 days, glucose utilization was severely depressed in all ipsilateral cortical regions but not within any contralateral cortical region. Analysis of these data suggests that more than one mechanism is responsible for the metabolic alterations occurring within brain regions remote from the site of irreversible damage. Results are discussed in light of the hemodynamic alterations occurring in this stroke model, which are presented in the accompanying report.     

Regional energy metabolism following short-term neural stem cell transplantation into the injured spinal cord

Stem cells have been shown to partly restore central nervous system (CNS) function after transplantation into the injured CNS. However, little is known about their influence on acute energy metabolism after spinal cord injury. The present study was designed to analyze regional changes in energy metabolites. Young adult mice were subjected to laminectomy with subsequent hemisection at the L2/3 vertebral level. Immediately thereafter a stable clone of murine neural stem cells (NSCs) was injected into the lesion site. After 4 and 24 h, spinal cords were removed and ATP, glucose, and lactate were analyzed by a bioluminescence approach in serial sections and compared to a laminectomized (intact control), hemisected-only or hemisected vehicle-injected control group. At both time points, ATP content of the hemisected group in the tissue segments adjacent to the lesion was increased when compared to the laminectomized control. At the lesion site ATP content decreased significantly at 24 h in the cell-transplanted group when compared to the laminectomized control group. Glucose content decreased at the lesion site and in segments adjacent to the lesion at both time points and in all experimental groups when compared to the laminectomized control group. Lactate content decreased significantly at 4 h in the caudal segments of the vehicle-injected group and in both adjacent segments of the transplanted group when compared to the laminectomized control. At the lesion site, lactate content decreased significantly at 4 and 24 h in the cell-transplanted group, when compared to the laminectomized control. The area of ATP decline at the lesion site 24 h postinjury was significantly lower in the vehicle control group as compared to the hemisected or transplanted group. The decrease in glucose combined with an increase in ATP in the lesion-adjacent segments may indicate that the tissue responds with an increased use of glucose to support itself with sufficient ATP. The significant decrease in glucose, lactate, and ATP in the cell-transplanted group at 24 h may indicate a high metabolic need of the stem cells. The lower area of ATP decline 24 h after vehicle administration suggests that the vehicle solution washes out toxic mediators, thus ameliorating hemisection-dependent secondary tissue damage.     

Does frontal cortex hypometabolism in progressive supranuclear palsy result from subcortical dysfunction?

Progressive supranuclear palsy (PSP), a neurodegenerative disease with frontal lobe-like features, shows brain hypometabolism which predominates in frontal cortex, although the most severe histopathological lesions are subcortical. To test the hypothesis of the subcortical origin of the metabolic dysfunction in frontal cortex, we used previously obtained data measured using positron emission tomography (PET) in PSP patients and controls to examine the metabolic links between cortical and subcortical brain regions. We calculated interregional correlations of metabolic values in PSP patients and we compared these values to those obtained in controls. Compared to 20 age-matched controls, the 20 PSP patients studied showed an increase in positive metabolic coupling between frontal and non-frontal cortical regions. There was an abnormal linkage between frontal cortex and thalamus hypometabolism, the latter partly coupled to caudate nucleus hypometabolism. This study suggests a subcortical origin for frontal cortex hypometabolism in which thalamic activity appears to play a pivotal role.     

Tomographic mapping of human cerebral metabolism: subcortical responses to auditory and visual stimulation

We measured cerebral glucose metabolism with positron computed tomography during audio-visual stimulation in 42 studies of 21 subjects. Metabolic activations and stimulus-induced asymmetries were examined in subcortical structures (thalamus, caudate, lenticular nuclei). Bilateral activations of the thalamus occurred with verbal stimuli. The head of the left caudate was activated when subjects used visual imagery as a strategy to identify sequences of tones. These two types of stimuli produced dominant (left) hemisphere cortical activations in this same group of subjects. Clinical evidence has implicated the participation of subcortical (thalamus and basal ganglia) structures in the processing of language and auditory information. The present results demonstrate this functional role directly in normal subjects.     

Reduced regional cerebral blood flow in Huntington''s disease studied by SPECT.

Regional cerebral blood flow (rCBF) was studied in 18 patients with Huntington's disease (HD) and 19 age- and sex-matched controls with high resolution single photon emission computerised tomography (SPECT), using Tc-99m-HMPAO. Significant reductions in tracer uptake were found in the caudate and lentiform nuclei (20 and 8%) and in the cerebral cortex, especially in the frontal and parietal areas (11-13%). No significant reductions were found in the thalamus, mesial temporal cortex, and occipital cortex. Fourteen patients had neuropsychological testing. Relationship between rCBF and cognitive function was tested by regression analysis. A linear relationship was found between test scores of Wisconsin Card Sorting Test, Picture Arrangement Test and blood flow in the caudate nucleus. Other tests of cognitive function (Block Design Test, Face and Word Recognition Test, Street Fragmented Pictures Test, and Similarities Test) correlated better with flow in the cortical regions believed to be involved in solving those particular tests. These findings indicate, that blood flow is reduced in both cortical and subcortical structures in symptomatic HD, and that both reductions in cortical and subcortical blood flow may be related to cognitive function in HD.     

The anatomical basis of somaesthetic temporal discrimination in humans.

Somaesthetic temporal discrimination (STD) is the ability to perceive as separate two successive somaesthetic stimuli applied to the same or different parts of the body. Paired electrical stimuli were applied to the index finger, using different time-intervals, to study the STD threshold (STDT) in 84 normal subjects and 51 patients with focal cerebral lesions. Abnormal STDT values were found on the affected side of patients with a lesion of the primary somatosensory cortex, and internal capsulethalamus. Lesions which did not produce sensory impairment but caused abnormal STDT were located in the posterior parietal cortex, the head of the caudate nucleus, the putamen, the medial thalamus and the lenticular nucleus. Frontal, temporal and occipital cortex lesions did not produce any abnormality in the STDT, but one patient with a bilateral lesion of the supplementary motor area (SMA) had abnormal STDT. These results indicate that normal perception of two somaesthetic stimuli as separate in time depends not only upon the integrity of the somatosensory pathway and primary somaesthetic cortex, but also of the posterior parietal cortex, SMA and subcortical structures such as the striatum and thalamus.     

Experimental hemiplegia in the monkey: basal ganglia glucose activity during recovery

Unilateral ablation of cerebral cortical areas 4 and 6 of Brodmann in the macaque monkey results in a dense contralateral hemiplegia that recovers partially with time. During the phase of dense hemiplegia, the local cerebral metabolic rate for glucose (lCMRGlc) is decreased significantly in the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus of the hemisphere ipsilateral to the lesion. In the present study, lCMRGlc in the basal ganglia was studied during the phase of partial recovery of motor activity. lCMRGlc was partially restored, and the greatest degree of restoration occurred in structures with direct connections to the cerebral cortex (caudate nucleus, putamen, subthalamic nucleus, substantia nigra, and red nucleus). Restoration was least in structures that do not receive direct connections from the cerebral cortex (the internal and external segments of the globus pallidus). The findings support the hypothesis that corticofugal activity accounts for a substantial degree of functional recovery.     

Development of gray matter atrophy in relapsing–remitting multiple sclerosis is not gender dependent: Results of a 5-year follow-up study

ObjectivesThe aim of this study was to explore the evolution of MRI related gender differences in patients with relapsing–remitting (RR) multiple sclerosis (MS) who participated in a clinical trial over the 5 years.Methods181 patients (39 males and 142 females) were assessed for clinical and neuroradiological disease activity over a period of 5 years. Clinical and MRI examination were performed at the baseline, 6, 12, 24, 36, 48 and 60 months. Longitudinal percentage volume changes in whole brain (PBVC), gray matter (PGMVC) white matter (PWMVC) cortex (PCVC), and lateral ventricles (PLVVC) were calculated by using direct methods (SIENA and SIENAX-multitimepoint). Absolute tissue volume changes of subcortical deep GM structures including caudate, putamen, globus pallidus, thalamus, hippocampus, amygdala and nucleus accumbens were estimated using FIRST, a model based segmentation/registration tool. T2 lesion volume (T2-LV) and lesion activity analyses were performed, using a contouring-threshold and subtraction techniques. All clinical and MRI variables were analyzed between males and females.ResultsGlobal (PBVC) and tissue specific (PGMVC, PWMVC, PCVC, PLVVC) brain volume changes showed no significant gender differences over the 5-year follow-up period. Although total subcortical deep GM, caudate, putamen, globus palidus, thalamus and nucleus accumbens normalized volumes were significantly larger in male subjects at baseline, the follow-up analysis showed no differences over the 5 years. There were no gender differences in lesion activity or T2-LV changes over the 5 years.ConclusionNo MRI lesion, global, tissue specific or regional brain volume gender change differences were found over the 5-year follow-up.     

Metabolic changes of subcortical structures in intractable focal epilepsy

PURPOSE: Intractable focal epilepsy is commonly associated with cortical glucose hypometabolism on interictal 2-deoxy-2[18F]-fluoro-D-glucose (FDG) positron emission tomography (PET). However, subcortical brain structures also may show hypometabolism on PET and volume changes on magnetic resonance imaging (MRI) studies, and these are less well understood in terms of their pathophysiology and clinical significance. In the present study, we analyzed alterations of glucose metabolism in subcortical nuclei and hippocampus by using FDG-PET in young patients with intractable epilepsy. METHODS: Thirty-seven patients (mean age, 7.5 years; age range, 1-27 years) with intractable frontal (n = 23) and temporal (n = 14) lobe epilepsy underwent FDG-PET scanning as part of their presurgical evaluation. Normalized glucose metabolism was measured in the thalamus and caudate and lentiform nuclei, as well as in hippocampus, both ipsi- and contralateral to the epileptic focus, and correlated with duration and age at onset of epilepsy, presence or absence of secondary generalization, location of the epileptic focus, and extent of cortical glucose hypometabolism. RESULTS: Long duration of epilepsy was associated with lower glucose metabolism in the ipsilateral thalamus and hippocampus. Duration of epilepsy was a significant predictor of ipsilateral thalamic glucose metabolism in both temporal and frontal lobe epilepsy. Presence of secondarily generalized seizures also was associated with lower normalized metabolism in the ipsilateral thalamus and hippocampus. Extent of cortical hypometabolism did not correlate with subcortical metabolism, and glucose metabolism in the caudate and lentiform nuclei did not show any correlation with the clinical variables. CONCLUSIONS: The findings suggest that metabolic dysfunction of the thalamus ipsilateral to the seizure focus may become more severe with long-standing temporal and frontal lobe epilepsy, and also with secondary generalization of seizures.     

Experimental meningitis in the rabbit. II. Cerebral energy metabolism in relation to increased cerebrospinal fluid concentrations of lactate

We have analyzed cerebral energy metabolism in rabbits with Streptococcus pneumoniae or Escherichia coli meningitis aiming at an increased understanding of the cerebrospinal fluid (CSF) lactacidosis observed in this disease. After intracisternal inoculation of bacteria the lactate concentration in the CSF increased to 9.7 +/- 0.7 (mean +/- SE) mmol/l compared to control values of 3.2 +/- 0.2 mmol/l. Simultaneously sampled brain tissue from parietal cortex, caudate nucleus, and thalamus showed no increase in lactate concentrations. The high-energy phosphate content decreased only marginally, phosphocreatine levels by 11-17% in the cortex and in the caudate nucleus, and adenosine triphosphate concentrations by 15%, but only in the caudate nucleus. Our results indicate that the CSF lactate increase in bacterial meningitis is not primarily linked to cerebral lactacidosis. The decreased concentrations of high-energy phosphates in diseased animals need further study but may be due to increased intracranial pressure and reduced capillary blood flow.     

Changes in Local Cerebral Glucose Utilization and Dopamine Metabolism in the Rat Brain Following Acute Administration of Haloperidol

Abstract: The effects of acute administration of haloperidol on local cerebral glucose utilization (LCGU) in 26 discrete regions of the rat brain were examined by the quantitative autoradiographic [¹⁴C] 2-deoxy-D-glucose technique and compared with the changes in dopamine (DA) metabolism in 13 brain regions examined by a high performance liquid chromatographic assay. A moderate dose (0.25 mg/kg) of acute haloperidol significantly reduced LCGU in a few brain regions; a high dose (1.0 mg/kg) reduced LCGU in 11 regions including the prefrontal cortex, thalamus and other subcortical structures, but not in the caudate putamen or accumbens nucleus. However, the levels of DA metabolite in the caudate-putamen, accumbens nucleus, prefrontal cortex, and medial thalamus were strikingly elevated with both doses of haloperidol. Thus, the changes in LCGU did not parallel presynaptic DA metabolism in terms of direction or distribution, and they might represent mainly the activities of postsynaptic sites.