Thalamic Metabolism Research Articles

Metabolismo talámico y situación neurológica tras un traumatismo craneoencefálico. Estudio mediante PET-FDG y morfometría basada en vóxel

ObjectiveTo study the relationship between thalamic metabolism and neurological outcome in patients who had sustained a traumatic brain injury (TBI). MethodsNineteen patients who had sustained a severe TBI and ten control subjects were included in this study. Six of the 19 patients had a low level of consciousness (vegetative state or minimally conscious state), while thirteen showed normal consciousness. All patients underwent a PET with 18F-FDG, 459.4 ± 470.9 days after the TBI. The FDG-PET images were normalized in intensity, with a metabolic template being created from data derived from all subjects. The thalamic trace was generated automatically with a mask of the region of interest in order to evaluate its metabolism. A comparison between the two groups was carried out by a two sample voxel-based T-test, under the General Linear Model (GLM) framework. ResultsPatients with low consciousness had lower thalamic metabolism (MNI-Talairach coordinates: 12, -24, 18; T=4.1) than patients with adequate awareness (14, -28, 6; T=5.5). Control subjects showed the greatest thalamic metabolism compared to both patients groups. These differences in metabolism were more pronounced in the internal regions of the thalamus. ConclusionsThe applied method may be a useful ancillary tool to assess neurological outcomes after a TBI, since it permits an objective quantitative assessment of metabolic function for groups of subjects. Our results confirm the vulnerability of the thalamus to suffering the effects of the acceleration-deceleration forces generated during a TBI. It is hypothesized that patients with low thalamic metabolism represent a subset of subjects highly vulnerable to neurological and functional disability after TBI.

Activated thalamic glucose metabolism after combined donepezil and psychosocial intervention

Effectiveness of donepezil in slowing the rate of cognitive decline in Alzheimer's disease (AD) has been established. Psychosocial interventions, such as reminiscence therapy and art therapy, are also known to have some clinical effects. However, combined effect of donepezil and psychosocial interventions on cerebral glucose metabolism has not been investigated. A case study using (18F) fluorodeoxyglucose and positron emission tomography revealed that cerebral glucose metabolism in the thalamus and fronto-subcortical network was stimulated after the combined intervention. These areas are considered not to be severely affected by pathological changes in AD. The comprehensive approach of donepezil and psychosocial interventions was judged to be effective for AD patients.

Platform Presentation—Loss of Striatal Dopaminergic Function and Thalamic Compensatory Mechanism During Phenocoversion of Preclinical Huntington's Disease

Objective To examine and validate changes in striatal dopaminergic function and regional brain metabolism during phenocoversion of preclinical Huntington's disease (pHD). Background Our recent PET study (Feigin et al., 2007) found progressive declines in striatal D2-receptor binding in pHD subjects over 44 months, correlating with decreased metabolism in the striatum. During this period, thalamic metabolism was initially elevated above normal and then fell to subnormal levels in the subjects who developed symptoms. To validate these findings, we extended the previous study two years, to 68 months, and now report the preliminary results. Design/Methods Twelve presymptomatic HD gene carriers (CAG repeat length: 41.6 ± 1.7; estimated years-to-onset: 10.3 ± 8.6 years) underwent PET scanning with both 11C-raclopride and [18F]fluorodeoxyglucose at baseline, 18, and 44 months. Of these, four subjects were diagnosed with HD during the first 44 months of the study. At 68 months, two symptomatic and two asymptomatic subjects were additionally scanned. Results In the four subjects at 68 months, both the caudate and putamen D2 binding were further decreased relative to values at the first three time points. The decrease in striatal D2 binding was more pronounced in the two symptomatic subjects than the two pHD subjects, with greater progressive declines in striatal metabolism in the symptomatic subjects. However, thalamic metabolism at 68 months was similar to 44 months, i.e., thalamic metabolism was close to the lower limit of normal in the two symptomatic subjects, but remained above normal in the two pHD subjects. Conclusion At the extended 68-month time point, concurrent decreases in striatal D2 binding and metabolism indicate steady focal loss of striatal projection neurons in pHD. Further, the findings at 68 months support our prior hypothesis that persistently elevated thalamic metabolism is an essential compensatory feature of the preclinical state, with normalization of thalamic metabolism as subjects approach phenoconversion.

Language and the Modulation of Impulsive Aggression

Language and the Modulation of Impulsive Aggression

SPG11 compound mutations in spastic paraparesis with thin corpus callosum

Autosomal recessive hereditary spastic paraparesis with thin corpus callosum (ARHSP-TCC) is being increasingly recognized as a variety of spastic paraplegia with mental retardation. SPG11 gene mutations have been reported to be associated with ARHSP-TCC. As an independent group, we investigated SPG11 gene involvement in four individuals not previously described with either recessive or sporadic HSP-TCC presentation. Chromosome 15q13-15 segregating autosomal disease haplotypes were different across the kindreds and sequencing of SPG11 identified four novel frameshift/nonsense segregating mutations and the R2034X mutation, which were in heterozygous compound status. The affected examined had decreased thalamic and bilateral paracentral frontal lobe metabolism on (18)F-flurodeoxyglucose PET. Loss-of-function SPG11 mutations are the major cause of autosomal recessive hereditary spastic paraparesis with thin corpus callosum in Southern Europe, even in apparently sporadic cases. Decreased thalamic metabolism was consistently a phenotypical SPG11 mutation hallmark.

Risk for metabolic syndrome predisposes to alterations in the thalamic metabolism

Risk factors for the metabolic syndrome (MetS) affect brain function and associate with asymptomatic brain infarctions in healthy individuals. We studied whether MetS risk factors alter cerebral metabolism. Eighteen non-smoking men (36 +/- 6years) were stratified into two groups according to their risk of developing the MetS. Individuals in the Risk group had a family history of type 2 diabetes, were pre-obese, had mild hypertension and higher fasting plasma glucose and serum insulin compared to the Control group with no risk factors. N-acetyl aspartate, choline, total creatine (tCr), myo-inositol, and glucose were studied in the thalamus, frontal cortex, and frontal white matter with proton magnetic resonance spectroscopy. The plasma glucose was 13% higher (p < 0.01) in the Risk group, but the brain glucose levels were comparable between the groups. In the Control group, the thalamic tCr correlated with the thalamic glucose level (r = 0.81, p = 0.015). In the Risk group, the tCr was 17% higher (p = 0.006) and correlated with the fasting plasma glucose concentration (r = 0.78, p = 0.013), but not with the thalamic glucose level. In conclusion, the increased tCr level in the Risk group suggests that a family history of type 2 diabetes together with MetS risk factors alters thalamic energy metabolism.

Rapid effects of brief intensive cognitive-behavioral therapy on brain glucose metabolism in obsessive-compulsive disorder

Brief intensive cognitive-behavioral therapy (CBT) using exposure and response prevention significantly improves obsessive-compulsive disorder (OCD) symptoms in as little as 4 weeks. However, it has been thought that much longer treatment was needed to produce the changes in brain function seen in neuroimaging studies of OCD. We sought to elucidate the brain mediation of response to brief intensive CBT for OCD and determine whether this treatment could induce functional brain changes previously seen after longer trials of pharmacotherapy or standard CBT. [(18)F]-fluorodeoxyglucose positron emission tomography brain scans were obtained on 10 OCD patients before and after 4 weeks of intensive individual CBT. Twelve normal controls were scanned twice, several weeks apart, without treatment. Regional glucose metabolic changes were compared between groups. OCD symptoms, depression, anxiety and overall functioning improved robustly with treatment. Significant changes in normalized regional glucose metabolism were seen after brief intensive CBT (P=0.04). Compared to controls, OCD patients showed significant bilateral decreases in normalized thalamic metabolism with intensive CBT but had a significant increase in right dorsal anterior cingulate cortex activity that correlated strongly with the degree of improvement in OCD symptoms (P=0.02). The rapid response of OCD to intensive CBT is mediated by a distinct pattern of changes in regional brain function. Reduction of thalamic activity may be a final common pathway for improvement in OCD, but response to intensive CBT may require activation of dorsal anterior cingulate cortex, a region involved in reappraisal and suppression of negative emotions.

Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's disease

Parkinson's disease (PD) is characterized by elevated expression of an abnormal metabolic brain network that is reduced by clinically effective treatment. We used fluorodeoxyglucose (FDG) positron emission tomography (PET) to determine the basis for motor improvement in 12 PD patients receiving unilateral subthalamic nucleus (STN) infusion of an adenoassociated virus vector expressing glutamic acid decarboxylase (AAV-GAD). After gene therapy, we observed significant reductions in thalamic metabolism on the operated side as well as concurrent metabolic increases in ipsilateral motor and premotor cortical regions. Abnormal elevations in the activity of metabolic networks associated with motor and cognitive functioning in PD patients were evident at baseline. The activity of the motor-related network declined after surgery and persisted at 1 year. These network changes correlated with improved clinical disability ratings. By contrast, the activity of the cognition-related network did not change after gene transfer. This suggests that modulation of abnormal network activity underlies the clinical outcome observed after unilateral STN AAV-GAD gene therapy. Network biomarkers may be used as physiological assays in early-phase trials of experimental therapies for PD and other neurodegenerative disease.

Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial

Dopaminergic neuronal loss in Parkinson's disease leads to changes in the circuitry of the basal ganglia, such as decreased inhibitory GABAergic input to the subthalamic nucleus. We aimed to measure the safety, tolerability, and potential efficacy of transfer of glutamic acid decarboxylase (GAD) gene with adeno-associated virus (AAV) into the subthalamic nucleus of patients with Parkinson's disease. We did an open label, safety and tolerability trial of unilateral subthalamic viral vector (AAV-GAD) injection in 11 men and 1 woman with Parkinson's disease (mean age 58.2, SD=5.7 years). Four patients received low-dose, four medium-dose, and four high-dose AAV-GAD at New York Presbyterian Hospital. Inclusion criteria consisted of Hoehn and Yahr stage 3 or greater, motor fluctuations with substantial off time, and age 70 years or less. Patients were assessed clinically both off and on medication at baseline and after 1, 3, 6, and 12 months at North Shore Hospital. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS), scales of activities of daily living (ADL), neuropsychological testing, and PET imaging with 18F-fluorodeoxyglucose. The trial is registered with the ClinicalTrials.gov registry, number NCT00195143. All patients who enrolled had surgery, and there were no dropouts or patients lost to follow-up. There were no adverse events related to gene therapy. Significant improvements in motor UPDRS scores (p=0.0015), predominantly on the side of the body that was contralateral to surgery, were seen 3 months after gene therapy and persisted up to 12 months. PET scans revealed a substantial reduction in thalamic metabolism that was restricted to the treated hemisphere, and a correlation between clinical motor scores and brain metabolism in the supplementary motor area. AAV-GAD gene therapy of the subthalamic nucleus is safe and well tolerated by patients with advanced Parkinson's disease, suggesting that in-vivo gene therapy in the adult brain might be safe for various neurodegenerative diseases.

Thalamic metabolism and symptom onset in preclinical Huntington's disease.

The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.

Correlation of PET and qEEG in normal subjects

Positron emission tomography (PET) and quantitative electroencephalography (qEEG) were obtained in 15 normal male subjects with eyes closed at rest. Correlations between qEEG variables and regional metabolism were examined as an approach to investigating the metabolic and neuroanatomical basis of the generation of the EEG. Analogous to the neurometric approach to qEEG, a normative 2-fluoro-deoxyglucose voxel data base was developed for the PET image. The PET image was transformed to an idealized cylindrical set of coordinates to allow registration with the Talairach stereotactic atlas. PET regions of interest for the thalamus, the left and right temporal lobes, the medial frontal cortex and the dorsolateral prefrontal cortex were defined using Talairach coordinates and correlated to the QEEG. Salient findings included a negative correlation of thalamic metabolism to alpha power and a positive correlation of medial frontal cortical metabolism to delta EEG power. The significance of these findings is discussed with reference to the existing literature on the physiology of the generation of the EEG.

Thin corpus callosum and amyotrophy in spastic paraplegia—Case report and review of literature

We report the clinical, structural, functional and genetic characterization of a 37-year-old Caucasian female, presenting as a sporadic case of complicated spastic paraplegia with thin corpus callosum (CC), cognitive impairment, amyotrophy of the hand muscles and a sensorimotor neuropathy and review the literature for spastic paraplegia with thin CC. Magnetic resonance imaging (MRI) examination revealed a thin CC with fronto-parietal cortical atrophy. 18Fluordesoxyglucose positron emission tomography (FDG–PET) showed reduced cortical and thalamic metabolism. By transcranial magnetic stimulation, we delineated a severe impairment of transcallosal inhibition. Sequence analysis did not reveal disease causing mutations in the genes SLC12A6 (Andermann), Spastin (SPG 4), BSCL2 (SPG 17) and Spartin (SPG 20). We reviewed the literature for HSP with thin CC and found 113 HSP patients with thin CC previously described (35 with linkage to chromosome 15q13–15). Thin CC and peripheral neuropathy often appear together in spastic paraplegia and might be indicative for combined degeneration mechanism of central and peripheral axons.

Correlation of interictal spike-wave with thalamic glucose metabolism in juvenile myoclonic epilepsy

The purpose of this study is to define metabolic correlates of generalized spike-wave discharges in juvenile myoclonic epilepsy. We investigated the alterations in glucose metabolism and possible correlations between the interictal epileptiform discharges and regional metabolism in patients with juvenile myoclonic epilepsy using a combined positron emission tomography/electroencephalography method. We found that the thalamic metabolism is slightly increased interictally in the patient group compared with controls. We also observed significant positive correlations between the amount of spike-wave activity and thalamic metabolism. Our results provide evidence that the thalamus has an important role in the generation of spontaneous generalized spike-wave discharges in juvenile myoclonic epilepsy.

Decreased cerebellar total creatine in episodic ataxia type 2: A 1 H MRS study

Episodic ataxia type 2 (EA2) affects mainly the cerebellum via mutations in the CACNA1A gene. The authors used proton MR spectroscopy to examine cerebellar and thalamic metabolism of nine mostly nonataxic EA2 family members (all with proven CACNA1A mutation) and nine healthy control subjects. Cerebellar total creatine was lower in the patient group (p = 0.005) than in control subjects, possibly reflecting an early sign of calcium channel dysfunction in EA2.

Partial recovery of brain metabolism in methamphetamine abusers after protracted abstinence.

Methamphetamine is a highly addictive drug of abuse that is neurotoxic to dopamine terminals. The authors recently reported that decreases in dopamine transporters (used as markers of dopamine terminals) in the striatum of methamphetamine abusers recover with protracted abstinence and that relative to comparison subjects, recently detoxified methamphetamine abusers have lower metabolism in the striatum and thalamus. In this study, the authors assessed whether metabolism recovers with protracted abstinence. Brain glucose metabolism was measured with positron emission tomography and [18F]fluorodeoxyglucose in five methamphetamine abusers who were evaluated after both a short (<6 months) and protracted (12-17 months) abstinence interval, eight methamphetamine abusers tested only after protracted abstinence, and 11 comparison subjects who were not drug users. Significantly greater thalamic, but not striatal, metabolism was seen following protracted abstinence relative to metabolism assessed after a short abstinence interval, and this increase was associated with improved performance in motor and verbal memory tests. Relative to the comparison subjects, the methamphetamine abusers tested after protracted abstinence had lower metabolism in the striatum (most accentuated in the caudate and nucleus accumbens) but not in the thalamus. The persistent decreases in striatal metabolism in methamphetamine abusers could reflect long-lasting changes in dopamine cell activity, and decreases in the nucleus accumbens could account for the persistence of amotivation and anhedonia in detoxified methamphetamine abusers. The recovery of thalamic metabolism could reflect adaptation responses to compensate for the dopamine deficits, and the associated improvement in neuropsychological performance further indicates its functional significance. These results suggest that while protracted abstinence may reverse some of the methamphetamine-induced alterations in brain function, other deficits persist.

Anatomical and functional brain variables associated with clozapine response in treatment-resistant schizophrenia

Clozapine alleviates the symptoms of a significant proportion of treatment-resistant schizophrenic patients. Previous studies suggest that the response to clozapine may be associated with prefrontal and temporal anatomy as well as with prefrontal, basal ganglia and thalamic metabolism. A sample of 25 treatment-resistant (TR) schizophrenic patients underwent magnetic resonance imaging (MRI) and 18F-deoxyglucose positron emission tomography (PET) before and after treatment with clozapine. We investigated the association between changes in positive, disorganized, and negative schizophrenic syndromes with clozapine treatment and a set of cerebral variables that included total intracranial volume (ICV); hippocampal, dorsolateral prefrontal (DLPF) and temporal gray-matter volume and metabolism; and metabolic activity of the thalamus, pallidum/putamen, and caudate head. Improvement in positive symptoms with clozapine was directly related to temporal gray-matter volume, whereas improvement of disorganization symptoms was inversely related to ICV and hippocampal volume. Patients with high baseline DLPF cortical volume and metabolic activity were more likely to experience improvement in their negative symptoms. We conclude that clinical improvement with clozapine may be related with the anatomy and metabolic activity of specific brain areas, with the structural integrity of the DLPF and temporal regions showing the maximum predictive capacity.

Decreased thalamic metabolism without thalamic magnetic resonance imaging abnormalities following shearing injury to the substantia nigra

A 36-year-old man had fallen about 8 metres. Radiographs showed a mandibular fracture, indicating rotatory force applied to the head. Fluid-attenuated inversion recovery (FLAIR) imaging showed hyperintensity in both medial temporal lobes, left medial midbrain, right midbrain including cerebral peduncle, left pulvinar, left external capsule, fornix, splenium of corpus callosum, and deep white matter of both frontal lobes. Quantitative [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) indicated markedly suppressed glucose metabolism in the left thalamus but not markedly in the striatum. At that time the neurologic examination demonstrated complete left hemiparesis, severe rigidity of the right upper extremity, and inability to move the right hand and fingers. Levodopa at 300–600mg/day improved movement of the fingers, decreased the rigidity in the extremity, and lessened the metabolic abnormality. Diminished metabolism in the left thalamus may have contributed to symptoms. The case illustrates the usefulness of PET in disclosing symptom causing abnormalities not detected by magnetic resonance imaging.

In vivo imaging of anaesthetic action in humans: approaches with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)

In vivo imaging of anaesthetic action in humans: approaches with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)

Cerebral metabolism in major depression and obsessive-compulsive disorder occurring separately and concurrently

Background: The frequent comorbidity of major depressive disorder (MDD) and obsessive-compulsive disorder (OCD) suggests a fundamental relationship between them. We sought to determine whether MDD and OCD have unique cerebral metabolic patterns that remain the same when they coexist as when they occur independently. Methods: [ 18F]-fluorodeoxyglucose positron emission tomography (PET) brain scans were obtained on 27 subjects with OCD alone, 27 with MDD alone, 17 with concurrent OCD+MDD, and 17 normal control subjects, all in the untreated state. Regional cerebral glucose metabolism was compared between groups. Results: Left hippocampal metabolism was significantly lower in subjects with MDD alone and in subjects with concurrent OCD+MDD than in control subjects or subjects with OCD alone. Hippocampal metabolism was negatively correlated with depression severity across all subjects. Thalamic metabolism was significantly elevated in OCD alone and in MDD alone. Subjects with concurrent OCD+MDD had significantly lower metabolism in thalamus, caudate, and hippocampus than subjects with OCD alone. Conclusions: Left hippocampal dysfunction was associated with major depressive episodes, regardless of primary diagnosis. Other cerebral metabolic abnormalities found in OCD and MDD occurring separately were not seen when the disorders coexisted. Depressive episodes occurring in OCD patients may be mediated by different basal ganglia-thalamic abnormalities than in primary MDD patients.

Increased thalamic N-acetylaspartate in male patients with familial bipolar I disorder

N-Acetylaspartate (NAA) in the anterior and mediodorsal thalamic regions was measured using proton magnetic resonance spectroscopic imaging ( 1H-MRSI) in 15 euthymic male patients with familial bipolar I disorder and compared to values in 15 male control subjects to determine if there was evidence for altered neuronal/axonal integrity. MRI tissue segmentation methods were also utilized to obtain tissue-contribution estimates for each MRSI voxel. Relative to the comparison group, the patients with bipolar I disorder demonstrated significantly higher NAA and creatine in both the right and left thalamus. NAA was also significantly higher in the left thalamus compared to the right in both bipolar I patients and controls. There were no group or lateralized differences in the percentages of different tissue types within the MRSI voxels, suggesting that the thalamic NAA and creatine alterations were not an artifact of variations in tissue type percentages in the MRSI voxels. There was also no significant association between NAA or creatine and illness duration. The findings of increased thalamic NAA bilaterally may represent neuronal hypertrophy or hyperplasia, reduced glial cell density, or abnormal synaptic and dendritic pruning. Increased thalamic creatine bilaterally may represent altered cellular energy metabolism and is consistent with prior studies demonstrating changes in thalamic metabolism in mood disorders.