Multi-atlas thalamic nuclei segmentation on standard T1-weighed MRI with application to normal aging.

Specific thalamic nuclei are implicated in healthy aging and age-related neurodegenerative diseases. However, few methods are available for robust automated segmentation of thalamic nuclei. The threefold aims of this study were to validate the use of a modified thalamic nuclei segmentation method on standard T1 MRI data, to apply this method to quantify age-related volume declines, and to test functional meaningfulness by predicting performance on motor testing. A modified version of THalamus Optimized Multi-Atlas Segmentation (THOMAS) generated 22 unilateral thalamic nuclei. For validation, we compared nuclear volumes obtained from THOMAS parcellation of white-matter-nulled (WMn) MRI data to T1 MRI data in 45 participants. To examine the effects of age/sex on thalamic nuclear volumes, T1 MRI available from a second data set of 121 men and 117 women, ages 20-86 years, were segmented using THOMAS. To test for functional ramifications, composite regions and constituent nuclei were correlated with Grooved Pegboard test scores. THOMAS on standard T1 data showed significant quantitative agreement with THOMAS from WMn data, especially for larger nuclei. Sex differences revealing larger volumes in men than women were accounted for by adjustment with supratentorial intracranial volume (sICV). Significant sICV-adjusted correlations between age and thalamic nuclear volumes were detected in 20 of the 22 unilateral nuclei and whole thalamus. Composite Posterior and Ventral regions and Ventral Anterior/Pulvinar nuclei correlated selectively with higher scores from the eye-hand coordination task. These results support the use of THOMAS for standard T1-weighted data as adequately robust for thalamic nuclear parcellation.

Performance ramifications of abnormal functional connectivity of ventral posterior lateral thalamus with cerebellum in abstinent individuals with Alcohol Use Disorder.

The extant literature supports the involvement of the thalamus in the cognitive and motor impairment associated with chronic alcohol consumption, but clear structure/function relationships remain elusive. Alcohol effects on specific nuclei rather than the entire thalamus may provide the basis for differential cognitive and motor decline in Alcohol Use Disorder (AUD). This functional MRI (fMRI) study was conducted in 23 abstinent individuals with AUD and 27 healthy controls to test the hypothesis that functional connectivity between anterior thalamus and hippocampus would be compromised in those with an AUD diagnosis and related to mnemonic deficits. Functional connectivity between 7 thalamic structures [5 thalamic nuclei: anterior ventral (AV), mediodorsal (MD), pulvinar (Pul), ventral lateral posterior (VLP), and ventral posterior lateral (VPL); ventral thalamus; the entire thalamus] and 14 "functional regions" was evaluated. Relative to controls, the AUD group exhibited different VPL-based functional connectivity: an anticorrelation between VPL and a bilateral middle temporal lobe region observed in controls became a positive correlation in the AUD group; an anticorrelation between the VPL and the cerebellum was stronger in the AUD than control group. AUD-associated altered connectivity between anterior thalamus and hippocampus as a substrate of memory compromise was not supported; instead, connectivity differences from controls selective to VPL and cerebellum demonstrated a relationship with impaired balance. These preliminary findings support substructure-level evaluation in future studies focused on discerning the role of the thalamus in AUD-associated cognitive and motor deficits.

Dissociable Contributions of Precuneus and Cerebellum to Subjective and Objective Neuropathy in HIV.

Neuropathy, typically diagnosed by the presence of either symptoms or signs of peripheral nerve dysfunction, remains a frequently reported complication in the antiretroviral (ART)-treated HIV population. This study was conducted in 109 healthy controls and 57 HIV-infected individuals to investigate CNS regions associated with neuropathy. An index of objective neuropathy was computed based on 4 measures: deep tendon ankle reflex, vibration sense (great toes), position sense (great toes), and 2-point discrimination (feet). Subjective neuropathy (self-report of pain, aching, or burning; pins and needles; or numbness in legs or feet) was also evaluated. Structural MRI data were available for 126/166 cases. The HIV relative to the healthy control group was impaired on all 4 signs of neuropathy. Within the HIV group, an objective neuropathy index of 1 (bilateral impairment on 1 measure) or 2 (bilateral impairment on at least 2/4 measures) was associated with older age and a smaller volume of the cerebellar vermis. Moderate to severe symptoms of neuropathy were associated with more depressive symptoms, reduced quality of life, and a smaller volume of the parietal precuneus. This study is consistent with the recent contention that ART-treated HIV-related neuropathy has a CNS component. Distinguishing subjective symptoms from objective signs of neuropathy allowed for a dissociation between the precuneus, a brain region involved in conscious information processing and the vermis, involved in fine tuning of limb movements. Graphical Abstract In HIV patients, objective signs of neuropathy correlated with smaller cerebellar vermis (red) volumes whereas subjective symptoms of neuropathy were associated with smaller precuneus (blue) volumes.

Thalamic volume deficit contributes to procedural and explicit memory impairment in HIV infection with primary alcoholism comorbidity.

Component cognitive and motor processes contributing to diminished visuomotor procedural learning in HIV infection with comorbid chronic alcoholism (HIV+ALC) include problems with attention and explicit memory processes. The neural correlates associated with this constellation of cognitive and motor processes in HIV infection and alcoholism have yet to be delineated. Frontostriatal regions are affected in HIV infection, frontothalamocerebellar regions are affected in chronic alcoholism, and frontolimbic regions are likely affected in both; all three of these systems have the potential of contributing to both visuomotor procedural learning and explicit memory processes. Here, we examined the neural correlates of implicit memory, explicit memory, attention, and motor tests in 26 HIV+ALC (5 with comorbidity for nonalcohol drug abuse/dependence) and 19 age-range matched healthy control men. Parcellated brain volumes, including cortical, subcortical, and allocortical regions, as well as cortical sulci and ventricles, were derived using the SRI24 brain atlas. Results indicated that smaller thalamic volumes were associated with poorer performance on tests of explicit (immediate and delayed) and implicit (visuomotor procedural) memory in HIV+ALC. By contrast, smaller hippocampal volumes were associated with lower scores on explicit, but not implicit memory. Multiple regression analyses revealed that volumes of both the thalamus and the hippocampus were each unique independent predictors of explicit memory scores. This study provides evidence of a dissociation between implicit and explicit memory tasks in HIV+ALC, with selective relationships observed between hippocampal volume and explicit but not implicit memory, and highlights the relevance of the thalamus to mnemonic processes.

In vivo investigation of cardiac metabolism in the rat using MRS of hyperpolarized [1-13C] and [2-13C]pyruvate.

Hyperpolarized (13)C MRS allows the in vivo assessment of pyruvate dehydrogenase complex (PDC) flux, which converts pyruvate to acetyl-coenzyme A (acetyl-CoA). [1-(13)C]pyruvate has been used to measure changes in cardiac PDC flux, with demonstrated increase in (13)C-bicarbonate production after dichloroacetate (DCA) administration. With [1-(13)C]pyruvate, the (13)C label is released as (13 CO2 /(13)C-bicarbonate, and, hence, does not allow us to follow the fate of acetyl-CoA. Pyruvate labeled in the C2 position has been used to track the (13)C label into the TCA (tricarboxylic acid) cycle and measure [5-(13)C]glutamate as well as study changes in [1-(13)C]acetylcarnitine with DCA and dobutamine. This work investigates changes in the metabolic fate of acetyl-CoA in response to metabolic interventions of DCA-induced increased PDC flux in the fed and fasted state, and increased cardiac workload with dobutamine in vivo in rat heart at two different pyruvate doses. DCA led to a modest increase in the (13)C labeling of [5-(13)C]glutamate, and a considerable increase in [1-(13)C]acetylcarnitine and [1,3-(13)C]acetoacetate peaks. Dobutamine resulted in an increased labeling of [2-(13)C]lactate, [2-(13)C]alanine and [5-(13)C]glutamate. The change in glutamate with dobutamine was observed using a high pyruvate dose but not with a low dose. The relative changes in the different metabolic products provide information about the relationship between PDC-mediated oxidation of pyruvate and its subsequent incorporation into the TCA cycle compared with other metabolic pathways. Using a high dose of pyruvate may provide an improved ability to observe changes in glutamate.

MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping.

Quantifying tissue iron concentration in vivo is instrumental for understanding the role of iron in physiology and in neurological diseases associated with abnormal iron distribution. Herein, we use recently-developed Quantitative Susceptibility Mapping (QSM) methodology to estimate the tissue magnetic susceptibility based on MRI signal phase. To investigate the effect of different regularization choices, we implement and compare ℓ1 and ℓ2 norm regularized QSM algorithms. These regularized approaches solve for the underlying magnetic susceptibility distribution, a sensitive measure of the tissue iron concentration, that gives rise to the observed signal phase. Regularized QSM methodology also involves a pre-processing step that removes, by dipole fitting, unwanted background phase effects due to bulk susceptibility variations between air and tissue and requires data acquisition only at a single field strength. For validation, performances of the two QSM methods were measured against published estimates of regional brain iron from postmortem and in vivo data. The in vivo comparison was based on data previously acquired using Field-Dependent Relaxation Rate Increase (FDRI), an estimate of MRI relaxivity enhancement due to increased main magnetic field strength, requiring data acquired at two different field strengths. The QSM analysis was based on susceptibility-weighted images acquired at 1.5 T, whereas FDRI analysis used Multi-Shot Echo-Planar Spin Echo images collected at 1.5 T and 3.0 T. Both datasets were collected in the same healthy young and elderly adults. The in vivo estimates of regional iron concentration comported well with published postmortem measurements; both QSM approaches yielded the same rank ordering of iron concentration by brain structure, with the lowest in white matter and the highest in globus pallidus. Further validation was provided by comparison of the in vivo measurements, ℓ1-regularized QSM versus FDRI and ℓ2-regularized QSM versus FDRI, which again yielded perfect rank ordering of iron by brain structure. The final means of validation was to assess how well each in vivo method detected known age-related differences in regional iron concentrations measured in the same young and elderly healthy adults. Both QSM methods and FDRI were consistent in identifying higher iron concentrations in striatal and brain stem ROIs (i.e., caudate nucleus, putamen, globus pallidus, red nucleus, and substantia nigra) in the older than in the young group. The two QSM methods appeared more sensitive in detecting age differences in brain stem structures as they revealed differences of much higher statistical significance between the young and elderly groups than did FDRI. However, QSM values are influenced by factors such as the myelin content, whereas FDRI is a more specific indicator of iron content. Hence, FDRI demonstrated higher specificity to iron yet yielded noisier data despite longer scan times and lower spatial resolution than QSM. The robustness, practicality, and demonstrated ability of predicting the change in iron deposition in adult aging suggest that regularized QSM algorithms using single-field-strength data are possible alternatives to tissue iron estimation requiring two field strengths.

Development and resolution of brain lesions caused by pyrithiamine- and dietary-induced thiamine deficiency and alcohol exposure in the alcohol-preferring rat: a longitudinal magnetic resonance imaging and spectroscopy study.

Wernicke's encephalopathy (WE) is characterized by lesions in thalamus, hypothalamus (including mammillary nuclei), and inferior colliculi, results in serious disabilities, has an etiology of thiamine deficiency, is treatable with thiamine, and occurs most commonly with alcoholism. Despite decades of study, whether alcohol exposure exacerbates the neuropathology or retards its resolution remains controversial. To examine patterns of brain damage and recovery resulting from thiamine deprivation with and without alcohol exposure, we conducted in vivo magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) at 3 T in alcohol-preferring (P) rats, which had voluntarily consumed large amounts of alcohol before thiamine manipulation. A total of 18 adult male P rats (nine alcohol-exposed) received a thiamine-deficient diet for 2 weeks: 10 (five alcohol-exposed) received intraperitoneal (i.p.) pyrithiamine (PT) and eight (four alcohol-exposed) received i.p. thiamine supplementation. Neurological signs developed by day 14. Rats were scanned before thiamine depletion and 18 and 35 days after thiamine repletion. Two-dimensional J-resolved MRS single-voxel spectra with water reference were collected in a voxel subtending the thalamus; metabolite quantification was corrected for voxel tissue content. MRI identified significant enlargement of dorsal ventricles and increase in signal intensities in thalamus, inferior colliculi, and mammillary nuclei of PT compared with thiamine-treated (TT) groups from MRI 1-2, followed by significant normalization from MRI 2-3 in thalamus and colliculi, but not mammillary nuclei and lateral ventricles. Voxel-by-voxel analysis revealed additional hyperintense signal clusters in the dorsal and ventral hippocampus and enlargement of the fourth ventricle. MRS showed a significant decline and then partial recovery in thalamic N-acetylaspartate, a marker of neuronal integrity, in PT compared with TT rats, with no change detected in creatine, choline, or glutamate. PT rats with prior alcohol exposure exhibited attenuated recovery in the thalamus and arrested growth of the corpus callosum; further, two of the five alcohol-exposed PT rats died prematurely. Parenchymal and ventricular changes with thiamine manipulation concur with human radiological signs of WE. The enduring macrostructural and neurochemical abnormalities involving critical nodes of Papez circuit carry liabilities for development of amnesia and incomplete recovery from other cognitive and motor functions subserved by the affected neural systems.

Differentiating pathologic delta from healthy physiologic delta in patients with Alzheimer disease.

STUDY OBJECTIVE: In patients with Alzheimer disease, the electroencephalogram during wakefulness shows pathologic signs of abundant, diffuse, large-amplitude delta activity. The carryover of this abnormal delta activity into non-rapid eye movement sleep raises the question of whether the observed delta electroencephalographic activity during sleep in Alzheimer disease in any way reflects normal physiologic delta activity slow-wave sleep. The objective of the study was to compare patients with Alzheimer disease with age-matched controls using an experimentally controlled procedure that can test the capacity of the nervous system to generate physiologic delta-frequency responses during sleep. SETTING: Research sleep laboratory. PARTICIPANTS: Seven ambulatory patients with Alzheimer disease (mean age = 70.0 +/- 5.77 years) meeting the National Institute of Neurological and Communicative Diseases and Stroke and Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer disease and 8 controls (mean age = 69.25 +/- 4.95 years), underwent at least 1 night of evoked-potential recordings. MEASUREMENT AND RESULTS: Data were collected during stage 2 sleep. Responses to stimuli were classified based on whether they produced a K-complex. Averages of K-complex responses were calculated, latencies and amplitudes of components evaluated, and K-complex incidence was determined. Relative to controls, subjects with Alzheimer disease produced significantly fewer evoked K-complexes (P < .001) and had substantially smaller N550 amplitudes than controls (P < .05). A lower probability of eliciting a K-complex correlated with greater dementia severity, as measured by the Mini Mental State Examination and Dementia Rating Scale. CONCLUSIONS: Despite observed increases in pathologic delta-frequency electroencephalographic activity, patients with Alzheimer disease have an impaired capacity to generate normal physiologic delta responses during non-rapid eye movement sleep.

Effects of age and sex on volumes of the thalamus, pons, and cortex.

Volumes of thalamus, pons, cortical gray matter, and white matter were derived from MR brain images of healthy men and women spanning the adult age range in order to delineate patterns of aging and to compare age and sex effects in thalamus and pons with such effects in cortical gray and white matter volumes. Men had larger intracranial volume (ICV) than women, but ICV did not correlate with age in either sex. Thalamic, pontine, and cortical white matter volumes did not differ between men and women once ICV differences were taken into account, but men had more cortical gray matter than women even after accounting for ICV. Volumes of pons and thalamus were associated, independent of ICV, in women but not in men. Thalamic volume declined linearly with age at a similar rate in both men and women, whereas cortical gray matter volume declined more steeply with age in men than women. Both pontine and cortical white matter volumes remained stable across the age span in both men and women.

Effects of alcohol dependence comorbidity and antipsychotic medication on volumes of the thalamus and pons in schizophrenia.

OBJECTIVE: Postmortem and in vivo brain imaging studies have identified abnormalities in the thalamus and the pons in both schizophrenia and alcoholism. The authors sought to determine whether patients with both schizophrenia and alcohol dependence would manifest exaggerated volume deficits in either structure. METHOD: Volumetric measures of the left and right thalamus and the pons were derived from magnetic resonance imaging scans obtained from 27 patients with schizophrenia, 19 patients with schizophrenia and comorbid alcohol dependence, 25 patients with alcohol dependence without comorbid axis I disorders, and 51 healthy comparison subjects. RESULTS: The alcohol-dependent patients had significant volume deficits in both the thalamus and the pons. Among patients with schizophrenia, there were no differences in thalamus volumes between those with and without comorbid alcohol dependence. However, patients with schizophrenia who were taking atypical antipsychotic medications had bilateral thalamic deficits, whereas those taking typical neuroleptics did not. Patients with schizophrenia and comorbid alcohol dependence had deficits in the pons. CONCLUSIONS: Patients with schizophrenia and comorbid alcohol dependence are at risk for alcohol-related reduction of pontine structures that are not necessarily affected by schizophrenia per se. The effect of alcohol dependence on the thalamus in schizophrenic patients may be mitigated by the type of neuroleptic medication they receive.

Low N-acetyl-aspartate and high choline in the anterior cingulum of recently abstinent methamphetamine-dependent subjects: a preliminary proton MRS study. Magnetic resonance spectroscopy.

Studies based on animal models report that methamphetamine (MA) abuse diminishes dopamine (DA) and serotonin innervation in frontal brain regions. In this in vivo human study, we used proton magnetic resonance spectroscopy (MRS), which yields measures of N-acetyl-aspartate (NAA), a marker of living neurons, to examine frontal brain regions possibly affected by methamphetamine dependence (MD). We tested the hypothesis that MD subjects would exhibit abnormally low levels of NAA, referenced to creatine (Cr), in anterior cingulate gray matter. We further hypothesized that the primary visual cortex, which receives relatively less DA innervation than the frontal brain regions, would show normal NAA/Cr ratios in MD subjects. Subjects included nine MD men (mean+/-standard deviation (S.D.)=32.5+/-6.4 years) and nine age-matched control men (mean+/-S.D.=32.7+/-6.8 years). The MD subjects were MA-free for 4-13 weeks. Proton MRS metabolites were expressed as ratios of creatine; the absolute values of which did not distinguish controls and MD subjects. With regard to metabolite ratios, the MD men had significantly lower NAA/Cr in the cingulum (mean+/-standard error (S.E.): control=1.46+/-0.03; MD=1.30+/-0.03; Mann-Whitney P=0.01) but not in the visual cortex (mean+/-S.E.: control=1.64+/-0.06; MD=1.69+/-11; Mann-Whitney P=0.52) relative to controls. These results provide evidence for NAA/Cr deficit that is selective to the anterior cingulum, at least with respect to visual cortex, in MD subjects. The neuronal compromise that these changes reflect may contribute to the attentional deficits and dampened reward system in MD.