Binu P. Thomas

Life-long aerobic exercise preserved baseline cerebral blood flow but reduced vascular reactivity to CO2

To examine the potential benefits of life‐long aerobic exercise on brain health, in particular cerebrovascular function.

Cerebrovascular reactivity in the brain white matter: magnitude, temporal characteristics, and age effects.

White matter (WM) comprises about half of the brain and its dysfunction is implicated in many brain disorders. While structural properties in healthy and diseased WM have been extensively studied, relatively little is known about the physiology underlying these structural characteristics. Recent advances in magnetic resonance (MR) technologies provided new opportunities to better understand perfusion and microvasculature in the WM. Here, we aim to evaluate vasodilatory capacity of the WM vasculature, which is thought to be important in tissue ischemia and autoregulation. Fifteen younger and fifteen older subjects performed a CO2 inhalation task while blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging (MRI) images were continuously collected. The cerebrovascular reactivity (CVR) index showed that the value of CVR in the WM (0.03±0.002%/mm Hg) was positive, but was significantly lower than that in the gray matter (GM) (0.22±0.01%/mm Hg). More strikingly, the WM response showed a temporal delay of 19±3 seconds compared with GM, which was attributed to the longer time it takes for extravascular CO2 to change. With age, WM CVR response becomes greater and faster, which is opposite to the changes seen in the GM. These data suggest that characteristics of WM CVR are different from that of GM and caution should be used when interpreting pathologic WM CVR results.

Brain gray matter phenotypes across the psychosis dimension

This study sought to examine whole brain and regional gray matter (GM) phenotypes across the schizophrenia (SZ)-bipolar disorder psychosis dimension using voxel-based morphometry (VBM 8.0 with DARTEL segmentation/normalization) and semi-automated regional parcellation, FreeSurfer (FS 4.3.1/64 bit). 3T T1 MPRAGE images were acquired from 19 volunteers with schizophrenia (SZ), 16 with schizoaffective disorder (SAD), 17 with psychotic bipolar I disorder (BD-P) and 10 healthy controls (HC). Contrasted with HC, SZ showed extensive cortical GM reductions, most pronounced in fronto-temporal regions; SAD had GM reductions overlapping with SZ, albeit less extensive; and BD-P demonstrated no GM differences from HC. Within the psychosis dimension, BD-P showed larger volumes in fronto-temporal and other cortical/subcortical regions compared with SZ, whereas SAD showed intermediate GM volumes. The two volumetric methodologies, VBM and FS, revealed highly overlapping results for cortical GM, but partially divergent results for subcortical volumes (basal ganglia, amygdala). Overall, these findings suggest that individuals across the psychosis dimension show both overlapping and unique GM phenotypes: decreased GM, predominantly in fronto-temporal regions, is characteristic of SZ but not of psychotic BD-P, whereas SAD display GM deficits overlapping with SZ, albeit less extensive.

Learning and Generalization in Schizophrenia: Effects of Disease and Antipsychotic Drug Treatment

BACKGROUND Schizophrenia involves alterations in hippocampal function. The implications of these alterations for memory function in the illness remain poorly understood. Furthermore, it remains unknown how memory is impacted by drug treatments for schizophrenia. The goal of this study was to delineate specific memory processes that are disrupted in schizophrenia and explore how they are affected by medication. We specifically focus on memory generalization--the ability to flexibly generalize memories in novel situations. METHODS Individuals with schizophrenia (n = 56) and healthy control subjects (n = 20) were tested on a computerized memory generalization paradigm. Participants first engaged in trial-by-error associative learning. They were then asked to generalize what they learned by responding to novel stimulus combinations. Individuals with schizophrenia were tested on or off antipsychotic medication, using a between-subject design in order to eliminate concerns about learning-set effects. RESULTS Individuals with schizophrenia were selectively impaired in their ability to generalize knowledge, despite having intact learning and memory accuracy. This impairment was found only in individuals tested off medication. Individuals tested on medication generalized almost as well as healthy control subjects. This between-group difference was selective to memory generalization. CONCLUSIONS These findings suggest that individuals with schizophrenia have a selective alteration in the ability to flexibly generalize past experience toward novel learning environments. This alteration is unaccompanied by global memory impairments. Additionally, the results indicate a robust generalization difference on the basis of medication status. These results suggest that hippocampal abnormalities in schizophrenia might be alleviated with antipsychotic medication, with important implications for understanding adaptive memory-guided behavior.

Neurobiology of self-awareness in schizophrenia: An fMRI study

Self-awareness (SA) is one of the core domains of higher cortical functions and is frequently compromised in schizophrenia. Deficits in SA have been associated with functional and psychosocial impairment in this patient population. However, despite its clinical significance, only a few studies have examined the neural substrates of self-referential processing in schizophrenia. The aim of this study was to assess self-awareness in schizophrenia using a functional magnetic resonance imaging (fMRI) paradigm designed to elicit judgments of self-reference in a simulated social context. While scanned, volunteers looked at visually-displayed sentences that had the volunteers own first name (self-directed sentence-stimulus) or an unknown other persons first name (other-directed sentence stimulus) as the grammatical subject of the sentence. The volunteers were asked to discern whether each sentence-stimulus was about the volunteer personally (during a self-referential cue epoch) or asked whether each statement was about someone else (during an other-referential cue epoch). We predicted that individuals with schizophrenia would demonstrate altered functional activation to self- and other-directed sentence-stimuli as compared to controls. Fifteen controls and seventeen schizophrenia volunteers completed clinical assessments and SA fMRI task on a 3T Philips 3.0 T Achieva system. The results showed significantly greater activation in schizophrenia compared to controls for cortical midline structures in response to self- vs. other-directed sentence-stimuli. These findings support results from earlier studies and demonstrate selective alteration in the activation of cortical midline structures associated with evaluations of self-reference in schizophrenia as compared to controls.

Neurobiology of decision-making in adolescents

The study examined the relationship between risk-taking behavior during selection of monetary rewards and activations in the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), brain regions that are associated with decision-making. Thirty-three adolescents with no personal or family history of any psychiatric illness were administered the Wheel of Fortune (WOF) task using a functional magnetic resonance imaging protocol. The WOF is a computerized two-choice, probabilistic monetary reward task. Selection of a reward, particularly a low-probability/high-magnitude reward choice, induced greater activations in dorsal ACC, ventrolateral OFC and mPFC than the control condition. Although similar findings have been reported by earlier studies, the results from this study were not impacted by reaction times and expected values and persisted even after controlling for sociodemographic factors. Post hoc analysis revealed greater activation of ACC and mPFC in response to selection of rewards of larger magnitude than those of smaller magnitude when the probability of reward was maintained constant. Adolescents with greater frequency of high-risk behavior (defined as low-probability/high-magnitude reward choice) had lower activation of ACC, OFC and mPFC than those who engaged in this behavior less frequently. These findings suggest individual differences in prefrontal cortical function with regards to decision-making process in adolescents.

Hippocampal Volume in Healthy Controls Given 3-Day Stress Doses of Hydrocortisone

In animal models, corticosterone elevations are associated with hippocampal changes that can be prevented with phenytoin. In humans, Cushing’s syndrome and long-term prescription corticosteroid use are associated with a reduction in the hippocampal volume. However, little is known about the effects of short-term corticosteroid administration on the hippocampus. The current report examines changes in the hippocampal volume during a brief hydrocortisone exposure and whether volumetric changes can be blocked by phenytoin. A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in healthy adults (n=17). Participants received hydrocortisone (160 mg/day)/placebo, phenytoin/placebo, both medications together, or placebo/placebo, with 21-day washouts between the conditions. Structural MRI scans and cortisol levels were obtained following each medication condition. No significant difference in the total brain volume was observed with hydrocortisone. However, hydrocortisone was associated with a significant 1.69% reduction in the total hippocampal volume compared with placebo. Phenytoin blocked the volume reduction associated with hydrocortisone. Reduction in hippocampal volume correlated with the change in cortisol levels (r=−0.58, P=0.03). To our knowledge, this is the first report of structural hippocampal changes with brief corticosteroid exposure. The correlation between the change in hippocampal volume and cortisol level suggests that the volume changes are related to cortisol elevation. Although the findings from this pilot study need replication, they suggest that the reductions in hippocampal volume occur even during brief exposure to corticosteroids, and that hippocampal changes can, as in animal models, be blocked by phenytoin. The results may have implications both for understanding the response of the hippocampus to stress as well as for patients receiving prescription corticosteroids.

Hippocampal novelty activations in schizophrenia: Disease and medication effects

We examined hippocampal activation in schizophrenia (SZ) with fMRI BOLD in response to the presentation of novel and familiar scenes. Voxel-wise analysis showed no group differences. However, anatomical region-of-interest analyses contrasting normal (NL), SZ-on-medication (SZ-ON), SZ-off-medication (SZ-OFF) showed substantial differences in MTL-based novelty responding, accounted for by the reduction in novelty responses in the SZ-OFF predominantly in the anterior hippocampus and parahippocampal cortex. These differences in novelty-based activation in the SZ-OFF group represent disease characteristics of schizophrenia without confounding effects of antipsychotic medication and illustrate the tendency of antipsychotic drug treatment to improve memory functions in schizophrenia.

Cerebral perfusion differences in women currently with and recovered from anorexia nervosa

Anorexia nervosa is a serious psychiatric disorder characterized by restricted eating, a pursuit of thinness, and altered perceptions of body shape and size. Neuroimaging in anorexia nervosa has revealed morphological and functional alterations in the brain. A better understanding of physiological changes in anorexia nervosa could provide a brain-specific health marker relevant to treatment and outcomes. In this study, we applied several advanced magnetic resonance imaging (MRI) techniques to quantify regional and global cerebral blood flow (CBF) in 25 healthy women (HC), 23 patients currently with anorexia (AN-C) and 19 patients in long-term weight recovery following anorexia (AN-WR). Specifically, CBF was measured with pseudo-continuous arterial spin labeling (pCASL) MRI and then verified by a different technique, phase contrast (PC) MRI. Venous T2 values were determined by T2 relaxation under spin tagging (TRUST) MRI, and were used to corroborate the CBF results. These novel techniques were implemented on a standard 3T MRI scanner without any exogenous tracers, and the total scan duration was less than 10min. Voxel-wise comparison revealed that the AN-WR group showed lower CBF in bilateral temporal and frontal lobes than the AN-C group. Compared with the HC group, the AN-C group also showed higher CBF in the right temporal lobe. Whole-brain-averaged CBF was significantly decreased in the AN-WR group compared with the AN-C group, consistent with the PC-MRI results. Venous T2 values were lower in the AN-WR group than in the AN-C group, consistent with the CBF results. A review of prior work examining CBF in anorexia nervosa is included in the discussion. This study identifies several differences in the cerebral physiological alterations in anorexia nervosa, and finds specific differences relevant to the current state of the disorder.

Reduced global brain metabolism but maintained vascular function in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment represents an early stage of Alzheimer’s disease, and characterization of physiological alterations in mild cognitive impairment is an important step toward accurate diagnosis and intervention of this condition. To investigate the extent of neurodegeneration in patients with mild cognitive impairment, whole-brain cerebral metabolic rate of oxygen in absolute units of µmol O2/min/100 g was quantified in 44 amnestic mild cognitive impairment and 28 elderly controls using a novel, non-invasive magnetic resonance imaging method. We found a 12.9% reduction (p = 0.004) in cerebral metabolic rate of oxygen in mild cognitive impairment, which was primarily attributed to a reduction in the oxygen extraction fraction, by 10% (p = 0.016). Global cerebral blood flow was not found to be different between groups. Another aspect of vascular function, cerebrovascular reactivity, was measured by CO2-inhalation magnetic resonance imaging and was found to be equivalent between groups. Therefore, there seems to be a global, diffuse diminishment in neural function in mild cognitive impairment, while their vascular function did not show a significant reduction.