Evidence for a unique association between fronto-cortical glycine levels and recent heavy drinking in treatment naïve individuals with alcohol use disorder.

Although the neurotransmitters/modulators glutamate and, more recently, glycine have been implicated in the development and maintenance of Alcohol Use Disorder (AUD) in preclinical research, human proton magnetic resonance spectroscopy (1H-MRS) studies have focused solely on the measurement of glutamate. The purpose of the present analysis was to examine the relative associations of brain glutamate and glycine levels with recent heavy drinking in 41 treatment naïve individuals with AUD using 1H-MRS. The present study is the first that we are aware of to report in vivo brain glycine levels from an investigation of addiction. Dorsal Anterior Cingulate Cortex (dACC) glutamate and glycine concentration estimates were obtained using Two-Dimensional J-Resolved Point Resolved Spectroscopy at 3 Tesla, and past 2-week summary estimates of alcohol consumption were assessed via the Timeline Followback method. Glutamate (ß = -0.44, t = -3.09, p = 0.004) and glycine (ß = -0.68, t = -5.72, p < 0.001) were each significantly, inversely associated with number of heavy drinking days when considered alone. However, when both variables were simultaneously entered into a single regression model, the effect of glutamate was no longer significant (ß = -0.11, t = -0.81, p = 0.42) whereas the effect of glycine remained significant (ß = -0.62, t = -4.38, p < 0.001). The present study extends the literature by demonstrating a unique, inverse association of brain glycine levels with recent heavy drinking in treatment naïve individuals with AUD. If replicated and extended, these data could lead to enhanced knowledge of how glycinergic systems change with alcohol consumption and AUD progression leading to pharmacological interventional/preventative strategies that modulate brain glycine levels.

Single pulse TMS to the DLPFC, compared to a matched sham control, induces a direct, causal increase in caudate, cingulate, and thalamic BOLD signal.

BACKGROUND: In the 20 years since our group established the feasibility of performing interleaved TMS/fMRI, no studies have reported direct comparisons of active prefrontal stimulation with a matched sham. Thus, for all studies there is concern about what is truly the TMS effect on cortical neurons. OBJECTIVE: After developing a sham control for use within the MRI scanner, we used fMRI to test the hypothesis of greater regional BOLD responses for active versus control stimulation. METHODS: We delivered 4 runs of interleaved TMS/fMRI with a limited field of view (16 slices, centered at AC-PC) to the left DLPFC (2 active, 2 control; counterbalanced) of 20 healthy individuals (F3; 20 pulses/run, interpulse interval:10-15sec, TR:1sec). In the control condition, 3 cm of foam was placed between the TMS coil and the scalp. This ensured magnetic field decay, but preserved the sensory aspects of each pulse (empirically evaluated in a subset of 10 individuals). RESULTS: BOLD increases in the cingulate, thalamus, insulae, and middle frontal gyri (p < 0.05, FWE corrected) were found during both active and control stimulation. However, relative to control, active stimulation caused elevated BOLD signal in the anterior cingulate, caudate and thalamus. No significant difference was found in auditory regions. CONCLUSION(S): This TMS/fMRI study evaluated a control condition that preserved many of the sensory features of TMS while reducing magnetic field entry. These findings support a relationship between single pulses of TMS and activity in anatomically connected regions, but also underscore the importance of using a sham condition in future TMS/fMRI studies.

Prestimulus EEG alpha oscillations modulate task-related fMRI BOLD responses to auditory stimuli.

EEG alpha-band activity is generally thought to represent an inhibitory state related to decreased attention and play a role in suppression of task-irrelevant stimulus processing, but a competing hypothesis suggests an active role in processing task-relevant information - one in which phase dynamics are involved. Here we used simultaneous EEG-fMRI and a whole-brain analysis to investigate the effects of prestimulus alpha activity on the event-related BOLD response during an auditory oddball task. We separately investigated the effects of the posterior alpha rhythm's power and phase on activity related to task-relevant stimulus processing and also investigated higher-level decision-related processing. We found stronger decision-related BOLD activity in areas late in the processing stream when subjects were in the high alpha power state prior to stimulus onset, but did not detect any effect in primary sensory regions. Our phase analysis revealed correlates in the bilateral thalamus, providing support for a thalamo-cortical loop in attentional modulations and suggesting that the cortical alpha rhythm acts as a cyclic modulator of task-related responses very early in the processing stream. Our results help to reconcile the competing inhibition and active-processing hypotheses for ongoing alpha oscillations and begin to tease apart the distinct roles and mechanisms underlying their power and phase.

Simultaneous EEG-fMRI reveals temporal evolution of coupling between supramodal cortical attention networks and the brainstem.

Cortical and subcortical networks have been identified that are commonly associated with attention and task engagement, along with theories regarding their functional interaction. However, a link between these systems has not yet been demonstrated in healthy humans, primarily because of data acquisition and analysis limitations. We recorded simultaneous EEG-fMRI while subjects performed auditory and visual oddball tasks and used these data to investigate the BOLD correlates of single-trial EEG variability at latencies spanning the trial. We focused on variability along task-relevant dimensions in the EEG for identical stimuli and then combined auditory and visual data at the subject level to spatially and temporally localize brain regions involved in endogenous attentional modulations. Specifically, we found that anterior cingulate cortex (ACC) correlates strongly with both early and late EEG components, whereas brainstem, right middle frontal gyrus (rMFG), and right orbitofrontal cortex (rOFC) correlate significantly only with late components. By orthogonalizing with respect to event-related activity, we found that variability in insula and temporoparietal junction is reflected in reaction time variability, rOFC and brainstem correlate with residual EEG variability, and ACC and rMFG are significantly correlated with both. To investigate interactions between these correlates of temporally specific EEG variability, we performed dynamic causal modeling (DCM) on the fMRI data. We found strong evidence for reciprocal effective connections between the brainstem and cortical regions. Our results support the adaptive gain theory of locus ceruleus-norepinephrine (LC-NE) function and the proposed functional relationship between the LC-NE system, right-hemisphere ventral attention network, and P300 EEG response.

Probing the frontostriatal loops involved in executive and limbic processing via interleaved TMS and functional MRI at two prefrontal locations: a pilot study.

BACKGROUND: The prefrontal cortex (PFC) is an anatomically and functionally heterogeneous area which influences cognitive and limbic processing through connectivity to subcortical targets. As proposed by Alexander et al. (1986) the lateral and medial aspects of the PFC project to distinct areas of the striatum in parallel but functionally distinct circuits. The purpose of this preliminary study was to determine if we could differentially and consistently activate these lateral and medial cortical-subcortical circuits involved in executive and limbic processing though interleaved transcranial magnetic stimulation (TMS) in the MR environment. METHODS: Seventeen healthy individuals received interleaved TMS-BOLD imaging with the coil positioned over the dorsolateral (EEG: F3) and ventromedial PFC (EEG: FP1). BOLD signal change was calculated in the areas directly stimulated by the coil and in subcortical regions with afferent and efferent connectivity to the TMS target areas. Additionally, five individuals were tested on two occasions to determine test-retest reliability. RESULTS: Region of interest analysis revealed that TMS at both prefrontal sites led to significant BOLD signal increases in the cortex under the coil, in the striatum, and the thalamus, but not in the visual cortex (negative control region). There was a significantly larger BOLD signal change in the caudate following medial PFC TMS, relative to lateral TMS. The hippocampus in contrast was significantly more activated by lateral TMS. Post-hoc voxel-based analysis revealed that within the caudate the location of peak activity was in the ventral caudate following medial TMS and the dorsal caudate following lateral TMS. Test-retest reliability data revealed consistent BOLD responses to TMS within each individual but a large variation between individuals. CONCLUSION: These data demonstrate that, through an optimized TMS/BOLD sequence over two unique prefrontal targets, it is possible to selectively interrogate the patency of these established cortical-subcortical networks in healthy individuals, and potentially patient populations.

Reduced transverse relaxation rate (RR2) for improved sensitivity in monitoring myocardial iron in thalassemia.

PURPOSE: To evaluate the reduced transverse relaxation rate (RR2), a new relaxation index which has been shown recently to be primarily sensitive to intracellular ferritin iron, as a means of detecting short-term changes in myocardial storage iron produced by iron-chelating therapy in transfusion-dependent thalassemia patients. MATERIALS AND METHODS: A single-breathhold multi-echo fast spin-echo sequence was implemented at 3 Tesla (T) to estimate RR2 by acquiring signal decays with interecho times of 5, 9 and 13 ms. Transfusion-dependent thalassemia patients (N = 8) were examined immediately before suspending iron-chelating therapy for 1 week (Day 0), after a 1-week suspension of chelation (Day 7), and after a 1-week resumption of chelation (Day 14). RESULTS: The mean percent changes in RR2, R2, and R2* off chelation (between Day 0 and 7) were 11.9 ± 8.9%, 5.4 ± 7.7% and -4.4 ± 25.0%; and, after resuming chelation (between Day 7 and 14), -10.6 ± 13.9%, -8.9 ± 8.0% and -8.5 ± 24.3%, respectively. Significant differences in R2 and RR2 were observed between Day 0 and 7, and between Day 7 and 14, with the greatest proportional changes in RR2. No significant differences in R2* were found. CONCLUSION: These initial results demonstrate that significant differences in RR2 are detectable after a single week of changes in iron-chelating therapy, likely as a result of superior sensitivity to soluble ferritin iron, which is in close equilibrium with the chelatable cytosolic iron pool. RR2 measurement may provide a new means of monitoring the short-term effectiveness of iron-chelating agents in patients with myocardial iron overload.

Single-trial discrimination for integrating simultaneous EEG and fMRI: identifying cortical areas contributing to trial-to-trial variability in the auditory oddball task.

The auditory oddball task is a well-studied stimulus paradigm used to investigate the neural correlates of simple target detection. It elicits several classic event-related potentials (ERPs), the most prominent being the P300 which is seen as a neural correlate of subjects' detection of rare (target) stimuli. Though trial-averaging is typically used to identify and characterize such ERPs, their latency and amplitude can vary on a trial-to-trial basis reflecting variability in the underlying neural information processing. Here we simultaneously recorded EEG and fMRI during an auditory oddball task and identified cortical areas correlated with the trial-to-trial variability of task-discriminating EEG components. Unique to our approach is a linear multivariate method for identifying task-discriminating components within specific stimulus- or response-locked time windows. We find fMRI activations indicative of distinct processes that contribute to the single-trial variability during target detection. These regions are different from those found using standard, including trial-averaged, regressors. Of particular note is the strong activation of the lateral occipital complex (LOC). The LOC was not seen when using traditional event-related regressors. Though LOC is typically associated with visual/spatial attention, its activation in an auditory oddball task, where attention can wax and wane from trial to trial, indicates that it may be part of a more general attention network involved in allocating resources for target detection and decision making. Our results show that trial-to-trial variability in EEG components, acquired simultaneously with fMRI, can yield task-relevant BOLD activations that are otherwise unobservable using traditional fMRI analysis.

The brain's orienting response: An event-related functional magnetic resonance imaging investigation.

An important function of the brain's orienting response is to enable the evaluation of novel, environmental events in order to prepare for potential behavioral action. Here, we assessed the event-related hemodynamic (erfMRI) correlates of this phenomenon using unexpected (i.e., novel) environmental sounds presented within the context of an auditory novelty oddball paradigm. In ERP investigations of the novelty oddball, repetition of the identical novel sound leads to habituation of the novelty P3, an ERP sign of the orienting response. Repetition also leads to an enhancement of a subsequent positivity that appears to reflect semantic analysis of the environmental sounds. In this adaptation for erfMRI recording, frequent tones were intermixed randomly with infrequent target tones and equally infrequent novel, environmental sounds. Subjects responded via speeded button press to targets. To assess habituation, some of the environmental sounds were repeated two blocks after their initial presentation. As expected, novel sounds and target tones led to activation of widespread, but somewhat different, neural networks. Contrary to expectation, however, there were no significant areas in which activation was reduced in response to second compared to first presentations of the novel sounds. Conversely, novel sounds relative to target tones engendered activity in the inferior frontal gyrus (BA 45) consistent with semantic analysis of these events. We conclude that a key concomitant of the orienting response is the extraction of meaning, thereby enabling one to determine the significance of the environmental perturbation and take appropriate goal-directed action.

Methods for noninvasive measurement of tissue iron in Cooley's anemia.

To examine the relationship between myocardial storage iron and body iron burden, as assessed by hepatic storage iron measurements, we studied 22 patients with transfusion-dependent thalassemia syndromes, all being treated with subcutaneous deferoxamine, and 6 healthy subjects. Study participants were examined with a Philips 1.5-T Intera scanner using three multiecho spin echo sequences with electrocardiographic triggering and respiratory navigator gating. Myocardial and hepatic storage iron concentrations were determined using a new magnetic resonance method that estimates total tissue iron stores by separately measuring the two principal forms of storage iron, ferritin and hemosiderin. In a subset of 10 patients with beta-thalassemia major, the hepatic storage iron concentration had been monitored repeatedly for 12-14 years by chemical analysis of tissue obtained by liver biopsy and by magnetic susceptometry. In this subset, we examine the relationship between hepatic iron concentration over time and our current magnetic resonance estimates of myocardial iron stores. No significant relationship was found between simultaneous estimates of myocardial and hepatic storage iron concentrations. By contrast, in the subset of 10 patients with beta-thalassemia major, the correlation between the 5-year average of hepatic iron concentration and the current myocardial storage iron was significant (R = .67, P = .03). In these patients, myocardial storage iron concentrations seem to reflect the control of body iron over a period of years. Magnetic resonance methods promise to provide more effective monitoring of iron deposition in vulnerable tissues, including the liver, heart, and endocrine organs, and could contribute to the development of iron-chelating regimens that more effectively prevent iron toxicity.

In vivo measurement of phosphorous markers of disease.

Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) has been utilized to study energy, carbohydrate, and phospholipid metabolism in vitro and in vivo in live tissues non-invasively. Despite its lack of sensitivity, its application has extended to in situ human tissues and organs since proper signal localization was devised. Follow-up of phosphocreatine in neuromuscular diseases and schizophrenia and follow-up of phospholipid-related molecules in tumors are described here to demonstrate the value of 31P-MRS as an imaging technique to determine in vivo markers of disease and in the diagnosis, prognosis, and follow-up of human diseases.