Recent studies have provided evidence of associations between neurochemistry and reading (dis)ability (Pugh et al., 2014). Based on a long history of studies indicating that fluent reading entails the automatic convergence of the written and spoken forms of language and our recently proposed Neural Noise Hypothesis (Hancock et al., 2017), we hypothesized that individual differences in cross-modal integration would mediate, at least partially, the relationship between neurochemical concentrations and reading. Cross-modal integration was measured in 231 children using a two-alternative forced (...) choice cross-modal matching task with three language conditions (letters, words, and pseudowords) and two levels of difficulty within each language condition. Neurometabolite concentrations of Choline (Cho), Glutamate (Glu), gamma-Aminobutyric (GABA), and N- acetyl-aspartate (NAA) were then measured in a subset of this sample (n = 70) with Magnetic Resonance Spectroscopy (MRS). A structural equation mediation model revealed that the effect of cross-modal word matching mediated the relationship between increased Glu (which has been proposed to be an index of neural noise) and poorer reading ability. In addition, the effect of cross-modal word matching fully mediated a relationship between increased Cho and poorer reading ability. Multilevel mixed effects models confirmed that lower Cho predicted faster cross-modal matching reaction time, specifically in the hard word condition. These Cho... (shrink)

Recent magnetic resonance imaging and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. 1 H magnetic resonance spectroscopy, through measurement of N -acetyl aspartate, a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter, such as axonal loss, may be particularly relevant to disease progression in this (...) group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N -acetyl derived groups. Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr was significantly lower in NAWM in patients than in controls, as was the absolute concentration of NA. There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group. (shrink)

Carbon monoxide intoxication leads to acute and chronic neurological deficits, but little is known about the specific noxious mechanisms. 1 H magnetic resonance spectroscopy may allow insight into the pathophysiology of CO poisoning by monitoring neurochemical disturbances, yet only limited information is available to date on the use of this protocol in determining the neurological effects of CO poisoning. To further examine the short-term and long-term effects of CO on the central nervous system, we have studied seven (...) patients with CO poisoning assessed by gray and white matter MRS, magnetic resonance imaging and neuropsychological testing. Five patients suffered from acute high-dose CO intoxication and were in coma for 1–6 days. In these patients, MRI revealed hyperintensities of the white matter and globus pallidus and also showed increased choline and decreased N -acetyl aspartate ratios to creatine, predominantly in the white matter. Lactate peaks were detected in two patients during the early phase of high-dose CO poisoning. Two patients with chronic low-dose CO exposure and without loss of consciousness had normal MRI and MRS scans. On follow-up. five of our seven patients had long-lasting intellectual impairment, including one individual with low-dose CO exposure. The MRS results showed persisting biochemical alterations despite the MRI scan showing normalization of morphological changes. In conclusion, the MRS was normal in patients suffering from chronic low-dose CO exposure; in contrast, patients with high-dose exposure showed abnormal gray and white matter levels of NAA/Cr, Cho/Cr and lactate, as detected by 1 H MRS, suggesting disturbances of neuronal function, membrane metabolism and anaerobic energy metabolism, respectively. Early increases in Cho/Cr and decreases of NAA/Cr may be related to a poor long-term outcome, but confirmation by future studies is needed. (shrink)

Gluten ataxia is a rare immune-mediated neurological disorder caused by the ingestion of gluten. The diagnosis is not straightforward as antibodies are present in only up to 38% of patients, but often at lower titers. The symptoms of ataxia may be mild at the onset but lead to permanent damage if remain untreated. It is characterized by damage to the cerebellum however, the pathophysiology of the disease is not clearly understood. The present study investigated the neurochemical profile of vermis and (...) right cerebellum and structural changes in various brain regions of patients with gluten ataxia and compared it with healthy controls. Volumetric 3-D T1 and T1-weighted magnetic resonance imaging in the three planes of the whole brain and single-voxel 1H- magnetic resonance spectroscopy of the vermis and right cerebellum were acquired on 3 T human MR scanner. The metabolite concentrations were estimated using LC Model while brain volumes were estimated using the online tool volBrain pipeline and CERES and corrected for partial volumes. The levels of neuro-metabolites were found to be significantly lower in vermis, while N-acetyl aspartate + N-acetyl aspartate glutamate and glycerophosphocholine + phosphocholine was lower in cerebellum regions in the patients with gluten ataxia compared to healthy controls. A significant reduction in the white matter of ; reduction in the volumes of cerebellum lobe and thalamus while lateral ventricles were increased in the patients with gluten ataxia compared to healthy controls. The reduced neuronal metabolites along with structural changes in the brain suggested neuronal degeneration in the patients with gluten ataxia. Our preliminary findings may be useful in understanding the gluten-induced cerebral damage and indicated that MRI and MRS may serve as a non-invasive useful tool in the early diagnosis, thereby enabling better management of these patients. (shrink)

In amblyopia, abnormal visual experience during development leads to an enduring loss of visual acuity in adulthood. Physiological studies in animal models suggest that intracortical GABAergic inhibition may mediate visual deficits in amblyopia. To better understand the relationship between visual cortical γ-aminobutyric acid (GABA) and perceptual suppression in persons with amblyopia (PWA), we employed magnetic resonance spectroscopy (MRS) to quantify GABA levels in both PWA and normally-sighted persons (NSP). In the same individuals, we obtained psychophysical measures of (...) perceptual suppression for a variety of ocular configurations. In PWA, we found a robust negative correlation between the depth of amblyopia (the difference in visual acuity between the amblyopic and non-amblyopic eyes) and GABA concentration that was specific to visual cortex and was not observed in a sensorimotor cortical control region. Moreover, lower levels of visual cortical GABA were associated with weaker perceptual suppression of the fellow eye by the amblyopic eye and stronger suppression of the amblyopic eye by the fellow eye. Taken together, our findings provide evidence that intracortical GABAergic inhibition is an important component of the pathology of human amblyopia and suggest possible therapeutic interventions to restore vision in the amblyopic eye through enhancement of visual cortical GABAergic signaling in PWA. (shrink)

Recent studies have demonstrated neural overlap between resting state activity and self-referential processing. This “rest-self” overlap occurs especially in anterior cortical midline structures like the perigenual anterior cingulate cortex (PACC). However, the exact neurotemporal and biochemical mechanisms remain to be identified. Therefore, we conducted a combined electroencephalography (EEG)-magnetic resonance spectroscopy (MRS) study. EEG focused on pre-stimulus (e.g., prior to stimulus presentation or perception) power changes to assess the degree to which those changes can predict subjects’ perception (and (...) judgment) of subsequent stimuli as high or low self-related. MRS measured resting state concentration of glutamate, focusing on PACC. High pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power significantly correlated with both perception of stimuli judged to be highly self-related and with resting state glutamate concentrations in the PACC. In sum, our results show (i) pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power and resting state glutamate concentration to mediate rest-self overlap that (ii) dispose or incline subjects to assign high degrees of self-relatedness to perceptual stimuli. (shrink)

Here we review 37 modern neuroimaging studies in an attempt to address this question posed by Halstead (1947) as he and other icons of the last century endeavored to understand how brain and behavior are linked through the expression of intelligence and reason. Reviewing studies from functional (i.e., functional magnetic resonance imaging, positron emission tomography) and structural (i.e., magnetic resonance spectroscopy, diffusion tensor imaging, voxel-based morphometry) neuroimaging paradigms, we report a striking consensus suggesting that variations (...) in a distributed network predict individual differences found on intelligence and reasoning tasks. We describe this network as the Parieto-Frontal Integration Theory (P-FIT). The P-FIT model includes, by Brodmann areas (BAs): the dorsolateral prefrontal cortex (BAs 6, 9, 10, 45, 46, 47), the inferior (BAs 39, 40) and superior (BA 7) parietal lobule, the anterior cingulate (BA 32), and regions within the temporal (BAs 21, 37) and occipital (BAs 18, 19) lobes. White matter regions (i.e., arcuate fasciculus) are also implicated. The P-FIT is examined in light of findings from human lesion studies, including missile wounds, frontal lobotomy/leukotomy, temporal lobectomy, and lesions resulting in damage to the language network (e.g., aphasia), as well as findings from imaging research identifying brain regions under significant genetic control. Overall, we conclude that modern neuroimaging techniques are beginning to articulate a biology of intelligence. We propose that the P-FIT provides a parsimonious account for many of the empirical observations, to date, which relate individual differences in intelligence test scores to variations in brain structure and function. Moreover, the model provides a framework for testing new hypotheses in future experimental designs. (shrink)

The neurotransmitters GABA and glutamate have been suggested to play a role in Major Depressive Disorder (MDD) through an imbalance between cortical inhibition and excitation. This effect has been highlighted in higher brain areas, such as the prefrontal cortex, but has also been posited in basic sensory cortices. Based on this, magnetic resonance spectroscopy (MRS) was used to investigate potential changes to GABA+ and glutamate+glutamine (Glx) concentrations within the occipital cortex in MDD patients (n = 25) and (...) healthy controls (n = 25). No difference in occipital GABA+ or Glx concentrations, nor in the GABA+/Glx ratio, was found between groups. An analysis of an extended MDD patient and unmatched control dataset (n = 90) found no correlation between metabolite concentrations and depressive symptoms. These results were integrated with prior studies through metabolite-specific meta-analyses, revealing no difference in occipital GABA and Glx concentrations between patients and controls. An effect of publication year on GABA group differences was found, suggesting that previously reported results may have been artifacts of measurement accuracy. Taken together, our results suggest that, contrary to some prior reports, MRS measurements of occipital GABA and Glx do not differ between MDD patients and controls. (shrink)

Gliomas can display marked changes in the concentrations of energy metabolism molecules such as creatine (Cr), phosphocreatine (PCr) and lactate, as measured using magnetic resonance spectroscopy (MRS). Moreover, the BOLD (blood oxygen level dependent) contrast enhancement in functional magnetic resonance imaging (fMRI) can be reduced or missing within or near gliomas, while neural activity is not significantly reduced (so-called neurovascular decoupling), so that the location of functionally eloquent areas using fMRI can be erroneous. In this (...) paper, we adapt a previously developed model of the coupling between neural activation, energy metabolism and hemodynamics, by including the venous dilatation Balloon model of Buxton and Frank. We show that decreasing the cerebral blood flow (CBF) baseline value, or the CBF increase fraction, results in a decrease of the BOLD signal and an increase of the lactate peak during a sustained activation. Baseline lactate and PCr levels are not significantly affected by CBF baseline reduction, but are altered even by a moderate decrease of mitochondrial respiration. Decreasing the total Cr and PCr concentration reduces the BOLD signal after the initial overshoot. In conclusion, we suggest that the coupled use of BOLD fMRI and MRS could contribute to a better understanding of the neurovascular and metabolic decoupling in gliomas. (shrink)

Focal brain metabolic effects detected by proton magnetic resonance spectroscopy (MRS) in obsessive-compulsive disorder (OCD) represent prospective indices of clinical status and guides to treatment design. Sampling bilateral pregenual anterior cingulate cortex (pACC), anterior middle cingulate cortex (aMCC), and thalamus in 40 adult patients and 16 healthy controls, we examined relationships of the neurometabolites glutamate+glutamine (Glx), creatine+phosphocreatine (Cr), and choline-compounds (Cho) with OCD diagnosis and multiple symptom types. The latter included OC core symptoms (Yale-Brown Obsessive-Compulsive Scale - (...) YBOCS), depressive symptoms (Montgomery-Åsberg Depression Rating Scale - MADRS), and general functioning (Global Assessment Scale - GAS). pACC Glx was 9.7% higher in patients than controls. Within patients, Cr and Cho correlated negatively with YBOCS and MADRS, while Cr correlated positively with the GAS. In aMCC, Cr and Cho correlated negatively with MADRS, while Cr in thalamus correlated positively with GAS. These findings present moderate support for glutamatergic and cingulocentric perspectives on OCD. Based on our prior metabolic model of OCD, we offer one possible interpretation of these group and correlational effects as consequences of a corticothalamic state of elevated glutamatergic receptor activity alongside below-normal glutamatergic transporter activity. (shrink)

The blood oxygen level dependent effect that provides the contrast in functional magnetic resonance imaging has been demonstrated to affect the linewidth of spectral peaks as measured with magnetic resonance spectroscopy and through this, may be used as an indirect measure of cerebral blood flow related to neural activity. By acquiring MR-spectra interleaved with frames without water suppression, it may be possible to image the BOLD effect and associated metabolic changes simultaneously through changes in the (...) linewidth of the unsuppressed water peak. The purpose of this study was to implement this approach with the MEGA-PRESS sequence, widely considered to be the standard sequence for quantitative measurement of GABA at field strengths of 3 T and lower, to observe how changes in both glutamate and GABA levels may relate to changes due to the BOLD effect. MR-spectra and fMRI were acquired from the occipital cortex of 20 healthy participants whilst undergoing intrascanner visual stimulation in the form of a red and black radial checkerboard, alternating at 8 Hz, in 90 s blocks comprising 30 s of visual stimulation followed by 60 s of rest. Results show very strong agreement between the changes in the linewidth of the unsuppressed water signal and the canonical haemodynamic response function as well as a strong, negative, but not statistically significant, correlation with the Glx signal as measured from the OFF spectra in MEGA-PRESS pairs. Findings from this experiment suggest that the unsuppressed water signal provides a reliable measure of the BOLD effect and that correlations with associated changes in GABA and Glx levels may also be measured. However, discrepancies between metabolite levels as measured from the difference and OFF spectra raise questions regarding the reliability of the respective methods. (shrink)

IntroductionCognitive impairment is a highly prevalent non-motor feature of Parkinson’s disease. A better understanding of the underlying pathophysiology may help in identifying therapeutic targets to prevent or treat dementia. This study sought to identify metabolic alterations in the prefrontal cortex, a key region for cognitive functioning that has been implicated in cognitive dysfunction in PD.MethodsProton Magnetic Resonance Spectroscopy was used to investigate metabolic changes in the PFC of a cohort of cognitively normal individuals without PD, as well (...) as PD participants with either normal cognition, mild cognitive impairment, or dementia. Ratios to Creatine resonance were obtained for glutamate, glutamine and glutamate combined, N-acetylaspartate, myoinositol, and total choline, and correlated with cognitive scores across multiple domains administered to the PD participants only.ResultsWhen individuals retain cognitive capabilities, the presence of Parkinson’s disease does not create metabolic disturbances in the PFC. However, when cognitive symptoms are present, PFC Glu/Cre ratios decrease with significant differences between the PD-NC and PPD groups. In addition, Glu/Cre ratios and memory scores were marginally associated, but not after Bonferroni correction.ConclusionThese preliminary findings indicate that fluctuations in prefrontal glutamate may constitute a biomarker for the progression of cognitive impairments in PD. We caution for larger MRS investigations of carefully defined PD groups. (shrink)