Changes in human brain glutamate concentration during hypoglycemia: insights into cerebral adaptations in hypoglycemia-associated autonomic failure in type 1 diabetes

Hypoglycemia-associated autonomic failure (HAAF) is a condition in which patients with type 1 diabetes (T1D) who experience frequent hypoglycemia develop defective glucose counter-regulation and become unable to sense hypoglycemia. Brain glutamate may be involved in the mechanism of HAAF. The goal of this study was to follow the human brain glutamate concentration during experimentally induced hypoglycemia in subjects with and without HAAF. ¹H magnetic resonance spectroscopy was used to track the occipital cortex glutamate concentration throughout a euglycemic clamp followed immediately by a hypoglycemic clamp. T1D patients with HAAF were studied in comparison to two control groups, i.e., T1D patients without HAAF and healthy controls (n=5 per group). Human brain glutamate concentration decreased (P⩽0.01) after the initiation of hypoglycemia in the two control groups, but a smaller trend toward a decrease in patients with HAAF did not reach significance (P>0.05). These findings are consistent with a metabolic adaptation in HAAF to provide higher glucose and/or alternative fuel to the brain, eliminating the need to oxidize glutamate. In an exploratory analysis, we detected additional metabolite changes in response to hypoglycemia in the T1D patient without HAAF control group, namely, increased aspartate and decreased lactate.     

Effects of hypoglycemia on functional magnetic resonance imaging response to median nerve stimulation in the rat brain.

The authors studied the effects of a standardized mild-moderate hypoglycemic stimulus (glucose clamp) on brain functional magnetic resonance imaging (fMRI) responses to median nerve stimulation in anesthetized rats. In the baseline period (plasma glucose 6.6 +/- 0.3 mmol/L), the MR signal changes induced by median nerve activation were determined within a fixed region of the somatosensory cortex from preinfusion activation maps. Subsequently, insulin and a variable glucose infusion were administered to decrease plasma glucose. The goal was to produce a stable hypoglycemic plateau (2.8 +/- 0.2 mmol/L) for 30 minutes. Thereafter, plasma glucose was restored to euglycemic levels (6.0 +/- 0.3 mmol/L). In the early phase of insulin infusion (15 to 30 minutes), before hypoglycemia was reached (4.7 +/- 0.3 mmol/L), the activation signal was unchanged. However, once the hypoglycemic plateau was achieved, the activation signal was significantly decreased to 57 +/- 6% of the preinfusion value. Control regions in the brain that were not activated showed no significant changes in MR signal intensity. Upon return to euglycemia, the activation signal change increased to within 10% of the original level. No significant activation changes were noted during euglycemic hyperinsulinemic clamp experiments. The authors concluded that fMRI can detect alterations in cerebral function because of insulin-induced hypoglycemia. The signal changes observed in fMRI activation experiments were sensitive to blood glucose levels and might reflect increases in brain metabolism that are limited by substrate deprivation during hypoglycemia.     

The neural circuitry underlying the executive control of auditory spatial attention

Although a fronto-parietal network has consistently been implicated in the control of visual spatial attention, the network that guides spatial attention in the auditory domain is not yet clearly understood. To investigate this issue, we measured brain activity using functional magnetic resonance imaging while participants performed a cued auditory spatial attention task. We found that cued orienting of auditory spatial attention activated a medial-superior distributed fronto-parietal network. In addition, we found cue-triggered increases of activity in the auditory sensory cortex prior to the occurrence of an auditory target, suggesting that auditory attentional control operates in part by biasing processing in sensory cortex in favor of expected target stimuli. Finally, an exploratory cross-study comparison further indicated several common frontal and parietal regions as being involved in the control of both visual and auditory spatial attention. Thus, the present findings not only reveal the network of brain areas underlying endogenous spatial orienting in the auditory modality, but also suggest that the control of spatial attention in different sensory modalities is enabled in part by some common, supramodal neural mechanisms.     

Temporal resolving power of spin echo and gradient echo fMRI at 3T with apparent diffusion coefficient compartmentalization

The temporal resolving power of blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) at 3T was investigated in the visual and auditory cortices of the human brain. By using controlled temporal delays and selective visual hemifield stimulation, regions with similar (left vs. right occipital cortex) and different (occipital cortex vs. auditory cortex) vascular architectures were compared. Estimates of the time-to-peak (TTP) of the BOLD hemodynamic response function (hrf) were obtained using a spin echo (SE) sequence and compared to those acquired using a traditional gradient echo (GE) sequence. The hrf TTP in the visual cortex was found to be 4.73 s and 4.21 s for GE and SE, respectively. The auditory cortex response was significantly delayed, with TTPs of 4.95 s and 4.51 s for GE and SE, respectively. The GE response was able to resolve visual stimuli separated by 250 ms, whereas SE could resolve stimuli 500 ms apart. Apparent-diffusion-coefficient (ADC) compartmentalization of the BOLD signal was applied to restrict the vascular sensitivity of the SE and GE sequences. Limiting the response to voxels with ADCs < 0.8 x 10(-3) mm(2)/s improved the temporal resolving power of GE and SE BOLD to 125 ms and 250 ms, respectively.     

Hypoglycemic brain injury: potentiation from respiratory depression and injury aggravation from hyperglycemic treatment overshoots.

Hypoglycemia can cause brain dysfunction, brain injury, and death. The present study seeks to broaden current information regarding mechanisms of hypoglycemic brain injury by investigating a novel etiology. The cat's high resistance to brain injury from hypoglycemia suggested that additional influences such as respiratory depression might play a facilitating role. Three groups of cats were exposed to fasting and insulin-induced hypoglycemia (HG; n = 6), euglycemic respiratory depression (RD; n = 5), and combined hypoglycemic respiratory depression (HG/RD; n = 10). The HG animals were maintained at <1.5 mmol (mean 1 mmol) serum glucose concentration for 2 to 6.6 hours. The respiratory depression was associated with PaO2 and PaCO2 values of approximately 50 mm Hg for 1 hour and of approximately 35 and approximately 75 mm Hg, respectively, for the second hour. Magnetic resonance diffusion-weighted imaging estimated brain energy state before, during, and after hypoglycemia. The hypoglycemic respiratory depression exposures were terminated either to euglycemia (n = 4) or to hyperglycemia (n = 6). Brain injury was assessed after 5 to 7 days of survival. Cats exposed to hypoglycemia alone maintained unchanged diffusion coefficients; that is, they lacked evidence of brain energy failure and all six remained brain-intact. Only 1 of 5 euglycemic RD but 10 of 10 HG/RD cats developed brain damage (HG and RD vs. HG/RD, P < 0.01). This difference in brain injury rates suggests injury potentiation by hypoglycemia and respiratory depression acting together. Three injury patterns emerged, including activation of microglia, selective neuronal necrosis, and laminar cortical necrosis. Widespread activation of microglia suggesting damage to neuronal cell processes affected all damaged brains. Selective neuronal necrosis affecting the cerebral cortex, hippocampus, and basal ganglia was observed in all but one case. Instances of laminar cortical necrosis were limited to cats exposed to hypoglycemic respiratory depression treated with hyperglycemia. Thus, treatment with hyperglycemia compared with euglycemia after hypoglycemic respiratory depression exposures significantly increased the brain injury scores (24 +/- 6 vs. 13 +/- 2 points; P < 0.05). This new experimental hypoglycemia model's contribution lies in recognizing additional factors that critically define the occurrence of hypoglycemic brain injury.     

Neural substrates of verbal memory impairments in adults with type 2 diabetes mellitus

Background: Verbal memory impairment is well documented in type 2 diabetes mellitus (T2DM) but, to date, the neural substrates remain unclear. The present study evaluated verbal memory and ascertained the degree of frontal and temporal lobe involvement in the anticipated verbal memory impairment among adults with T2DM. Method: Forty-six late-middle-aged and elderly adults with T2DM and 50 age-, sex-, and education-matched adults without T2DM underwent medical evaluation, verbal memory assessment, and brain magnetic resonance imaging (MRI) evaluations. Results: As anticipated, participants with T2DM had clear verbal memory impairments. Consistent with prior reports, we found volume reductions restricted to the hippocampus. Our diffusion tensor imaging analysis revealed that participants with T2DM had extensive cerebral gray and white matter microstructural abnormalities predominantly in the left hemisphere, with a larger concentration present in the temporal lobe. In contrast, we uncovered mostly nonspecific microstructural abnormalities in the absence of tissue loss in the frontal lobe. Of great importance, we present the first evidence among participants with T2DM linking verbal memory impairment and compromised microstructural integrity of the left parahippocampal gyrus, a key memory-relevant structure. Conclusions: Our results suggest that the hippocampus and parahippocampal gyrus may be particularly vulnerable to the deleterious effects of T2DM. The parahippocampal gyrus in particular may play a crucial role in the verbal memory impairments frequently reported in T2DM. Future studies should employ methods such as resting state functional magnetic resonance imaging and diffusion tensor imaging tractography to better characterize network connectivity, which may help further characterize the verbal memory impairment frequently reported in T2DM.     

Auditory processing of sine tones before,during and after ECT in depressed patients by fMRI

Our goal was to assess treatment effects of electroconvulsive therapy (ECT) on acoustic processing in major depression. We hypothesized that (1) depression is related to functional alterations in auditory networks, and that (2) pre-treatment alterations in auditory networks are reversible through treatment with ECT. Acoustic perception of 20 severely depressed and 20 age and gender matched healthy controls was investigated by 3 T functional magnetic resonance imaging employing repeated stimulation by sine tones. Prior to ECT, depressed patients presented a multimodal recruitment of additional brain areas including regions of the secondary visual system (cuneus, lingualis) and the medial frontal cortex. During ECT, signal intensities were reduced compared to pre-ECT values and controls. Activation of several regions increased after ECT. Our data suggest that depression is accompanied by cortical dysfunction including impaired auditory processing of non-speech stimuli. This might be based on overall alterations of brain metabolism indicating functional impairment.     

Comparing the effects of auditory deprivation and sign language within the auditory and visual cortex

To investigate neural plasticity resulting from early auditory deprivation and use of American Sign Language, we measured responses to visual stimuli in deaf signers, hearing signers, and hearing nonsigners using functional magnetic resonance imaging. We examined "compensatory hypertrophy" (changes in the responsivity/size of visual cortical areas) and "cross-modal plasticity" (changes in auditory cortex responses to visual stimuli). We measured the volume of early visual areas (V1, V2, V3, V4, and MT+). We also measured the amplitude of responses within these areas, and within the auditory cortex, to a peripheral visual motion stimulus that was attended or ignored. We found no major differences between deaf and hearing subjects in the size or responsivity of early visual areas. In contrast, within the auditory cortex, motion stimuli evoked significant responses in deaf subjects, but not in hearing subjects, in a region of the right auditory cortex corresponding to Brodmann's areas 41, 42, and 22. This hemispheric selectivity may be due to a predisposition for the right auditory cortex to process motion; earlier studies report a right hemisphere bias for auditory motion in hearing subjects. Visual responses within the auditory cortex of deaf subjects were stronger for attended than ignored stimuli, suggesting top-down processes. Hearing signers did not show visual responses in the auditory cortex, indicating that cross-modal plasticity can be attributed to auditory deprivation rather than sign language experience. The largest effects of auditory deprivation occurred within the auditory cortex rather than the visual cortex, suggesting that the absence of normal input is necessary for large-scale cortical reorganization to occur.     

Using real-time fMRI neurofeedback to restore right occipital cortex activity in patients with left visuo-spatial neglect: proof-of-principle and preliminary results

Hemineglect is common after right parietal stroke, characterised by impaired awareness for stimuli in left visual space, with suppressed neural activity in the right visual cortex due to losses in top-down attention signals. Here we sought to assess whether hemineglect patients are able to up-regulate their right visual cortex activity using auditory real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback. We also examined any effect of this training procedure on neglect severity. Two different neurofeedback methods were used. A first group of six patients was trained to up-regulate their right visual cortex activity and a second group of three patients was trained to control interhemispheric balance between their right and left visual cortices. Over three sessions, we found that the first group successfully learned to control visual cortex activity and showed mild reduction in neglect severity, whereas the second group failed to control the feedback and showed no benefit. Whole brain analysis further indicated that successful up-regulation was associated with a recruitment of bilateral fronto-parietal areas. These findings provide a proof of concept that rt-fMRI neurofeedback may offer a new approach to the rehabilitation of hemineglect symptoms, but further studies are needed to identify effective regulation protocols and determine any reliable impact on clinical symptoms.     

Dissociating explicit and implicit category knowledge with fMRI

Neuroimaging of healthy volunteers identified separate neural systems supporting the expression of category knowledge depending on whether the learning mode was intentional or incidental. The same visual category was learned either intentionally or implicitly by two separate groupsof participants. During a categorization test, functional magnetic resonance imaging (fMRI) was used to compare brain activity evoked by category members and nonmembers. After implicit learning, when participants had learned the category incidentally, decreased occipital activity was observed for novel categorical stimuli compared with noncategorical stimuli. In contrast, after intentional learning, novel categorical stimuli evoked increased activity in the hippocampus, right prefrontal cortex, left inferior temporal cortex, precuneus, and posterior cingulate. Even though the categorization test was identical in the two conditions, the differences in brain activity indicate differing representations of category knowledge depending on whether the category had been learned intentionally or implicitly.     

Deactivation of sensory-specific cortex by cross-modal stimuli

Visual and auditory cortices traditionally have been considered to be "modality-specific." Thus, their activity has been thought to be unchanged by information in other sensory modalities. However, using functional magnetic resonance imaging (fMRI), the present experiments revealed that ongoing activity in the visual cortex could be modulated by auditory information and ongoing activity in the auditory cortex could be modulated by visual information. In both cases, this cross-modal modulation of activity took the form of deactivation. Yet, the deactivation response was not evident in either cortical area during the paired presentation of visual and auditory stimuli. These data suggest that cross-modal inhibitory processes operate within traditional modality-specific cortices and that these processes can be switched on or off in different circumstances.     

Processing of food stimuli is selectively enhanced during insulin-induced hypoglycemia in healthy men

Recently it has been reported that during insulin-induced hypoglycemia selective attention is directed to food stimuli suggesting an adaptive cognitive strategy to escape from this potentially dangerous metabolic state. Here, we tested this hypothesis using a short-term memory task. We also aimed to define a hypoglycemic threshold level at which such an adaptive cognitive strategy first occurs. Fifteen healthy men underwent stepwise hypoglycemic (plasma glucose: 4.1-3.6-3.1-2.6 mmol/l) and euglycemic clamp experiments. Clamps were performed in a single blind fashion within a cross-over design with the order balanced across subjects. During the clamps cognitive function tests (short-term recall of food-related and non-food-related words; Stroop task) were applied at baseline and each hypoglycemic plateau, and at the corresponding time intervals of the euglycemic clamp. Performance on all cognitive function tests applied deteriorated during the hypoglycemic as compared to the euglcemic clamp (all P<0.02). Separate analyses at each hypoglycemic plateau revealed that food and non-food related short-term memory was similar during baseline and mild hypoglycemia. However, at the hypoglycemic target level of 2.6 mmol/l recall of food related words was higher than non-food related words when compared to the euglycemic control clamp condition (p=0.024). Performance on the word-color conflict Stroop task became significantly impaired first at the lowest hypoglycemic plateau (2.6 mmol/l), while performance on the Stroop subtests 'color naming' and 'word reading' were already impaired at higher plasma glucose levels (3.6 and 3.1 mmol/l; respectively). Collectively, data of the Stroop task indicate that the control of attention via executive mechanisms is less sensitive to insulin-induced hypoglycemia than pre-attentive automated stimulus processing (reading, naming). If executive control of attention becomes affected by hypoglycemia, cognitive resources appear to be preferentially allocated to the processing of food stimuli.     

Bilateral basal ganglia lesions after hypoglycemic coma in a 6-year-old child

Imaging findings of brain damage due to neonatal hypoglycemia are known; however, the effect of childhood hypoglycemia on the brain has not been described well. The authors present the case of a 6-year-old girl who had seizures secondary to hypoglycemia followed up for 1 year as epilepsy. The patient had experienced a hypoglycemic coma attack about 1 year before. Brain magnetic resonance imaging showed atrophy of the cerebrum and cerebellum and bilateral symmetrically hyperintense lesions in the putamina. The patient was diagnosed with hypoglycemia due to hyperinsulinism.     

Sensory mapping in a congenitally deaf subject: MEG and fRMI studies of cross-modal non-plasticity

It has been proposed that the auditory cortex of deaf subjects may provide an example of cross-modal compensatory plasticity. We investigated whether sensory stimulation could elicit responses from auditory areas of a congenitally deaf subject. Neuromagnetic fields were recorded using a 37-channel biomagnetometer under conditions of: 1) visual stimulation; 2) somatosensory stimulation; and 3) a simple motor task. Visual items were reversing checkerboards and single light spots, presented in various portions of the visual field; somatosensory stimuli were pneumatic taps delivered to individual digit-segments and the lip; the motor task was self-paced finger tapping. In addition, functional magnetic resonance imaging was used to observe the activation elicited by full-field checkerboard and sign language stimuli. No responses to passively presented visual or somatosensory stimuli were observed in the auditory cortex. In contrast, somatosensory, motor, and visual cortices revealed evoked magnetic responses comparable to those from control subjects, indicating canonical anatomic and physiological organization in these areas. These data suggest that primary projection areas do not reveal obvious plastic effects. We suggest that in the human auditory cortex compensatory plasticity emerges primarily as a property of non-primary areas and is best observed under attentionally demanding conditions. Hum. Brain Mapping 5:437–444, 1997. © 1997 Wiley-Liss, Inc.     

Increasing cortical activity in auditory areas through neurofeedback functional magnetic resonance imaging

We report a functional magnetic resonance imaging method to deliver task-specific brain activities as biofeedback signals to guide individuals to increase cortical activity in auditory areas during sound stimulation. A total of 11 study participants underwent multiple functional magnetic resonance imaging scan sessions, while the changes in the activated cortical volume within the primary and secondary auditory areas were fed back to them between scan sessions. On the basis of the feedback information, participants attempted to increase the number of significant voxels during the subsequent trial sessions by adjusting their level of attention to the auditory stimuli. Results showed that the group of individuals who received the feedback were able to increase the activation volume and blood oxygenation level-dependent signal to a greater degree than the control group.     

Neural correlates of auditory repetition priming: reduced fMRI activation in the auditory cortex

Repetition priming refers to enhanced or biased performance with repeatedly presented stimuli. Modality-specific perceptual repetition priming has been demonstrated behaviorally for both visually and auditorily presented stimuli. In functional neuroimaging studies, repetition of visual stimuli has resulted in reduced activation in the visual cortex, as well as in multimodal frontal and temporal regions. The reductions in sensory cortices are thought to reflect plasticity in modality-specific neocortex. Unexpectedly, repetition of auditory stimuli has resulted in reduced activation in multimodal and visual regions, but not in the auditory temporal lobe cortex. This finding puts the coupling of perceptual priming and modality-specific cortical plasticity into question. Here, functional magnetic resonance imaging was used with environmental sounds to reexamine whether auditory priming is associated with reduced activation in the auditory cortex. Participants heard environmental sounds (e.g., animals, machines, musical instruments, etc.) in blocks, alternating between initial and repeated presentations, and decided whether or not each sound was produced by an animal. Repeated versus initial presentations of sounds resulted in repetition priming (faster responses) and reduced activation in the right superior temporal gyrus, bilateral superior temporal sulci, and right inferior prefrontal cortex. The magnitude of behavioral priming correlated positively with reduced activation in these regions. This indicates that priming for environmental sounds is associated with modification of neural activation in modality-specific auditory cortex, as well as in multimodal areas.     

Primary and multisensory cortical activity is correlated with audiovisual percepts

Incongruent auditory and visual stimuli can elicit audiovisual illusions such as the McGurk effect where visual /ka/ and auditory /pa/ fuse into another percept such as/ta/. In the present study, human brain activity was measured with adaptation functional magnetic resonance imaging to investigate which brain areas support such audiovisual illusions. Subjects viewed trains of four movies beginning with three congruent /pa/ stimuli to induce adaptation. The fourth stimulus could be (i) another congruent /pa/, (ii) a congruent /ka/, (iii) an incongruent stimulus that evokes the McGurk effect in susceptible individuals (lips /ka/ voice /pa/), or (iv) the converse combination that does not cause the McGurk effect (lips /pa/ voice/ ka/). This paradigm was predicted to show increased release from adaptation (i.e. stronger brain activation) when the fourth movie and the related percept was increasingly different from the three previous movies. A stimulus change in either the auditory or the visual stimulus from /pa/ to /ka/ (iii, iv) produced within‐modality and cross‐modal responses in primary auditory and visual areas. A greater release from adaptation was observed for incongruent non‐McGurk (iv) compared to incongruent McGurk (iii) trials. A network including the primary auditory and visual cortices, nonprimary auditory cortex, and several multisensory areas (superior temporal sulcus, intraparietal sulcus, insula, and pre‐central cortex) showed a correlation between perceiving the McGurk effect and the fMRI signal, suggesting that these areas support the audiovisual illusion. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Cerebral response to 'voiceness': a functional magnetic resonance imaging study

We evaluated the response of the voice-selective areas of the auditory cortex to sound 'voiceness', that is, the degree to which an auditory stimulus resembles human voice. Normal participants were scanned using event-related functional magnetic resonance imaging while passively listening to stimuli drawn from a 'voiceness' continuum generated via auditory morphing between sounds of voice and sounds of musical instruments. The voice-selective areas of the left and right superior temporal sulcus did not show the expected relation between 'voiceness' and size effect. Instead, superior temporal sulcus activity seemed mostly driven by sound naturalness, with largest activity differences observed for the intermediate, voice-instrument hybrid stimuli.     

Task-irrelevant visual letters interact with the processing of speech sounds in heteromodal and unimodal cortex

Letters and speech sounds are the basic units of correspondence between spoken and written language. Associating auditory information of speech sounds with visual information of letters is critical for learning to read; however, the neural mechanisms underlying this association remain poorly understood. The present functional magnetic resonance imaging study investigates the automaticity and behavioral relevance of integrating letters and speech sounds. Within a unimodal auditory identification task, speech sounds were presented in isolation (unimodally) or bimodally in congruent and incongruent combinations with visual letters. Furthermore, the quality of the visual letters was manipulated parametrically. Our analyses revealed that the presentation of congruent visual letters led to a behavioral improvement in identifying speech sounds, which was paralleled by a similar modulation of cortical responses in the left superior temporal sulcus. Under low visual noise, cortical responses in superior temporal and occipito-temporal cortex were further modulated by the congruency between auditory and visual stimuli. These cross-modal modulations of performance and cortical responses during an unimodal auditory task (speech identification) indicate the existence of a strong and automatic functional coupling between processing of letters (orthography) and speech (phonology) in the literate adult brain.     

Cortical depth profiles of auditory and visual 7 T functional MRI responses in human superior temporal areas

Invasive neurophysiological studies in nonhuman primates have shown different laminar activation profiles to auditory vs. visual stimuli in auditory cortices and adjacent polymodal areas. Means to examine the underlying feedforward vs. feedback type influences noninvasively have been limited in humans. Here, using 1‐mm isotropic resolution 3D echo‐planar imaging at 7 T, we studied the intracortical depth profiles of functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) signals to brief auditory (noise bursts) and visual (checkerboard) stimuli. BOLD percent‐signal‐changes were estimated at 11 equally spaced intracortical depths, within regions‐of‐interest encompassing auditory (Heschl''s gyrus, Heschl''s sulcus, planum temporale, and posterior superior temporal gyrus) and polymodal (middle and posterior superior temporal sulcus) areas. Effects of differing BOLD signal strengths for auditory and visual stimuli were controlled via normalization and statistical modeling. The BOLD depth profile shapes, modeled with quadratic regression, were significantly different for auditory vs. visual stimuli in auditory cortices, but not in polymodal areas. The different depth profiles could reflect sensory‐specific feedforward versus cross‐sensory feedback influences, previously shown in laminar recordings in nonhuman primates. The results suggest that intracortical BOLD profiles can help distinguish between feedforward and feedback type influences in the human brain. Further experimental studies are still needed to clarify how underlying signal strength influences BOLD depth profiles under different stimulus conditions.