Unmasking Latent Inhibitory Connections in Human Cortex to Reveal Dormant Cortical Memories.

Balance of cortical excitation and inhibition (EI) is thought to be disrupted in several neuropsychiatric conditions, yet it is not clear how it is maintained in the healthy human brain. When EI balance is disturbed during learning and memory in animal models, it can be restabilized via formation of inhibitory replicas of newly formed excitatory connections. Here we assess evidence for such selective inhibitory rebalancing in humans. Using fMRI repetition suppression we measure newly formed cortical associations in the human brain. We show that expression of these associations reduces over time despite persistence in behavior, consistent with inhibitory rebalancing. To test this, we modulated excitation/inhibition balance with transcranial direct current stimulation (tDCS). Using ultra-high-field (7T) MRI and spectroscopy, we show that reducing GABA allows cortical associations to be re-expressed. This suggests that in humans associative memories are stored in balanced excitatory-inhibitory ensembles that lie dormant unless latent inhibitory connections are unmasked.

Multi-center reproducibility of neurochemical profiles in the human brain at 7 T.

The purpose of this work was to harmonize data acquisition and post-processing of single voxel proton MRS ((1) H-MRS) at 7 T, and to determine metabolite concentrations and the accuracy and reproducibility of metabolite levels in the adult human brain. This study was performed in compliance with local institutional human ethics committees. The same seven subjects were each examined twice using four different 7 T MR systems from two different vendors using an identical semi-localization by adiabatic selective refocusing spectroscopy sequence. Neurochemical profiles were obtained from the posterior cingulate cortex (gray matter, GM) and the corona radiata (white matter, WM). Spectra were analyzed with LCModel, and sources of variation in concentrations ('subject', 'institute' and 'random') were identified with a variance component analysis. Concentrations of 10-11 metabolites, which were corrected for T1 , T2 , magnetization transfer effects and partial volume effects, were obtained with mean Cramér-Rao lower bounds below 20%. Data variances and mean concentrations in GM and WM were comparable for all institutions. The primary source of variance for glutamate, myo-inositol, scyllo-inositol, total creatine and total choline was between subjects. Variance sources for all other metabolites were associated with within-subject and system noise, except for total N-acetylaspartate, glutamine and glutathione, which were related to differences in signal-to-noise ratio and in shimming performance between vendors. After multi-center harmonization of acquisition and post-processing protocols, metabolite concentrations and the sizes and sources of their variations were established for neurochemical profiles in the healthy brain at 7 T, which can be used as guidance in future studies quantifying metabolite and neurotransmitter concentrations with (1) H-MRS at ultra-high magnetic field.

Initial experience with seven tesla magnetic resonance spectroscopy of hypothalamic GABA during hyperinsulinemic euglycemia and hypoglycemia in healthy humans.

PURPOSE: Hypothalamic GABA signaling has been shown to regulate the hormonal response to hypoglycemia in animals. The hypothalamus is a challenging brain region for magnetic resonance spectroscopy (MRS) due to its small size and central location. To investigate the feasibility of measuring GABA in the hypothalamus in humans, ultra-high field MRS was used. METHODS: GABA levels in the hypothalamus and occipital cortex (control region) were measured in healthy volunteers during euglycemia and hypoglycemia at 7 tesla using short-echo STEAM (TE = 8 ms, TR = 5 s). RESULTS: Hypothalamic GABA levels were quantified with a mean within-session test-retest coefficient of variance of 9%. Relatively high GABA levels were observed in the hypothalamus compared with other brain regions. Hypothalamic GABA levels were 3.5 ± 0.3 µmol/g during euglycemia (glucose 89 ± 6 mg/dL) vs. 3.0 ± 0.4 µmol/g during hypoglycemia (glucose 61 ± 3 mg/dL) (P = 0.06, N = 7). In the occipital cortex, GABA levels remained constant at 1.4 ± 0.4 vs.1.4 ± 0.3 µmol/g (P = 0.3, N = 5) as glucose fell from 91 ± 4 to 61 ± 4 mg/dL. CONCLUSION: GABA concentration can be quantified in the human hypothalamus and shows a trend toward decrease in response to an acute fall in blood glucose. These methods can be used to further investigate role of GABA signaling in the counterregulatory response to hypoglycemia in humans.

Multimodal investigation of fMRI and fNIRS derived breath hold BOLD signals with an expanded balloon model.

Multimodal investigation of blood oxygenation level-dependent (BOLD) signals, using both functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI), may give further insight to the underlying physiological principles and the detailed transient dynamics of the vascular response. Utilizing a breath hold task (BHT), we measured deoxy-hemoglobin (HbR) and oxy-hemoglobin (HbO) changes via fNIRS and blood oxygen level dependent (BOLD) changes by fMRI. Measurements were taken in four volunteers asynchronously and carefully aligned for comparative analysis. In order to describe the main stimulus in BHT, partial pressure of carbon dioxide (PaCO(2)) parameter was integrated into the balloon model as the driving function of cerebral blood flow (CBF) which led to the development of an expanded balloon model (EBM). During BHT, the increase in HbR was observed later than the BOLD peak and coincided temporally with its post-stimulus undershoot. Further investigation of these transients with a PaCO(2) integrated balloon model suggests that post-stimulus undershoot measured by fMRI is dominated by slow return of cerebral blood volume (CBV). This was confirmed by fNIRS measurements. In addition, the BOLD signal decreased with the increase of the initial level of PaCO(2) derived from EBM, indicating an effect of basal CBF level on the BOLD signal. In conclusion, a multimodal approach with an appropriate biophysical model gave a comprehensive description of the hemodynamic response during BHT.