Jakob Udby Blicher

Baseline GABA concentration and fMRI response

Coordination between glutamatergic excitatory neurons and gamma-aminobutyric acid (GABA)-ergic inhibitory interneurons is fundamental to the regulation of neuronal firing rates and is believed to have relevance to functional magnetic resonance imaging (fMRI) contrast. While much is known regarding the molecular behavior of excitatory and inhibitory processes, comparatively less is known regarding the role of such processes in explaining variations in fMRI and related hemodynamic imaging metrics. The relationship between baseline GABA levels, as measured by MR spectroscopy, and hemodynamic contrasts from four sequences in human visual cortex are investigated (n=12; field strength=3.0 T): blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF)-weighted arterial spin labelling (ASL), cerebral blood volume (CBV)-weighted vascular-space-occupancy (VASO), and arterial CBV (aCBV)-weighted inflow VASO (iVASO). Results indicate that baseline GABA levels (GABA+ macromolecules normalized to creatine) inversely correlate with BOLD reactivity (R=-0.70; P=0.01) and magnitude CBV-weighted VASO reactivity (R=-0.71; P=0.01). A trend for significance was found between baseline aCBV-weighted iVASO (R=-0.50; P=0.10) and baseline GABA. A positive correlation was found between baseline CBF-weighted ASL signal and GABA (R=0.65; P=0.02) and ASL time-to-peak and baseline GABA (R=0.58; P=0.05). These findings demonstrate that both the dominant BOLD fMRI contrast, as well as other emerging MR hemodynamic contrasts, have signal variations that are linked to baseline GABA levels.

The capillary dysfunction hypothesis of Alzheimer's disease

It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimers disease (AD). This is difficult to reconcile with the hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity.

The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke.

Cerebral Blood Flow, Blood Volume, and Oxygen Metabolism Dynamics in Human Visual and Motor Cortex as Measured by Whole-Brain Multi-Modal Magnetic Resonance Imaging

The development of neuroimaging methods to characterize flow-metabolism coupling is crucial for understanding mechanisms that subserve oxygen delivery. Functional magnetic resonance imaging (fMRI) using blood-oxygenation-level-dependent (BOLD) contrast reflects composite changes in cerebral blood volume (CBV), cerebral blood flow (CBF), and the cerebral metabolic rate of oxygen consumption (CMRO2). However, it is difficult to separate these parameters from the composite BOLD signal, thereby hampering MR-based flow-metabolism coupling studies. Here, a novel, noninvasive CBV-weighted MRI approach (VASO-FLAIR with 3D GRASE (GRadient-And-Spin-Echo)) is used in conjunction with CBF-weighted and BOLD fMRI in healthy volunteers (n=7) performing simultaneous visual (8 Hz flashing-checkerboard) and motor (1 Hz unilateral joystick) tasks. This approach allows for CBV, CBF, and CMRO2 to be estimated, yielding (mean±s.d.): ΔCBF=63%±12%, ΔCBV=17%±7%, and ΔCMRO2=13%±11% in the visual cortex, and ΔCBF=46%±11%, ΔCBV=8%±3%, and ΔCMRO2=12%±13% in the motor cortex. Following the visual and motor tasks, the BOLD signal became more negative (P=0.003) and persisted longer (P=0.006) in the visual cortex compared with the motor cortex, whereas CBV and CBF returned to baseline earlier and equivalently. The proposed whole-brain technique should be useful for assessing regional discrepancies in hemodynamic reactivity without the use of intravascular contrast agents.

The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage.

The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.

Cortical excitability in chronic stroke and modulation by training: a TMS study.

Background. A possible role for GABA in regulating cortical plasticity after stroke has been proposed. Objective. To investigate changes in intracortical inhibitory and facilitatory circuits in the affected hemisphere more than 6 months after stroke, as well as modulation of excitability by a single training session. Methods. A total of 22 patients >6 months after stroke were compared to age- and gender-matched healthy participants. Cortical excitability was assessed by transcranial magnetic stimulation (TMS), including paired-pulse stimulation, before and up to 30 minutes after a single 15-minute session of 1 Hz thumb abduction-adduction movements. Results. At baseline, TMS showed decreased intracortical inhibition in the affected hemisphere of patients (P = .004) compared to healthy participants. After training a short-lasting decline in motor evoked potentials was observed in both patients (P = .002) and healthy participants (P = .06). Moreover, in healthy participants, inhibitory activity decreased up to 30 minutes after training whereas no significant change was seen in the patients. Conclusions. The findings indicate that inhibitory intracortical circuits are less active after stroke, and no change in inhibitory activity is evident after a single training session. This may indicate that intracortical disinhibition is beneficial during recovery and that an impaired capacity for modulation remains in the chronic stage of stroke.

Continuous Theta-Burst Stimulation Demonstrates a Causal Role of Premotor Homunculus in Action Understanding

Although it is well established that regions of premotor cortex (PMC) are active during action observation, it remains controversial whether they play a causal role in action understanding. In the experiment reported here, we used off-line continuous theta-burst stimulation (cTBS) to investigate this question. Participants received cTBS over the hand and lip areas of left PMC, in separate sessions, before completing a pantomime-recognition task in which half of the trials contained pantomimed hand actions, and half contained pantomimed mouth actions. The results reveal a double dissociation: Participants were less accurate in recognizing pantomimed hand actions after receiving cTBS over the hand area than over the lip area and less accurate in recognizing pantomimed mouth actions after receiving cTBS over the lip area than over the hand area. This finding constrains theories of action understanding by showing that somatotopically organized regions of PMC contribute causally to action understanding and, thus, that the mechanisms underpinning action understanding and action performance overlap.

Capillary Transit Time Heterogeneity and Flow-Metabolism Coupling after Traumatic Brain Injury

Most patients who die after traumatic brain injury (TBI) show evidence of ischemic brain damage. Nevertheless, it has proven difficult to demonstrate cerebral ischemia in TBI patients. After TBI, both global and localized changes in cerebral blood flow (CBF) are observed, depending on the extent of diffuse brain swelling and the size and location of contusions and hematoma. These changes vary considerably over time, with most TBI patients showing reduced CBF during the first 12hours after injury, then hyperperfusion, and in some patients vasospasms before CBF eventually normalizes. This apparent neurovascular uncoupling has been ascribed to mitochondrial dysfunction, hindered oxygen diffusion into tissue, or microthrombosis. Capillary compression by astrocytic endfeet swelling is observed in biopsies acquired from TBI patients. In animal models, elevated intracranial pressure compresses capillaries, causing redistribution of capillary flows into patterns argued to cause functional shunting of oxygenated blood through the capillary bed. We used a biophysical model of oxygen transport in tissue to examine how capillary flow disturbances may contribute to the profound changes in CBF after TBI. The analysis suggests that elevated capillary transit time heterogeneity can cause critical reductions in oxygen availability in the absence of ‘classic’ ischemia. We discuss diagnostic and therapeutic consequences of these predictions.

GABA Levels Are Decreased After Stroke and GABA Changes During Rehabilitation Correlate With Motor Improvement

Background and Objective. γ-Aminobutyric acid (GABA) is the dominant inhibitory neurotransmitter in the brain and is important in motor learning. We aimed to measure GABA content in primary motor cortex poststroke (using GABA-edited magnetic resonance spectroscopy [MRS]) and in relation to motor recovery during 2 weeks of constraint-induced movement therapy (CIMT). Methods. Twenty-one patients (3-12 months poststroke) and 20 healthy subjects were recruited. Magnetic resonance imaging structural T1 and GABA-edited MRS were performed at baseline and after CIMT, and once in healthy subjects. GABA:creatine (GABA:Cr) ratio was measured by GABA-edited MRS. Motor function was measured using Wolf Motor Function Test (WMFT). Results. Baseline comparison between stroke patients (n = 19) and healthy subjects showed a significantly lower GABA:Cr ratio in stroke patients (P < .001) even after correcting for gray matter content in the voxel (P < .01) and when expressing GABA relative to N-acetylaspartic acid (NAA; P = .03). After 2 weeks of CIMT patients improved significantly on WMFT, but no consistent change across the group was observed for the GABA:Cr ratio (n = 17). However, the extent of improvement on WMFT correlated significantly with the magnitude of GABA:Cr changes (P < .01), with decreases in GABA:Cr ratio being associated with better improvements in motor function. Conclusions. In patients 3 to 12 months poststroke, GABA levels are lower in the primary motor cortex than in healthy subjects. The observed association between GABA and recovery warrants further studies on the potential use of GABA MRS as a biomarker in poststroke recovery.

Long-term reproducibility of GABA magnetic resonance spectroscopy

Recent findings suggest that cortical gamma aminobutyric acid (GABA) levels may provide a surrogate marker for a number of psychiatric and neurological conditions, as well as behavioural traits. However, the natural variability of GABA levels in the human brain over long periods of time (>8 days) has not yet been studied. The purpose of this work was to investigate the long-term variability of GABA concentrations in the human occipital cortex. Nineteen healthy male participants were recruited and underwent two sessions of magnetic resonance spectroscopy (MRS) to determine occipital GABA levels with an average between-session interval of 7 months. We assessed between-session variability, as well as the correlation between session 1 and session 2 GABA measurements. The mean coefficient of variation between sessions was 4.3% (bootstrap 95% confidence interval: 2.5, 6.4), which is comparable to reported GABA variability measurements over much shorter time intervals (<8 days). A significant positive correlation was observed between session 1 and session 2 GABA measurements (r=0.53, p=0.014), and the intra-class correlation coefficient was calculated to be 0.52 which was also statistically significant (p=0.012). These findings establish experimentally that GABA concentrations in the occipital cortex, as measured by MRS, are relatively stable over periods as long as 7 months. The findings have significant implications for the internal validity of longitudinal studies of GABA levels in the human brain, and they lend foundational support to studies relating GABA levels to behavioural traits in healthy individuals.