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Magnetic Resonance Imaging. Fig. 2. Schematic representation of the relationship between neuronal activity and the hemodynamic response function. fMRI allows to assess various processes involved such as changes in CBF, CBV, and changes in BOLD contrast. (Adapted from Martin and Sibson 2008.)

important to note that an intact neurovascular coupling is essential for the reliability of functional MRI signals.

To elucidate the complex mechanism of neurovascular coupling, further fMRI methods have been developed directly assessing the vascular response to neuronal activation such as CBF and CBV changes. Recently, MR arterial spin labeling (ASL) techniques have been described to measure regional CBF. For this purpose, the arterial blood flowing into the brain is magnetically labeled at the level of the common carotid artery. In this way, arterial blood can be used as endogenous contrast agent. Regional CBF values can be estimated from the difference of the MR signal intensities before and during labeling of the inflowing arterial spins taking the finite lifetime of the magnetically labeled state into consideration. ASL is independent of contrast agent administration and allows therefore continuous CBF monitoring. As CBF changes are supposed to be proportional to neuronal activity, ASL presents itself an attractive method for providing a more direct readout of neuronal activity than BOLD and CBV measurements, which are highly nonlinear. Furthermore, CBF measurements are less susceptible to magnetic field variations than BOLD fMRI based on fast-gradient echo sequences.

For the assessment of local CBV values, MRI methods have been developed using exogenous contrast agents with a long plasma half-life such as iron oxide nanoparticles leading to an increase in the R2 and R2* relaxation rates. A few minutes after intravenous administration of the contrast agent, a steady-state concentration is reached. The relative change in local relaxation rates R2 and R2*

is proportional to the amount of contrast agent in the tissue and thus proportional to the local CBV. Subsequently, neuronal activity prompting local CBV changes can be detected by measuring relative changes in local relaxation rates R2*. As oxygen extraction decreases for increasing flow rates and the ► BOLD Contrast decreases at lower magnetic field strength, CBV measurements are more sensitive than fMRI based on the BOLD contrast.

Stimulation Paradigms

A key component of fMRI experiments is the ► Stimulation Paradigm applied to evoke brain activity. A variety of different stimuli ranging from no stimulation (restingstate fMRI) over thermal, sensory, mechanical, visual, or auditory to pharmacological stimuli have been used during fMRI studies. The rationale behind resting state fMRI is to investigate activation differences between a healthy control group and patients suffering, e.g., from schizophrenia (Pearlson and Calhoun 2007) as these experiments do not rely on the ability of the patient to perform certain tasks. Aside from resting state fMRI, which analyzes spontaneous activity/hemodynamic changes in the brain, fMRI studies always rely on at least two measurements comparing state A (e.g., the resting state) with state B (e.g., during stimulus-induced activation). When designing fMRI studies, it is important to consider the dynamics of the hemodynamic response to neuronal activity, which determines the time resolution that can be achieved in the experiment.

In ► Pharmacological fMRI (► phMRI), the functional response to ligand-induced receptor stimulation or inhibition after drug administration is assessed throughout the brain using the above-described fMRI methods. Consequently, phMRI, like all fMRI methods, relies on intact neurovascular coupling and assesses the functional response induced by drug administration. In humans, phMRI involves BOLD signal acquisition before, during, and after the administration of a drug, while in animals CBF and CBV measurements are also widely established. phMRI studies in the rat measuring BOLD or CBV changes confirmed sufficient sensitivity to detect dose-dependent effects of systemically administered receptor ligands. Assessment of alterations in magnitude and spatial extend of neuronal activity induced by pharmacological targeting has been successfully demonstrated for various neurotransmitter systems such as the dopami-nergic, ► opioid, ► GABAergic, glutamatergic, or canna-binoid system. Figure 3 shows an example of phMRI in the mouse. Acute administration of the GABAA receptor antagonist bicuculline led to region-specific CBV changes. The impact and potential of phMRI in the area of psychopharmacology will be discussed in the following for the example of mood and anxiety disorders. Investigations using in vivo neuroimaging techniques within the field of major (clinical) depression and anxiety disorders are largely dominated by measuring serotonergic (5-hydroxytryptamine; 5-HT) neurotransmission and receptor level and their response to medication treatment as alterations in serotonin neurotransmitter system have been clearly implicated in the pathophysiology of these two ► neuropsychiatric disorders. Based on the availability of radiolabeled 5-HT receptor ligands, distinct ► serotonin receptor populations have been imaged using positron emission tomography (PET) and single positron emission tomography (SPECT). On the other hand, the nature of serotonergic neurocircuitries can be investigated using phMRI by modifying endogenous neuro-transmitter levels or manipulating their receptor activity by specific ligands. Most phMRI studies investigated the 5-HT2C receptor system as one of the main targets for novel anxiolytic drugs. Among the different ligands used, meta-chlorophenylpiperazine (m-CPP), a mixed 5-HT1B/2C receptor agonist, has been advanced as a useful pharmacological substance for fMRI studies of regional activation in rats and in human beings. Furthermore, the acute and chronic effect of SSRI on region-specific neuronal activation measured by BOLD-fMRI in human beings has been examined using citalopram or in the rats using

► fluoxetine. The literature on phMRI investigating specifically the 5-HT1A receptor is rather sparse, but represents an attractive field of research given that 5-HT1A autoreceptor desensitization is one of the suggested mechanisms of action of chronic antidepressants (i.e.,

► selective serotonin re-uptake inhibitors, SSRIs) and might be responsible for the delayed onset of antidepres-sants under clinical conditions. Using CBV-fMRI, decreased activity across several brain areas of the rats was mapped with the strongest effects in ► hippocampus and septum after acute administration of the 5-HT1A receptor agonist 8-OH-DPAT.

Data Analysis and Interpretation

The analysis of fMRI data turns out to be especially challenging because of the complex relationship between the physiological processes involved (Fig. 2) and,

Magnetic Resonance Imaging. Fig. 3. Example of phMRI in the mouse. CBV changes in the mouse brain during infusion of the GABAa receptor antagonist bicuculline. (a) Percentage DCBV activity maps of brain section +0.74 mm relative to the Bregma showing the highest activity in cortical areas. (b) Temporal profile for three different ROIs (see brain atlas inlet: green=cortex, blue=striatum, orange = control ROI) highlighting the region specificity of the induced CBV changes.

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