Specific structuro-metabolic pattern of thalamic subnuclei in fatal familial insomnia: A PET/MRI imaging study.

BACKGROUND: Dysfunction of the thalamus has been proposed as a core mechanism of fatal familial insomnia. However, detailed metabolic and structural alterations in thalamic subnuclei are not well documented. We aimed to address the multimodal structuro-metabolic pattern at the level of the thalamic nuclei in fatal familial insomnia patients, and investigated the clinical presentation of primary thalamic alterations. MATERIALS AND METHODS: Five fatal familial insomnia patients and 10 healthy controls were enrolled in this study. All participants underwent neuropsychological assessments, polysomnography, electroencephalogram, and cerebrospinal fluid tests. MRI and fluorodeoxyglucose PET were acquired on a hybrid PET/MRI system. Structural and metabolic changes were compared using voxel-based morphometry analyses and standardized uptake value ratio analyses, focusing on thalamic subnuclei region of interest analyses. Correlation analysis was conducted between gray matter volume and metabolic decrease ratios, and clinical features. RESULTS: The whole-brain analysis showed that gray matter volume decline was confined to the bilateral thalamus and right middle temporal pole in fatal familial insomnia patients, whereas hypometabolism was observed in the bilateral thalamus, basal ganglia, and widespread cortices, mainly in the forebrain. In the regions of interest analysis, gray matter volume and metabolism decreases were prominent in bilateral medial dorsal nuclei, anterior nuclei, and the pulvinar, which is consistent with neuropathological and clinical findings. A positive correlation was found between gray matter volume and metabolic decrease ratios. CONCLUSIONS: Our study revealed specific structuro-metabolic pattern of fatal familial insomnia that demonstrated the essential roles of medial dorsal nuclei, anterior nuclei, and pulvinar, which may be a potential biomarker in diagnosis. Also, primary thalamic subnuclei alterations may be correlated with insomnia, neuropsychiatric, and autonomic symptoms sparing primary cortical involvement.

Imaging in vivo glutamate fluctuations with [(11)C]ABP688: a GLT-1 challenge with ceftriaxone.

Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [(11)C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [(11)C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BP(ND)) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [(11)C]ABP688 BP(ND) in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.

Design, construction, and validation of an MRI-compatible vibrotactile stimulator intended for clinical use.

Vibrotactile stimulation has been used successfully to activate the human somatosensory pathway in functional magnetic resonance imaging (fMRI) experiments. The design and characterization of these devices are of particular interest in frequency discrimination tasks and investigations of the somatopic organization of sensory areas. However, few have investigated the utility of vibrotactile stimulation in a clinical context. We have previously demonstrated that vibrotactile stimulation can provide robust activations in areas targeted in stereotactic functional neurosurgical procedures used for tumour resection (i.e.: primary and secondary somatosensory areas) and subcortical targets for thalamic pain and movement disorders (i.e.: sensory thalamus). The main contribution of this manuscript is the presentation of the design, materials, construction, and validation of a novel vibrotactile stimulator intended for clinical use. The thalamic activations are also compared to a digital atlas in order to evaluate anatomical localization. The proposed stimulator was constructed entirely from non-ferromagnetic parts, uses compressed air to deliver stimulation using computer control, and stimulates the entirety of the hand and fingers to ensure robust somatosensory activations. In addition, this stimulator is constructed entirely from "off-the-shelf" parts and would be easily replicated due to the simplicity of design and the relatively small expense of the parts required. The device was tested by stimulating the right hand of 10 normal controls (5 females, 5 males, all right handed; age range: 25-42 years, mean: 30.9 years, standard deviation: 5.2 years) during an fMRI experiment. The results demonstrate significant single subject activations of primary and secondary somatosensory cortices and of the sensory thalamus.

Robust S1, S2, and thalamic activations in individual subjects with vibrotactile stimulation at 1.5 and 3.0 T.

Functional magnetic resonance imaging (fMRI) is often used to enhance visualization and provide target localization during the planning phase of neurosurgical procedures. Although parametric maps have been used to identify areas of eloquent cortex such as the primary (S1) and secondary (S2) somatosensory areas for tumor surgery, to date, few fMRI methods exist to localize subcortical targets for surgical interventions used to treat movement disorders. The scanning time required to obtain statistically significant functional signals must be balanced against the possibility of movement artifacts and patient discomfort. We propose a vibrotactile stimulation technique to activate the somatosensory pathway for neurosurgical planning and perform a sensitivity analysis to determine the amount of time required to achieve significant activations of S1, S2, and sensory thalamus in individual subjects. Bilateral stimulation experiments were carried out on two MRI scanners (n = 13 at 1.5 T; n = 5 at 3.0 T). The analysis demonstrates that statistically significant functional activations can be achieved in clinically acceptable times: 16 min at 1.5 T (26/26 experiments) and 6 min at 3.0 T (10/10) for S1 activations; 24 min at 1.5 T (22/26) and 18 min at 3.0 T for S2 activations (9/10); and 32 min at 1.5 T (15/26) and 18 min at 3.0 T (10/10) for activation of thalamic nuclei. These results demonstrate that S1 and S2 activations are robust at 1.5 and 3.0 T, and that robust thalamic activations in individual subjects are possible at 3.0 T. These techniques demonstrate that this technique can be used for preoperative planning for surgical candidates.

MDMA-evoked changes in cerebral blood flow in living porcine brain: correlation with hyperthermia.

3,4-Methylenedioxymethamphetamine (MDMA) acutely releases intraneuronal dopamine and serotonin and evokes hyperthermia which is linked to toxicity for serotonin fibers. The acute effects of MDMA on cerebral blood flow (CBF) in living brain have not been described in an animal model of MDMA intoxication. We predicted that MDMA-induced hyperthermia should correlate with increased CBF in the hypothalamus, a serotonin-rich brain region subserving thermoregulation. To test this prediction, we used positron emission tomography with statistical parametric mapping for exploratory analysis of the focal changes in the magnitude of CBF in the anesthetized female Landrace pig (n = 9) at 30 and 150 min after acute challenge with MDMA-HCl (1 mg/kg, i.v.). The MDMA treatment was followed by increased CBF in the occipital cortex and in the medial mesencephalon overlapping the dorsal raphé nucleus, and reduced CBF in the cerebellar vermis and in a cluster in the medulla encompassing the left locus coeruleus. The individual increase of body temperature correlated positively with increased CBF in the vicinity of the raphé nucleus, in the hypothalamus (regions linked to thermoregulation), and also in the medial frontal cortex, which together comprise the regions receiving the most dense serotonin innervations in pig brain. Thus, individual differences in the susceptibility to MDMA-induced hyperthermia in this population correlated with the magnitude of focal increases in CBF within specific brain regions endowed with a dense serotonin innervation, including regions linked to thermoregulation.

Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression.

CONTEXT: The serotonin hypothesis of depression invokes a relative or absolute deficit of serotonin neurotransmission. Reduced synthesis of serotonin in the brain pathways mediating the expression of mood (ie, the limbic cortex) is a plausible candidate mechanism. OBJECTIVES: To measure and compare, using the alpha-[(11)C]methyl-l-tryptophan/positron emission tomography method, the brain trapping constant of alpha-[(11)C]methyl-l-tryptophan (K*, milliliters per gram per minute), an index of serotonin synthesis, in brain areas involved in the regulation of mood in patients with major depression (MD) and age- and sex-matched controls. DESIGN: Between-group comparison. SETTING: Department of Psychiatry and Montreal Neurological Institute, McGill University. PARTICIPANTS: Seventeen medication-free outpatients with a current episode of MD (9 women: mean +/- SD age, 41 +/- 11 years; 8 men: mean +/- SD age, 41 +/- 11 years) and 17 controls (9 women: mean +/- SD age, 37 +/- 15 years; 8 men: mean +/- SD age, 32.5 +/- 9.9 years). Main Outcome Measure Normalized K*, normalized to the global mean, was measured in the dorsolateral prefrontal, anterior cingulate, and mesial temporal cortices; the thalamus; and the caudate nucleus. RESULTS: Compared with age- and sex-matched controls, normalized K* was significantly decreased bilaterally in female patients with MD in the anterior cingulate cortex, in the left anterior cingulate cortex in male patients with MD, and in the left mesial temporal cortex in male and female patients with MD (P<.001 for all). Exploratory analyses identified additional patient-control differences for normalized K* (eg, inferior frontal gyrus and superior parietal lobule), most of which, once corrected for 38 multiple comparisons, lost their significance. Morphometric measurements of the cingulate cortex divisions confirmed that the reduction of normalized K* in depressed patients was not attributable to a reduction in gray matter volume. Normalized K* in the anterior cingulate cortex did not correlate with ratings of depression severity collected at the time of scan. CONCLUSIONS: Reduction of normalized K*, an index of serotonin synthesis, in parts of the limbic and paralimbic cortices may contribute to the biochemical alterations associated with MD.