Ketamine effects on brain function--simultaneous fMRI/EEG during a visual oddball task.

BACKGROUND: Behavioral and electrophysiological human ketamine models of schizophrenia are used for testing compounds that target the glutamatergic system. However, corresponding functional neuroimaging models are difficult to reconcile with functional imaging and electrophysiological findings in schizophrenia. Resolving the discrepancies between different observational levels is critical to understand the complex pharmacological ketamine action and its usefulness for modeling schizophrenia pathophysiology. METHODS: We conducted a within-subject, randomized, placebo-controlled pharmacoimaging study in twenty-four male volunteers. Subjects were given low-dose S-ketamine (bolus prior to functional imaging: 0.1mg/kg during 5min, thereafter continuous infusion: 0.015625mg/kg/min reduced by 10% every ten minutes) or placebo while performing a visual oddball task during simultaneous functional magnetic resonance imaging (fMRI) with continuous recording of event-related potentials (P300) and electrodermal activity (EDA). Before and after intervention, psychopathological status was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale. RESULTS: P300 amplitude and corresponding BOLD responses were diminished in the ketamine condition in cortical regions being involved in sensory processing/selective attention. In both measurement modalities separation of drug conditions was achieved with area under the curve (AUC) values of up to 0.8-0.9. Ketamine effects were also observed in the clinical, behavioral and peripheral physiological domains (Positive and Negative Syndrome Scale, reaction hit and false alarm rate, electrodermal activity and heart rate) which were in part related to the P300/fMRI measures. CONCLUSION: The findings from our ketamine experiment are consistent across modalities and directly related to observations in schizophrenia supporting the validity of the model. Our investigation provides the first prototypic example of a pharmacoimaging study using simultaneously acquired fMRI/EEG.

Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate.

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.

Cortical dysfunction in patients with Huntington's disease during working memory performance.

Previous functional neuroimaging studies on executive function suggested multiple functionally aberrant cortical regions in patients with Huntington's disease (HD). However, little is known about the neural mechanisms of working memory (WM) function in this patient population. The objective of this study was to investigate the functional neuroanatomy of WM in HD patients. We used event-related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in 16 healthy control subjects and 12 mild to moderate stage HD patients. We excluded incorrectly performed trials to control for potential accuracy-related activation confounds. Voxel-based morphometry (VBM) was used to control for confounding cortical and subcortical atrophy. We found that HD patients were slower and less accurate than healthy controls across all WM load levels. In addition, HD patients showed lower activation in the left dorso- and ventrolateral prefrontal cortex, the left inferior parietal cortex, the left putamen, and the right cerebellum at high WM load levels only. VBM revealed gray matter differences in the bilateral caudate nucleus and the thalamus, as well as in inferior parietal and right lateral prefrontal regions. However, volumetric abnormalities in the patient group did not affect the activation differences obtained during WM task performance. These findings demonstrate that WM-related functional abnormalities in HD patients involve distinct WM network nodes associated with cognitive control and subvocal rehearsal. Moreover, aberrant cortical function in HD patients may occur in brain regions, which are relatively well preserved in terms of brain atrophy.

Thalamic atrophy in Huntington's disease co-varies with cognitive performance: a morphometric MRI analysis.

The pattern of motor, behavioral and cognitive symptoms in Huntington's disease (HD) implicates dysfunction of basal-ganglia-thalamo-cortical circuits. This study explored if cognitive performance in HD is correlated with localized cerebral changes. Psychomotor functions were investigated by verbal fluency, Stroop color word and Digit Symbol tests in 44 HD patients and 22 controls. Three-dimensional magnetic resonance imaging (MRI) data were analyzed with regard to regional gray matter changes by use of the observer-independent whole-brain-based approach of voxel-based morphometry (VBM). Using statistical parametric mapping, the MRI data of the HD patients were analyzed in an ANCOVA including the individual results of the neuropsychological tests. Besides striatal areas, symmetrical regional atrophy of the thalamus was found to co-vary significantly with cognitive performance (P < 0.001, corrected for multiple comparisons). In particular, thalamic subnuclei projecting to prefrontal areas (dorsomedial subnucleus) and connected to the striatum (centromedian/parafascicular and ventrolateral nuclear complex) displayed volume loss, in agreement with neuropathological studies. These results suggest that thalamic degeneration contributes in an important way to the impairment of executive function in early HD. Patients who are impaired in executive tests display structural double lesions of the basal-ganglia-thalamo-cortical circuitry both at the striatal and at the thalamic level.