Irene Neuner

High resolution BrainPET combined with simultaneous MRI.

UNLABELLED After the successful clinical introduction of PET/CT, a novel hybrid imaging technology combining PET with the versatile attributes of MRI is emerging. At the Forschungszentrum Jülich, one of four prototypes available worldwide combining a commercial 3T MRI with a newly developed BrainPET insert has been installed, allowing simultaneous data acquisition with PET and MRI. The BrainPET is equipped with LSO crystals of 2.5 mm width and Avalanche photodiodes (APD) as readout electronics. Here we report on some performance characteristics obtained by phantom studies and also on the initial BrainPET studies on various patients as compared with a conventional HR+ PET-only scanner. MATERIAL, METHODS The radiotracers [18F]-fluoro-ethyl-tyrosine (FET), [11C]-flumazenil and [18F]-FP-CIT were applied. RESULTS Comparing the PET data obtained with the BrainPET to those of the HR+ scanner demonstrated the high image quality and the superior resolution capability of the BrainPET. Furthermore, it is shown that various MR images of excellent quality could be acquired simultaneously with BrainPET scans without any relevant artefacts. DISCUSSION, CONCLUSION Initial experiences with the hybrid MRI/BrainPET indicate a promising basis for further developments of this unique technique allowing simultaneous PET imaging combined with both anatomical and functional MRI.

White-matter abnormalities in Tourette syndrome extend beyond motor pathways

Tourette syndrome is a neuropsychiatric disorder with the cardinal symptoms of motor and vocal tics. Often tics are accompanied by comorbidities such as obsessive-compulsive disorder, attention-deficit-hyperactivity disorder or depression. Research has mainly focused on the cortico-striato-thalamo circuit, but clinical symptoms and recent neuroimaging studies reporting altered resting network connectivity have suggested abnormalities in Tourette syndrome beyond the major motor circuits. We acquired diffusion-weighted data at 1.5T in nineteen adult patients fulfilling the DSM-IV-TR criteria for Tourette syndrome and in a healthy control group. Diffusion tensor imaging (DTI) analysis in our adult TS sample shows a decrease of FA and increase in radial diffusivity in the corticospinal tract. There are widespread changes (reduced FA and increased radial diffusivity) in the anterior and posterior limb of the internal capsule. Furthermore, it confirms prior findings of altered interhemispheric connectivity as indicated by a FA-decrease in the corpus callosum. In addition, our results indicate that TS is not restricted to motor pathways alone but affects association fibres such as the inferior fronto-occipitalis fascicle, the superior longitudinal fascicle and fascicle uncinatus as well. Tics are the hallmark of Tourette syndrome, so the involvement of the corticospinal tract fits in well with clinical symptoms. Cortical regions as well as limbic structures take part in the modulation of tics. Our findings of alterations in long association fibre tracts and the corpus callosum are a potential source for hindered interhemispheric and transhemispheric interaction. The change in radial diffusivity points toward a deficit in myelination as one pathophysiological factor in Tourette syndrome.

Imaging the where and when of tic generation and resting state networks in adult Tourette patients

Introduction: Tourette syndrome (TS) is a neuropsychiatric disorder with the core phenomenon of tics, whose origin and temporal pattern are unclear. We investigated the When and Where of tic generation and resting state networks (RSNs) via functional magnetic resonance imaging (fMRI). Methods: Tic-related activity and the underlying RSNs in adult TS were studied within one fMRI session. Participants were instructed to lie in the scanner and to let tics occur freely. Tic onset times, as determined by video-observance were used as regressors and added to preceding time-bins of 1 s duration each to detect prior activation. RSN were identified by independent component analysis (ICA) and correlated to disease severity by the means of dual regression. Results: Two seconds before a tic, the supplementary motor area (SMA), ventral primary motor cortex, primary sensorimotor cortex and parietal operculum exhibited activation; 1 s before a tic, the anterior cingulate, putamen, insula, amygdala, cerebellum and the extrastriatal-visual cortex exhibited activation; with tic-onset, the thalamus, central operculum, primary motor and somatosensory cortices exhibited activation. Analysis of resting state data resulted in 21 components including the so-called default-mode network. Network strength in those regions in SMA of two premotor ICA maps that were also active prior to tic occurrence, correlated significantly with disease severity according to the Yale Global Tic Severity Scale (YGTTS) scores. Discussion: We demonstrate that the temporal pattern of tic generation follows the cortico-striato-thalamo-cortical circuit, and that cortical structures precede subcortical activation. The analysis of spontaneous fluctuations highlights the role of cortical premotor structures. Our study corroborates the notion of TS as a network disorder in which abnormal RSN activity might contribute to the generation of tics in SMA.

The Default Mode Network and EEG Regional Spectral Power: A Simultaneous fMRI-EEG Study

Electroencephalography (EEG) frequencies have been linked to specific functions as an “electrophysiological signature” of a function. A combination of oscillatory rhythms has also been described for specific functions, with or without predominance of one specific frequency-band. In a simultaneous fMRI-EEG study at 3 T we studied the relationship between the default mode network (DMN) and the power of EEG frequency bands. As a methodological approach, we applied Multivariate Exploratory Linear Optimized Decomposition into Independent Components (MELODIC) and dual regression analysis for fMRI resting state data. EEG power for the alpha, beta, delta and theta-bands were extracted from the structures forming the DMN in a region-of-interest approach by applying Low Resolution Electromagnetic Tomography (LORETA). A strong link between the spontaneous BOLD response of the left parahippocampal gyrus and the delta-band extracted from the anterior cingulate cortex was found. A positive correlation between the beta-1 frequency power extracted from the posterior cingulate cortex (PCC) and the spontaneous BOLD response of the right supplementary motor cortex was also established. The beta-2 frequency power extracted from the PCC and the precuneus showed a positive correlation with the BOLD response of the right frontal cortex. Our results support the notion of beta-band activity governing the “status quo” in cognitive and motor setup. The highly significant correlation found between the delta power within the DMN and the parahippocampal gyrus is in line with the association of delta frequencies with memory processes. We assumed “ongoing activity” during “resting state” in bringing events from the past to the mind, in which the parahippocampal gyrus is a relevant structure. Our data demonstrate that spontaneous BOLD fluctuations within the DMN are associated with different EEG-bands and strengthen the conclusion that this network is characterized by a specific electrophysiological signature created by combination of different brain rhythms subserving different putative functions.

Advances in multimodal neuroimaging: hybrid MR-PET and MR-PET-EEG at 3 T and 9.4 T.

Multi-modal MR-PET-EEG data acquisition in simultaneous mode confers a number of advantages at 3 T and 9.4 T. The three modalities complement each other well; structural-functional imaging being the domain of MRI, molecular imaging with specific tracers is the strength of PET, and EEG provides a temporal dimension where the other two modalities are weak. The utility of hybrid MR-PET at 3 T in a clinical setting is presented and critically discussed. The potential problems and the putative gains to be accrued from hybrid imaging at 9.4 T, with examples from the human brain, are outlined. Steps on the road to 9.4 T multi-modal MR-PET-EEG are also illustrated. From an MR perspective, the potential for ultra-high resolution structural imaging is discussed and example images of the cerebellum with an isotropic resolution of 320 μm are presented, setting the stage for hybrid imaging at ultra-high field. Further, metabolic imaging is discussed and high-resolution images of the sodium distribution are presented. Examples of tumour imaging on a 3 T MR-PET system are presented and discussed. Finally, the perspectives for multi-modal imaging are discussed based on two on-going studies, the first comparing MR and PET methods for the measurement of perfusion and the second which looks at tumour delineation based on MRI contrasts but the knowledge of tumour extent is based on simultaneously acquired PET data.

Aripiprazole in the pharmacotherapy of Gilles de la Tourette syndrome in adult patients

Despite the ongoing development of neuroleptics, typical or first-generation neuroleptics are still considered as the first choice in the treatment of Gilles de la Tourette syndrome (GTS). In many European countries, tiapride is the first line of treatment favoured in most cases, while risperidone, pimozide and haloperidol are listed as second choice. Unfortunately, antipsychotics often show tachyphylactic effects in the treatment of GTS so that a switch to another neuroleptic agent becomes inevitable. Thus it is important to ensure a wide selection of different drugs is available. Another promising candidate in the treatment of tics may be aripiprazole, a D2-receptor partial agonist. We present the retrospective analysis of 10 clinical cases of adult patients from the tic clinics in Aachen (Germany) and Zurich (Switzerland) who were treated with aripiprazole. Tics and disturbances were assessed using the Yale Global Tic Severity Scale (YGTSS). All YGTSS-subscores, with the exception of the complexity of vocal tics, improved significantly. The data includes three cases with long-term intake for at least 18 months. During this period, no tachyphylactic effect was visible. A double-blind trial against placebo or other neuroleptics is advisable to verify the efficacy of aripiprazole in the pharmacotherapy of GTS.

From psychosurgery to neuromodulation: deep brain stimulation for intractable Tourette syndrome.

Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics. It is often associated with depression, obsessive-compulsive symptoms, self-injurious behaviour and attention deficit-hyperactivity disorder (ADHD). In intractable patients, neuromodulation using deep brain stimulation (DBS) has widely replaced psychosurgery. Three different key structures are defined for DBS, the medial portion of the thalamus, the globus pallidus internus and the anterior limb of the internal capsule/nucleus accumbens. This is a comprehensive overview on the effect of DBS on motor and non-motor symptoms using different case series and two larger studies.

Electrophysiology meets fMRI: neural correlates of the startle reflex assessed by simultaneous EMG-fMRI data acquisition.

The startle reflex provides a unique tool for the investigation of sensorimotor gating and information processing. Simultaneous EMG–fMRI acquisition (i.e., online stimulation and recording in the MR environment) allows for the quantitative assessment of the neuronal correlates of the startle reflex and its modulations on a single trial level. This serves as the backbone for a startle response informed fMRI analysis, which is fed by data acquired in the same brain at the same time. We here present the first MR study using a single trial approach with simultaneous acquired EMG and fMRI data on the human startle response in 15 healthy young men. It investigates the neural correlates for isolated air puff startle pulses (PA), prepulse–pulse inhibition (PPI), and prepulse facilitation (PPF). We identified a common core network engaged by all three conditions (PA, PPI, and PPF), consisting of bilateral primary and secondary somatosensory cortices, right insula, right thalamus, right temporal pole, middle cingulate cortex, and cerebellum. The cerebellar vermis exhibits distinct activation patterns between the startle modifications. It is differentially activated with the highest amplitude for PPF, a lower activation for PA, and lowest for PPI. The orbital frontal cortex exhibits a differential activation pattern, not for the type of startle response but for the amplitude modification. For pulse alone it is close to zero; for PPI it is activated. This is in contrast to PPF where it shows deactivation. In addition, the thalamus, the cerebellum, and the anterior cingulate cortex add to the modulation of the startle reflex. Hum Brain Mapp, 2010.

In vivo evidence of deep brain stimulation-induced dopaminergic modulation in Tourette's syndrome

To the Editor: D ue to its large effect size, deep brain stimulation (DBS) is progressively considered in the treatment of medicationresistant Tourette’s syndrome (TS) (1). Nevertheless, the underlying beneficial mechanisms of DBS in TS are still a matter of debate (2,3). Treatment strategies (D2-receptor antagonists) as well as previous research results point to a dysfunction of basal gangliarelated circuits and hyperactive dopaminergic innervations (4 – 8). It might thus be hypothesized that DBS acts via modulation of dopamine transmission; however, corresponding in vivo evidence is lacking, except for one positive single-patient [F]fallypride-positron emission tomography (FP) investigation (9). In fact, FP allows for quantification of D2/3-receptor availability in striatal and extrasriatal regions within a single positron emission tomography (PET) can but requires more than 3 hours of acquisition time. Because TS atients suffer from heavy motor tics, a long-term anesthesia was ecessary during the PET scan. Encouraged by the observation of elevant FP-binding changes within the pilot-investigation, we proeeded to enlarge the number of such investigations. This investigation was approved by the local ethics committee nd the German drug safety and radiation safety authorities. Three atients (two men, one woman) (Table 1) suffering from medicaion-resistant TS were investigated. The two male patients underent prior bilateral thalamic DBS in the pallidal and nigral input egions of the thalamus (Th). The female patient (Patient 3) underent a left-sided unilateral thalamic stimulation, because the leftided intraoperative test-stimulation revealed already-complete tic uppression (detailed electrode positions) (Table 2). They all responded with substantial improvements in the Yale Global Tic Severity Scale (YGTSS) (reductions of 30%– 80%) (Table 1). The PET scans were scheduled 6 months after the surgery. For an orientating comparison with stimulation-free conditions we used FP-PET results of eight age-matched healthy subjects (seven men/ one woman; age: 19 –29 years; mean SD: 23.6 3.8). The FP-radiosynthesis has been described previously (10). Each patient experienced two PET scans (first: “stimulator-on”; second: “stimulator-off”) under general propofol/remifentanil anesthesia of 4 –5 hours in duration (3 hours: FP-scan; 1 hour: anesthesia preparation; 1 hour: latency between stimulation deactivation and ligand injection [second scan]). Control subjects were scanned without

Amygdala hypersensitivity in response to emotional faces in Tourette's patients.

Abstract Objectives. Tourettes syndrome is characterised by motor and vocal tics as well as a high level of impulsivity and emotional dysregulation. Neuroimaging studies point to structural changes of the basal ganglia, prefrontal cortex and parts of the limbic system. However, there is no link between behavioural symptoms and the structural changes in the amygdala. One aspect of daily social interaction is the perception of emotional facial expressions, closely linked to amgydala function. Methods. We therefore investigated via fMRI the implicit discrimination of six emotional facial expressions in 19 adult Tourettes patients. Results. In comparison to healthy control group, Tourettes patients showed significantly higher amygdala activation, especially pronounced for fearful, angry and neutral expressions. The BOLD-activity of the left amygdala correlated negatively with the personality trait extraversion. Conclusions. We will discuss these findings as a result of either deficient frontal inhibition due to structural changes or a desynchronization in the interaction of the cortico-striato-thalamo-cortical network within structures of the limbic system. Our data show an altered pattern of implicit emotion discrimination and emphasize the need to consider motor and non-motor symptoms in Tourettes syndrome in the choice of both behavioural and pharmacological treatment.