Michael Orth

The cortical silent period: intrinsic variability and relation to the waveform of the transcranial magnetic stimulation pulse.

OBJECTIVE To assess the variability of the duration of the contralateral cortical silent period (CSP) between individuals and to assess the effect of different transcranial magnetic stimulation (TMS) pulse waveforms. METHODS In Expt. 1, CSP duration, and the motor-evoked potential (MEP) amplitude and area were measured in the first dorsal interosseous muscle (FDI) of 11 subjects on 3 separate occasions using a TMS intensity of 150% active motor threshold (AMT). In Expt. 2, the stimulation intensity was varied between 100% AMT and 150% AMT. In both sets of experiments, 3 types of TMS pulse were used: monophasic posterior-anterior (PA) induced current in the brain, monophasic anterior-posterior induced current (AP), and biphasic PA/AP stimulation. RESULTS Experiment 1: Between-subject variation in CSP duration was high. In addition, the duration after PA stimulation was significantly shorter than after AP or PA/AP stimulation. However, there was a good correlation between CSP duration and the area, or amplitude, of the MEP. This meant that calculating the ratio of duration/amplitude or duration/area reduced intersubject variability and eliminated differences between TMS pulses. Experiment 2: increasing stimulation intensity increased the mean value of all parameters, but with significantly lower values for PA than other forms of stimulation. The ratios of duration/amplitude or duration/area did not differ between current flow directions and were relatively constant for intensities 130-150% AMT. CONCLUSIONS Between-subject variation in the duration of the CSP is high. A given intensity of stimulation (expressed in %AMT) produces a shorter CSP for PA stimulation than for AP or PA/AP stimulation. SIGNIFICANCE If the ratio (CSP duration)/(MEP size) is calculated, then intersubject variability is reduced, and TMS pulse type differences are eliminated.

Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease

As a Mendelian neurodegenerative disorder, the genetic risk of Huntingtons disease (HD) is conferred entirely by an HTT CAG repeat expansion whose length is the primary determinant of the rate of pathogenesis leading to disease onset. To investigate the pathogenic process that precedes disease, we used genome-wide association (GWA) analysis to identify loci harboring genetic variations that alter the age at neurological onset of HD. A chromosome 15 locus displays two independent effects that accelerate or delay onset by 6.1 years and 1.4 years, respectively, whereas a chromosome 8 locus hastens onset by 1.6 years. Association at MLH1 and pathway analysis of the full GWA results support a role for DNA handling and repair mechanisms in altering the course of HD. Our findings demonstrate that HD disease modification in humans occurs in nature and offer a genetic route to identifying in-human validated therapeutic targets in this and other Mendelian disorders.

The variability of intracortical inhibition and facilitation

OBJECTIVE To assess the variability of transcranial magnetic stimulation paired pulse measurements of cortical excitability between subjects, between sessions and within subjects within sessions. METHODS In experiment 1, intracortical inhibition and facilitation were assessed with a fixed conditioning stimulus intensity (CSI) of 80% of active motor threshold (AMT) whereas in experiment 2, the effect of different CSIs (60-110% of AMT) was investigated. RESULTS Experiment 1 revealed that subjects differed significantly in the degree of inhibition and facilitation. Between sessions the variability was substantial as predicted by high within session variability. Experiment 2 allowed determination of individual thresholds for inhibition and facilitation. These thresholds were the best predictor of the amount of inhibition or facilitation at a given CSI. Across subjects we observed a high correlation of the threshold for inhibition (expressed in terms of maximum stimulator output) with AMT (r=0.93). Results for facilitation were more variable. CONCLUSIONS The variability was high if a single CSI was used to compare the percent intracortical inhibition or facilitation between subjects, or between sessions. Much less variable was the threshold for intracortical inhibition/facilitation, which was highly correlated to AMT. We suggest that the ratio of CSI:AMT is a robust and useful additional measure of the integrity of neuronal circuits underlying intracortical inhibition/facilitation.

The Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL) Development and validation

Background: Gilles de la Tourette syndrome (GTS) is a chronic neuropsychiatric disorder which has a significant detrimental impact on the health-related quality of life (HR-QOL) of patients. However, no patient-reported HR-QOL measures have been developed for this population. Objective: The development and validation of a new scale for the quantitative assessment of HR-QOL in patients with GTS. Methods: In stage 1 (item generation), a pool of 40 potential scale items was generated based on interviews with 133 GTS outpatients, literature review, and consultation with experts. In stage 2 (scale development), these items were administered to a sample of 192 GTS outpatients. Standard statistical methods were used to develop a rating scale satisfying criteria for acceptability, reliability, and validity. In stage 3 (scale evaluation), the psychometric properties of the resulting scale were tested in a second sample of 136 subjects recruited through the UK-Tourette Syndrome Association. Results: Response data analysis and item reduction methods led to a final 27-item GTS-specific HR-QOL scale (GTS-QOL) with four subscales (psychological, physical, obsessional, and cognitive). The GTS-QOL demonstrated satisfactory scaling assumptions and acceptability; both internal consistency reliability and test-retest reliability were high (Cronbach alpha ≥0.8 and intraclass correlation coefficient ≥0.8); validity was supported by interscale correlations (range 0.5–0.7), confirmatory factor analysis, and correlation patterns with other rating scales and clinical variables. Conclusions: The Gilles de la Tourette syndrome (GTS)–specific health-related quality of life (HR-QOL) scale (GTS-QOL) is proposed as a new disease-specific patient-reported scale for the measurement of HR-QOL in patients with GTS, taking into account the complexity of the clinical picture of GTS.

Structural Changes in the Somatosensory System Correlate with Tic Severity in Gilles de la Tourette Syndrome.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. Previous structural MRI studies have identified regional abnormalities in grey matter, especially in the basal ganglia. These findings are consistent with the assumption of alterations in cortico-striato-thalamo-cortical circuits and dopaminergic neurotransmission playing a major role in the pathophysiology of GTS. Additionally, recent imaging studies suggested an involvement of sensory-motor cortices in the pathophysiology of GTS. However, little is known about the role of white matter changes in GTS. In this study, we aimed to examine whether GTS is associated with abnormalities in white matter microstructure and whether these changes are correlated with tic severity. In a morphometric study based on diffusion tensor MRI of the whole brain, we compared brain tissue diffusion characteristics between 15 unmedicated adults with GTS without psychiatric co-morbidity and 15 healthy age- and sex-matched controls. We performed voxel-based morphometry (VBM) of regional fractional anisotropy (FA) values to identify regional differences in white matter microstructure between the groups. We also tested for a linear relationship between regional FA values and clinical scores of tic severity. Probabilistic fibre tracking was applied to characterize anatomical connectivity of those areas showing differences in regional FA. Compared with healthy controls, GTS patients showed bilateral FA increases in white matter underlying the post- and precentral gyrus, below the left supplementary motor area, and in the right ventro-postero-lateral part of the thalamus. The peak increase in FA was located below the left postcentral gyrus. Probabilistic tractography identified transcallosal and ipsilateral cerebello-thalamo-cortical pathways of the somatosensory system passing through this subcortical region. In patients, regional FA in this region showed an inverse linear relationship with tic severity. These findings demonstrate, for the first time, structural alterations in somatosensory pathways in GTS. Changes of water diffusion characteristics point towards reduced branching in somatosensory pathways in GTS patients. The negative correlation between higher regional FA values and fewer tics suggests that these alterations of white matter microstructure represent adaptive reorganization of somatosensory processing in GTS.

Observing Huntington's Disease: the European Huntington's Disease Network's REGISTRY.

Background: Huntingtons disease (HD) is a rare triplet repeat (CAG) disorder. Advanced, multi-centre, multi-national research frameworks are needed to study simultaneously multiple complementary aspects of HD. This includes the natural history of HD, its management and the collection of clinical information and biosamples for research. Methods: We report on cross-sectional data of the first 1766 participants in REGISTRY, the European Huntingtons Disease Networks (EHDN), multi-lingual, multi-national prospective observational study of HD in Europe. Data collection (demographics, phenotype, genotype, medication, co-morbidities, biosamples) followed a standard protocol. Results: Phenotype, and the HD genotype, of manifest HD participants across different European regions was similar. Motor onset was most common (48%) with a non-motor onset in more than a third of participants. Motor signs increased, and cognitive abilities and functional capacity declined as the disease burden (CAGn-35.5) X age) increased. A life-time history of behavioural symptoms was common, but the behavioural score was not related to disease burden. One fifth of participants had severe psychiatric problems, e.g. suicidal ideation and attempts, and/or irritability/aggression, with psychosis being less common. Participants on anti-dyskinetic medication had a higher motor and lower cognitive score, were older, and more prone to physical trauma. A higher motor and a lower cognitive score predicted more advanced disease. Conclusions: The unparalleled collection of clinical data and biomaterials within the EHDNs REGISTRY can expedite the search for disease modifiers (genetic and environmental) of age at onset and disease progression that could be harnessed for the development of novel treatments.

Multispectral brain morphometry in Tourette syndrome persisting into adulthood

Tourette syndrome is a childhood-onset neuropsychiatric disorder with a high prevalence of attention deficit hyperactivity and obsessive-compulsive disorder co-morbidities. Structural changes have been found in frontal cortex and striatum in children and adolescents. A limited number of morphometric studies in Tourette syndrome persisting into adulthood suggest ongoing structural alterations affecting frontostriatal circuits. Using cortical thickness estimation and voxel-based analysis of T1- and diffusion-weighted structural magnetic resonance images, we examined 40 adults with Tourette syndrome in comparison with 40 age- and gender-matched healthy controls. Patients with Tourette syndrome showed relative grey matter volume reduction in orbitofrontal, anterior cingulate and ventrolateral prefrontal cortices bilaterally. Cortical thinning extended into the limbic mesial temporal lobe. The grey matter changes were modulated additionally by the presence of co-morbidities and symptom severity. Prefrontal cortical thickness reduction correlated negatively with tic severity, while volume increase in primary somatosensory cortex depended on the intensity of premonitory sensations. Orbitofrontal cortex volume changes were further associated with abnormal water diffusivity within grey matter. White matter analysis revealed changes in fibre coherence in patients with Tourette syndrome within anterior parts of the corpus callosum. The severity of motor tics and premonitory urges had an impact on the integrity of tracts corresponding to cortico-cortical and cortico-subcortical connections. Our results provide empirical support for a patho-aetiological model of Tourette syndrome based on developmental abnormalities, with perturbation of compensatory systems marking persistence of symptoms into adulthood. We interpret the symptom severity related grey matter volume increase in distinct functional brain areas as evidence of ongoing structural plasticity. The convergence of evidence from volume and water diffusivity imaging strengthens the validity of our findings and attests to the value of a novel multimodal combination of volume and cortical thickness estimations that provides unique and complementary information by exploiting their differential sensitivity to structural change.

Models of Parkinson's disease

Parkinsons disease (PD) is a heterogenous disease likely to be caused by more than one specific aetiological factor. In rare familial cases of PD with similar clinical features to the idiopathic form of the disease, the underlying genetic cause has been identified. These PD‐associated genes have been manipulated to create animal and cell culture models of the disease that have helped to further our understanding of the pathogenesis of PD, particularly concerning causes of the selective loss of dopaminergic neurons at the molecular level. In addition, these models will aid the future development of rational therapeutic strategies. This study briefly reviews toxin‐induced models and the genetics of PD. It focuses on recently developed animal models of PD, as well as in vitro approaches to model the disease.

Motor cortex excitability and comorbidity in Gilles de la Tourette syndrome

Background: Gilles de la Tourette syndrome (GTS) is often complicated by comorbid attention-deficit/hyperactivity disorder (ADHD) or obsessive–compulsive disorder (OCD). This study examines whether motor cortex excitability differs between uncomplicated GTS patients and those complicated by ADHD or OCD. Methods: Motor thresholds, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), and short latency afferent inhibition (SAI) were measured using transcranial magnetic stimulation (TMS) in 29 untreated GTS patients (18 uncomplicated, six with comorbid ADHD, five with comorbid OCD) and 24 healthy subjects. Tic severity was rated with standard clinical scales. Results: Patients had slightly higher resting (RMT) and active motor thresholds (AMT). The threshold of SICI and ICF expressed as a percentage of each individual’s AMT was similar in controls and GTS patients. Above threshold, GTS patients had less SICI and more ICF. SICI was similar in all subgroups, but ICF differed significantly between them. Patients with GTS+ADHD had more ICF than controls, uncomplicated GTS patients or GTS+OCD patients; ICF was similar in these other groups. GTS patients as a whole had reduced SAI. Uncomplicated GTS patients or GTS+ADHD patients had less SAI than controls or GTS+OCD patients. Conclusions: GTS with ADHD comorbidity is associated with more extensive changes in the excitability of motor cortex circuits than uncomplicated GTS or GTS+OCD. The extent to which various different neuronal circuits are affected may be relevant for the phenotype of Tourette spectrum disorders.

Dissecting the Gilles de la Tourette spectrum: a factor analytic study on 639 patients

Background Recent studies using quantitative methods, such as principal component factor analysis, hierarchical cluster analysis and latent class analysis have suggested that Gilles de la Tourette syndrome (GTS) should no longer be considered a unitary condition as in current classification systems. Objective To identify quantitative components of GTS symptomatology using a large, well characterised cohort of singleton individuals with GTS in order to inform future genetic studies with more homogeneous phenotypes. Methods Principal component factor analysis with oblique rotation was used to analyse symptom data from a sample of 639 patients recruited at two tertiary referral centres using identical schedules during the period 1980–2008. Results Three Factors were identified: (1) complex motor tics and echo-paliphenomena; (2) attention deficit and hyperactivity symptoms plus aggressive behaviours; and (3) complex vocal tics and coprophenomena. Obsessive compulsive behaviours loaded significantly on the first two factors. The three factors accounted for 48.5% of the total symptomatic variance. Conclusions GTS is a phenotypically heterogeneous condition encompassing simple tics, specific complex tics and associated behavioural problems. The results, coupled with previous findings, identified a clinical continuum of complex tics, hyperactivity/impulsivity symptoms and semantically relevant utterances and gestures. A better characterisation of the GTS phenotypes will help to identify susceptibility genes.