Perspectives of Implementation of Closed-Loop Deep Brain Stimulation: From Neurological to Psychiatric Disorders.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. SUMMARY: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. KEY MESSAGES: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.

Corticospinal adaptations following resistance training and its relationship with strength: A systematic review and multivariate meta-analysis.

Neural adaptations to resistance training (RT) and their correlation with muscle strength remain partially understood. We conducted a systematic review and multivariate meta-analysis to examine the effects of metronome-paced (MP), self-paced (SP), and isometric (IM) training on M1 and corticospinal pathway activity. Following MP RT, a significant increase in corticospinal excitability was observed, correlating with increased strength. Conversely, no significant relationship was found after SP or IM training. RT also reduced the duration of the cortical silent period, but this change did not predict strength changes and was not specific to any training modality. No significant effects were found for short-interval intracortical inhibition. Our findings suggest that changes in corticospinal excitability may contribute to strength gains after RT. Furthermore, the relationship between these adaptations and strength appears dependent on the type of training performed.

Homocysteine levels, genetic background, and cognitive impairment in Parkinson's disease.

BACKGROUND: Hyperhomocysteinemia is considered an independent risk factor for cognitive impairment. OBJECTIVE: To study the correlation between homocysteine levels and cognitive impairment in patients with PD. METHODS: We conducted a case-control study that included 246 patients with PD, of whom 32 were cognitively impaired. The levels of homocysteine, folate, and vitamin B12 were measured in peripheral blood. Multivariate logistic regression analysis was applied to determine differences in homocysteine levels between PD patients with and without cognitive impairment. A meta-analysis was performed to clarify the role of Hcy levels in PD with cognitive decline. Five polymorphisms in genes involved in Hcy metabolism, including MTHFR rs1801133 and rs1801131, COMT rs4680, MTRR rs1801394, and TCN2 rs1801198, were genotyped. RESULTS: Our case-control study showed that homocysteine levels were associated with cognitive impairment in PD after adjusting for possible confounding factors such as levodopa equivalent daily dose. The results of our meta-analysis further supported the positive association between homocysteine levels and cognition in PD. We found that the MTHFR rs1801133 TT genotype led to higher homocysteine levels in PD patients, whereas the MTHFR rs1801131 CC genotype resulted in higher folate levels. However, the polymorphisms studied were not associated with cognitive impairment in PD. CONCLUSIONS: Increased homocysteine levels were a risk factor for cognitive decline in PD. However, no association was found between polymorphisms in genes involved in homocysteine metabolism and cognitive impairment in PD. Large-scale studies of ethnically diverse populations are required to definitively assess the relationship between MTHFR and cognitive impairment in PD.

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration.

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study.

INTRODUCTION: We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia. METHODS: The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models. RESULTS: Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02). CONCLUSIONS: Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.

Peripheral Immune Profile and Neutrophil-to-Lymphocyte Ratio in Parkinson's Disease.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is a well-established inflammatory marker, but its role in Parkinson's disease (PD) remains unclear. OBJECTIVES: To determine whether a different peripheral immune profile and NLR were present in PD patients. METHODS: We conducted a case-control study that included 377 PD patients and 355 healthy controls (HCs). Leukocytes, subpopulations, and the NLR were measured. Multivariate linear regression analyses were applied to determine the differences between groups and the association between NLR and clinical characteristics in PD. A meta-analysis was performed to clarify the association between NLR and PD. RESULTS: In our case-control study, the NLR was significantly higher in PD patients compared with HCs (2.47 ± 1.1 vs. 1.98 ± 0.91, P < 0.001). No association between NLR and age at onset, disease severity, or disease duration was found. The meta-analysis showed that the NLR was likely to be higher in PD patients. CONCLUSIONS: PD patients had an altered peripheral immune profile and a higher NLR compared with HCs. © 2021 International Parkinson and Movement Disorder Society.

Levodopa-Induced Dyskinesia in Parkinson Disease Specifically Associates With Dopaminergic Depletion in Sensorimotor-Related Functional Subregions of the Striatum.

PURPOSE: To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum. METHODS: Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker's Initiative using mixed linear model analysis. RESULTS: Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker's Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = -2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time. CONCLUSION: Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

Impaired motor cortical plasticity associated with cannabis use disorder in young adults.

Maladaptive cortical plasticity has been described in individuals with heroin and methamphetamine addiction and may mediate other substance abuse disorders. It is unknown whether cannabis dependence in humans alters the capacity for induction of cortical plasticity. The aim of this study was to non-invasively investigate cortical plasticity with transcranial magnetic stimulation in young adults who meet DSM-5 criteria for cannabis use disorder (CUD). Thirty men (ages 20- 30) who used cannabis daily over the previous 6 months (15 diagnosed of CUD) and 15 demographically matched non-users were enrolled in this study. All participants underwent two sessions of theta burst stimulation (TBS) in which either continuous TBS (cTBS; 600 pulses, 80% active motor threshold) or intermittent TBS (iTBS; 2-s train of cTBS repeated every 10 s for a total of 190 s, 600 pulses) was applied over the primary motor cortex. The effects of these protocols were assessed by analysing the contralateral motor evoked potentials (MEPs). The relationships between cortical plasticity and problematic cannabis use, degree of dependence, and nicotine addiction were also investigated. Significant MEP inhibition after cTBS was observed in both cannabis users without CUD and non-users, while this inhibition was not seen in cannabis users with CUD. Strikingly, less motor cortical plasticity was observed in subjects with severe problematic cannabis use. No significant differences between users and non-users were found in the iTBS-induced cortical plasticity measures. Our study provides the first evidence of maladaptive cortical plasticity associated with cannabis use disorder and problematic cannabis use in humans.

3D Printing of Diffuse Low-Grade Gliomas Involving Eloquent Cortical Areas and Subcortical Functional Pathways: Technical Note.

BACKGROUND: Surgical resection of diffuse low-grade gliomas (DLGGs) involving cortical eloquent areas and subcortical functional pathways represents a challenge in neurosurgery. Patient-specific, 3-dimensional (3D)-printed models of head and brain structures have emerged in recent years as an educational and clinical tool for patients, doctors, and surgical residents. METHODS: Using multimodal high-definition magnetic resonance imaging data, which incorporates information from specific task-based functional neuroimaging and diffusion tensor imaging tractography and rapid prototyping technologies with specialized software and "in-house" 3D printing, we were able to generate 3D-printed head models that were used for preoperative patient education and consultation, surgical planning, and resident training in 2 complicated DLGG surgeries. RESULTS: This 3D-printed model is rapid prototyped and shows a means to model individualized, diffuse, low-level glioma in 3D space with respect to cortical eloquent areas and subcortical pathways. Survey results from 8 surgeons with different levels of expertise strongly support the use of this model for surgical planning, intraoperative surgical guidance, doctor-patient communication, and surgical training (>95% acceptance). CONCLUSIONS: Spatial proximity of DLGG to cortical eloquent areas and subcortical tracts can be readily assessed in patient-specific 3D printed models with high fidelity. 3D-printed multimodal models could be helpful in preoperative patient consultation, surgical planning, and resident training.

Short-afferent inhibition and cognitive impairment in Parkinson's disease: A quantitative review and challenges.

Traditionally, Parkinson's disease (PD) has been considered a single neurotransmitter (dopaminergic) disease. However, research over the past 20 years has shed light on the involvement of multiple neurotransmission systems, in particular, the cholinergic system. Research has mainly focused on the role of this system in the pathophysiology of PD and its implications in the development of motor and non-motor disorders. Short-latency sensory afferent inhibition (SAI), investigates sensori-motor integration, and has emerged as a putative neurophysiological marker of cholinergic function in the human brain. In this quantitative review, a moderate-to-severe reduction in SAI was observed in PD patients. Furthermore, through moderator analysis, the impairment of SAI was shown to be associated with disease duration and therapeutic state. Patients under dopaminergic agents ("on" state) displayed worse SAI than those after dopaminergic agent withdrawal ("off"). We further assess the potential value of SAI as a marker of cognitive impairment in PD, and its association with four specific cognitive domains. This analysis revealed that patients with cognitive impairment displayed significantly lower levels of SAI than those without cognitive impairment. To conclude, a set of challenges to be addressed before SAI can be validated as a useful clinical tool in PD are presented.

Chronic adult-onset of growth hormone/IGF-I hypersecretion improves cognitive functions and LTP and promotes neuronal differentiation in adult rats.

AIM: Besides their metabolic and endocrine functions, the growth hormone (GH) and its mediated factor, the insulin-like growth factor I (IGF-I), have been implicated in different brain functions, including neurogenesis. Long-lasting elevated GH and IGF-I levels result in non-reversible somatic, endocrine and metabolic morbidities. However, the subcutaneous implantation of the GH-secreting (GH-S) GC cell line in rats leads to the controllable over-secretion of GH and elevated IGF-I levels, allowing the experimental study of their short-term effects on brain functions. METHODS: Adult rats were implanted with GC cells and checked 10 weeks later, when a GH/IGF-I-secreting tumour was already formed. RESULTS: Tumour-bearing rats acquired different operant conditioning tasks faster and better than controls and tumour-resected groups. They also presented better retentions of long-term memories in the passive avoidance test. Experimentally evoked long-term potentiation (LTP) in the hippocampus was also larger and longer lasting in the tumour bearing than in the other groups. Chronic adult-onset of GH/IGF-I hypersecretion caused an acceleration of early progenitors, facilitating a faster neural differentiation, maturation and integration in the dentate gyrus, and increased the complexity of dendritic arbours and spine density of granule neurons. CONCLUSION: Thus, adult-onset hypersecretion of GH/IGF-I improves neurocognitive functions, long-term memories, experimental LTP and neural differentiation, migration and maturation.

Abnormal cerebellar connectivity and plasticity in isolated cervical dystonia.

There is increasing evidence that supports the role of the cerebellum in the pathophysiology of dystonia. We used transcranial magnetic stimulation to test the hypothesis that patients with cervical dystonia may have a disrupted cerebellar cortical connectivity at rest, and that cerebellar plasticity is altered too. We enrolled 12 patients with isolated cervical dystonia and 13 controls. A paired-pulse transcranial magnetic stimulation protocol was applied over the right cerebellum and the left primary motor area. Changes in the amplitude of motor evoked potentials were analysed. Continuous and intermittent Theta Burst Stimulation over the cerebellum was also applied. The effects of these repetitive protocols on cortical excitability, on intra-cortical circuits and on cerebellar cortical inhibition were analysed. In healthy subjects, but not in dystonic patients, a conditioning stimulus over the cerebellum was able to inhibit the amplitude of the motor evoked potentials from primary motor cortex. In healthy subjects continuous and intermittent cerebellar Theta Burst Stimulation were able to decrease and increase respectively motor cortex excitability. Continuous Theta Burst Stimulation was able to abolish the cerebellar cortical inhibition observed in basal condition. These effects were not observed in patients with cervical dystonia. Cerebellar cortical connectivity and cerebellar plasticity is altered at rest in patients with cervical dystonia.

Tremor stability index: a new tool for differential diagnosis in tremor syndromes.

See Vidailhet et al. (doi:10.1093/brain/awx140) for a scientific commentary on this article. Misdiagnosis among tremor syndromes is common, and can impact on both clinical care and research. To date no validated neurophysiological technique is available that has proven to have good classification performance, and the diagnostic gold standard is the clinical evaluation made by a movement disorders expert. We present a robust new neurophysiological measure, the tremor stability index, which can discriminate Parkinson's disease tremor and essential tremor with high diagnostic accuracy. The tremor stability index is derived from kinematic measurements of tremulous activity. It was assessed in a test cohort comprising 16 rest tremor recordings in tremor-dominant Parkinson's disease and 20 postural tremor recordings in essential tremor, and validated on a second, independent cohort comprising a further 55 tremulous Parkinson's disease and essential tremor recordings. Clinical diagnosis was used as gold standard. One hundred seconds of tremor recording were selected for analysis in each patient. The classification accuracy of the new index was assessed by binary logistic regression and by receiver operating characteristic analysis. The diagnostic performance was examined by calculating the sensitivity, specificity, accuracy, likelihood ratio positive, likelihood ratio negative, area under the receiver operating characteristic curve, and by cross-validation. Tremor stability index with a cut-off of 1.05 gave good classification performance for Parkinson's disease tremor and essential tremor, in both test and validation datasets. Tremor stability index maximum sensitivity, specificity and accuracy were 95%, 95% and 92%, respectively. Receiver operating characteristic analysis showed an area under the curve of 0.916 (95% confidence interval 0.797­1.000) for the test dataset and a value of 0.855 (95% confidence interval 0.754­0.957) for the validation dataset. Classification accuracy proved independent of recording device and posture. The tremor stability index can aid in the differential diagnosis of the two most common tremor types. It has a high diagnostic accuracy, can be derived from short, cheap, widely available and non-invasive tremor recordings, and is independent of operator or postural context in its interpretation.

Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease.

The dual syndrome hypothesis for cognitive impairment in Parkinson's disease (PD) establishes a dichotomy between a frontrostriatal dopamine-mediated syndrome, which leads to executive deficits, and a posterior cortical syndrome, which leads to dementia. Certain genes have been linked to these syndromes although the exact contribution is still controversial. The study's objective was to investigate the role of APOE, MAPT, COMT, SNCA and GBA genes in the dual syndromes. We genotyped APOE (rs429358 and rs7412), MAPT (rs9468), COMT (rs4680) and SNCA (rs356219) risk polymorphisms and sequenced GBA in a cohort of 298 PD patients. The degree of dopaminergic depletion was investigated with [123I]FP-CIT SPECTs and the presence of dementia was ascertained with a long-term review based on established criteria. The association between genetic and imaging parameters was studied with linear regression, and the relationship with dementia onset with Cox regression. We found that APOE2 allele (Pput = 0.002; Pcau = 0.01), the minor allele 'G' in SNCA polymorphism (Pput = 0.02; Pcau = 0.006) and GBA deleterious variants in (Pput = 0.01; Pcau = 0.001) had a detrimental effect on striatal [123I]FP-CIT uptake in PD. Conversely, Met/Met carriers in COMT polymorphism had increased caudate uptake (Pcau = 0.03). The development of dementia was influenced by APOE4 allele (HR = 1.90; P = 0.03) and GBA deleterious variants (HR = 2.44; P = 0.01). Finally, we observed no role of MAPT locus in any of the syndromes. As a conclusion, APOE2, SNCA, COMT and GBA influence frontostriatal dysfunction whereas APOE4 and GBA influence the development of dementia, suggesting a double-edged role of GBA. The dichotomy of the dual syndromes may be driven by a broad dichotomy in these genetic factors.

Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype.

Parkinson's disease (PD) patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA), a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT) availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36), intermediate (I, n = 22), and tremor-dominant (TD, n = 17) subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001) and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25%) and I (45%) patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype.

Trait- and state-dependent cortical inhibitory deficits in bipolar disorder.

OBJECTIVES: Euthymic patients with bipolar disorder (BD) have deficits in cortical inhibition. However, whether cortical inhibitory deficits are trait- or state-dependent impairments is not yet known and their relationship with psychiatric symptoms is not yet understood. In the present study, we examined trait- and state-dependent cortical inhibitory deficits and evaluated the potential clinical significance of these deficits. METHODS: Nineteen patients with bipolar I disorder were evaluated using the paired-pulse transcranial stimulation protocol, which assessed cortical inhibition during an acute manic episode. Cortical inhibition measures were compared with those obtained in 28 demographically matched healthy controls. A follow-up assessment was performed in 15 of these patients three months later, when there was remission from their mood and psychotic symptoms. The association between cortical inhibitory measures and severity of psychiatric symptoms was also studied. RESULTS: During mania, patients showed decreased short-interval intracortical and transcallosal inhibition, as well as a normal cortical silent period and long-interval cortical inhibition. These findings were the same during euthymia. Symptoms associated with motor hyperactivity were correlated negatively with the degree of cortical inhibition. These correlations were not significant when a Bonferroni correction was applied. CONCLUSIONS: The present longitudinal study showed cortical inhibitory deficits in patients with BD, and supports the hypothesis that cortical inhibitory deficits in BD are trait dependent. Further research is necessary to confirm the clinical significance of these deficits.

Executive n-back tasks for the neuropsychological assessment of working memory.

Working memory (WM) has been defined as a cerebral function which allows us to maintain and manipulate information "online". One of the most widely used paradigms to assess WM is the n-back test. Despite its extensive application, some authors have questioned its capacity to assess the manipulation of WM load. The present study introduces a new version of the n-back test to carry out this assessment. We use functional near-infrared spectroscopy (fNIRS) to evaluate prefrontal cortex (PFC) activation. The modified n-back requires monitoring of sequentially presented stimuli (in this case the days of the week). The target response relates to a stimulus which appears previously, from 0 to 2 items back, on the computer screen. Our data reveals that while modified and unmodified n-back activate the same regions of the left PFC, our modified 2-back version shows significantly higher activation in the left dorsolateral PFC (DLPFC) and the left frontal opercula. These results suggest that increased complexity in verbal WM tasks entail greater executive control, which would lead to an increase in cerebral blood flow to the areas associated with verbal WM. Therefore, an increase in the manipulation of WM load in verbal tasks reflects greater physiological activity in the left DLPFC and the left frontal opercula. The modified n-back test may also be incorporated into the armamentarium of valid instruments for the neuropsychological assessment of the maintenance and manipulation of verbal information in tasks requiring working memory.

GDNF gene is associated with tourette syndrome in a family study.

BACKGROUND: Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. METHODS: We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). RESULTS: The polymorphism rs3096140 in glial cell line-derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10(-4) ). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found. CONCLUSIONS: As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary.

Aberrant cortical associative plasticity associated with severe adult Tourette syndrome.

BACKGROUND: Recent studies have shown altered cortical plasticity in adult patients with Tourette syndrome. However, the clinical significance of this finding remains elusive. METHODS: Motor cortical plasticity was evaluated in 15 adult patients with severe Tourette syndrome and 16 healthy controls using the paired associative stimulation protocol by transcranial magnetic stimulation. Associations between paired associative stimulation-induced plasticity and relevant clinical variables, including cortical excitability, psychiatric comorbidities, drug treatment and tic severity, were assessed. RESULTS: Motor cortical plasticity was abnormally increased in patients with Tourette syndrome compared with healthy subjects. This abnormal plasticity was independently associated with tic severity. CONCLUSION: Patients with severe Tourette syndrome display abnormally increased cortical associative plasticity. This aberrant cortical plasticity was associated with tic severity, suggesting an underlying mechanism for tic pathophysiology.