Addressing the sources of inter-subject variability in E-field parameters in anodal tDCS stimulation over motor cortical network.

Objetive: .Although transcranial direct current stimulation constitutes a non-invasive neuromodulation technique with promising results in a great variety of applications, its clinical implementation is compromised by the high inter-subject variability reported. This study aims to analyze the inter-subject variability in electric fields (E-fields) over regions of the cortical motor network under two electrode montages: the classical C3Fp2 and an alternative P3F3, which confines more the E-field over this region.Approach.Computational models of the head of 98 healthy subjects were developed to simulate the E-field under both montages. E-field parameters such as magnitude, focality and orientation were calculated over three regions of interest (ROI): M1S1, supplementary motor area (SMA) and preSMA. The role of anatomical characteristics as a source of inter-subject variability on E-field parameters and individualized stimulation intensity were addressed using linear mixed-effect models.Main results.P3F3 showed a more confined E-field distribution over M1S1 than C3Fp2; the latter elicited higher E-fields over supplementary motor areas. Both montages showed high inter-subject variability, especially for the normal component over C3Fp2. Skin, bone and CSF ROI volumes showed a negative association with E-field magnitude irrespective of montage. Grey matter volume and montage were the main sources of variability for focality. The curvature of gyri was found to be significantly associated with the variability of normal E-fields.Significance.Computational modeling proves useful in the assessment of E-field variability. Our simulations predict significant differences in E-field magnitude and focality for C3Fp2 and P3F3. However, anatomical characteristics were also found to be significant sources of E-field variability irrespective of electrode montage. The normal E-field component better captured the individual variability and low rate of responder subjects observed in experimental studies.

TMS intensity and focality correlation with coil orientation at three non-motor regions.

Objective. The aim of this study is to define the best coil orientations for transcranial magnetic stimulation (TMS) for three clinically relevant brain areas: pre-supplementary motor area (pre-SMA), inferior frontal gyrus (IFG), and posterior parietal cortex (PPC), by means of simulations in 12 realistic head models of the electric field (E-field).Methods. We computed the E-field generated by TMS in our three volumes of interest (VOI) that were delineated based on published atlases. We then analysed the maximum intensity and spatial focality for the normal and absolute components of the E-field considering different percentile thresholds. Lastly, we correlated these results with the different anatomical properties of our VOIs.Results. Overall, the spatial focality of the E-field for the three VOIs varied depending on the orientation of the coil. Further analysis showed that differences in individual brain anatomy were related to the amount of focality achieved. In general, a larger percentage of sulcus resulted in better spatial focality. Additionally, a higher normal E-field intensity was achieved when the coil axis was placed perpendicular to the predominant orientations of the gyri of each VOI. A positive correlation between spatial focality and E-field intensity was found for PPC and IFG but not for pre-SMA.Conclusions. For a rough approximation, better coil orientations can be based on the individual's specific brain morphology at the VOI. Moreover, TMS computational models should be employed to obtain better coil orientations in non-motor regions of interest.Significance. Finding better coil orientations in non-motor regions is a challenge in TMS and seeks to reduce interindividual variability. Our individualized TMS simulation pipeline leads to fewer inter-individual variability in the focality, likely enhancing the efficacy of the stimulation and reducing the risk of stimulating adjacent, non-targeted areas.

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly.

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.

Clinical features and neuropsychological profile in vascular parkinsonism.

BACKGROUND: The clinical profile in vascular parkinsonism (VP) patients is well described in the literature, but little is known about the neuropsychological features of this disease. The aim of our study was to evaluate the clinical characteristics and the profile of cognitive impairment in patients with VP. METHODS: We prospectively evaluated 12 patients with VP, 15 with Parkinson's disease (PD) and 13 healthy controls (HC) with similar age and sex distribution. Different clinical and demographic details were collected. All subjects underwent detailed neurological and neuropsychological examinations. The neuropsychological tests included analysis of global efficiency, executive function, verbal memory, language and visuospatial function. RESULTS: VP patients exhibited lower disease duration, older age at onset and higher frequency of cardiovascular risk factors. Non-motor symptoms were found to be more frequent in PD. We found that VP patients developed cognitive impairment with a significantly higher frequency than HC of a similar age. Additionally, we found that these patients had a global pattern of cognitive impairment, including executive function, verbal memory and language. Only visuospatial function was more impaired in PD than in HC. CONCLUSIONS: Our data contribute to clarify the pattern of neuropsychological impairment in VP. Therefore, in the clinical evaluation, besides assessing the motor status of the patient, given that these symptoms are frequently found not to be self-reported complaints, the neurologist should evaluate them routinely as a comprehensive assessment of this disease.

Parieto-motor cortical dysfunction in primary cervical dystonia.

BACKGROUND: Dystonia is considered as a motor network disorder involving the dysfunction of the posterior parietal cortex, a region involved in preparing and executing reaching movements. OBJECTIVE/HYPOTHESIS: We used transcranial magnetic stimulation to test the hypothesis that cervical dystonic patients may have a disrupted parieto-motor connectivity. METHODS: We enrolled 14 patients with primary cervical dystonia and 14 controls. A paired-pulse transcranial magnetic stimulation protocol was applied over the right posterior parietal cortex and the right primary motor area. Changes in the amplitudes of motor evoked potential were analyzed as an index of parieto-motor effective connectivity. Patients and healthy subjects were also evaluated with a reaching task. Reaction and movement times were measured. RESULTS: In healthy subjects, but not in dystonic patients, there was a facilitation of motor evoked potential amplitudes when the conditioning parietal stimulus preceded the test stimulus applied over the primary motor area by 4 ms. Reaction and movement times were significantly slower in patients than in controls. In dystonic patients, the relative strength of parieto-motor connectivity correlated with movement times. CONCLUSIONS: Parieto-motor cortical connectivity is impaired in cervical dystonic patients. This neurophysiological trait is associated with slower reaching movements.