Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic system, leading to a variety of motor and nonmotor symptoms. The currently available symptomatic therapy loses efficacy over time, indicating the need for new therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) has emerged as one of the potential candidates for PD therapy. Intermittent theta burst stimulation (iTBS), an excitatory protocol of rTMS, has been shown to be beneficial in several animal models of neurodegeneration, including PD. The aim of this study was to investigate the effects of prolonged iTBS on motor performance and behavior and the possible association with changes in the NMDAR subunit composition in the 6-hydroxydopamine (6-OHDA)-induced experimental model of PD. Two-month-old male Wistar rats were divided into four groups: controls, 6-OHDA rats, 6-OHDA + iTBS protocol (two times/day/three weeks) and the sham group. The therapeutic effect of iTBS was evaluated by examining motor coordination, balance, spontaneous forelimb use, exploratory behavior, anxiety-like, depressive/anhedonic-like behavior and short-term memory, histopathological changes and changes at the molecular level. We demonstrated the positive effects of iTBS at both motor and behavioral levels. In addition, the beneficial effects were reflected in reduced degeneration of dopaminergic neurons and a subsequent increase in the level of DA in the caudoputamen. Finally, iTBS altered protein expression and NMDAR subunit composition, suggesting a sustained effect. Applied early in the disease course, the iTBS protocol may be a promising candidate for early-stage PD therapy, affecting motor and nonmotor deficits.

Intermittent theta burst stimulation attenuates oxidative stress and reactive astrogliosis in the streptozotocin-induced model of Alzheimer's disease-like pathology.

Introduction: Intracerebroventricularly (icv) injected streptozotocin (STZ) is a widely used model for sporadic Alzheimer's disease (sAD)-like pathology, marked by oxidative stress-mediated pathological progression. Intermittent theta burst stimulation (iTBS) is a noninvasive technique for brain activity stimulation with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for several neurological diseases, including AD. The present study aims to investigate the effect of the iTBS protocol on the animal model of STZ-induced sAD-like pathology in the context of antioxidant, anti-inflammatory, and anti-amyloidogenic effects in the cortex, striatum, hippocampus, and cerebellum. Methods: Male Wistar rats were divided into four experimental groups: control (icv normal saline solution), STZ (icv STZ-3 mg/kg), STZ + iTBS (STZ rats subjected to iTBS protocol), and STZ + Placebo (STZ animals subjected to placebo iTBS noise artifact). Biochemical assays and immunofluorescence microscopy were used to evaluate functional and structural changes. Results: The icv STZ administration induces oxidative stress and attenuates antioxidative capacity in all examined brain regions. iTBS treatment significantly reduced oxidative and nitrosative stress parameters. Also, iTBS decreased Aß-1-42 and APP levels. The iTBS enhances antioxidative capacity reported as elevated activity of its enzymatic and non-enzymatic components. In addition, iTBS elevated BDNF expression and attenuated STZ-induced astrogliosis confirmed by decreased GFAP+/VIM+/C3+ cell reactivity in the hippocampus. Discussion: Our results provide experimental evidence for the beneficial effects of the applied iTBS protocol in attenuating oxidative stress, increasing antioxidant capacity and decreasing reactive astrogliosis in STZ-administrated rats.

Intermittent Theta Burst Stimulation Ameliorates Cognitive Deficit and Attenuates Neuroinflammation via PI3K/Akt/mTOR Signaling Pathway in Alzheimer's-Like Disease Model.

Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however, exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer's-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups-controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for 15 days and TMT sham group. After 3 weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD.

Downregulation of CD73/A2AR-Mediated Adenosine Signaling as a Potential Mechanism of Neuroprotective Effects of Theta-Burst Transcranial Magnetic Stimulation in Acute Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a chronic neurodegenerative disease caused by autoimmune-mediated inflammation in the central nervous system. Purinergic signaling is critically involved in MS-associated neuroinflammation and its most widely applied animal model-experimental autoimmune encephalomyelitis (EAE). A promising but poorly understood approach in the treatment of MS is repetitive transcranial magnetic stimulation. In the present study, we aimed to investigate the effect of continuous theta-burst stimulation (CTBS), applied over frontal cranial bone, on the adenosine-mediated signaling system in EAE, particularly on CD73/A2AR/A1R in the context of neuroinflammatory activation of glial cells. EAE was induced in two-month-old female DA rats and in the disease peak treated with CTBS protocol for ten consecutive days. Lumbosacral spinal cord was analyzed immunohistochemically for adenosine-mediated signaling components and pro- and anti-inflammatory factors. We found downregulated IL-1ß and NF- κB-ir and upregulated IL-10 pointing towards a reduction in the neuroinflammatory process in EAE animals after CTBS treatment. Furthermore, CTBS attenuated EAE-induced glial eN/CD73 expression and activity, while inducing a shift in A2AR expression from glia to neurons, contrary to EAE, where tight coupling of eN/CD73 and A2AR on glial cells is observed. Finally, increased glial A1R expression following CTBS supports anti-inflammatory adenosine actions and potentially contributes to the overall neuroprotective effect observed in EAE animals after CTBS treatment.

Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients.

INTRODUCTION: Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment. METHODS: This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit. RESULTS: Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.

Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson's disease psychosis.

INTRODUCTION: Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Results from short-term, placebo-controlled studies demonstrated a positive benefit/risk profile. This multi-year, open-label study assessed long-term safety and tolerability of pimavanserin. METHODS: This was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS). RESULTS: Of 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years). CONCLUSIONS: Long-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.

Effect of Transcranial Direct Current Stimulation Combined With Patient-Controlled Intravenous Morphine Analgesia on Analgesic Use and Post-Thoracotomy Pain. A Prospective, Randomized, Double-Blind, Sham-Controlled, Proof-of-Concept Clinical Trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is used for various chronic pain conditions, but experience with tDCS for acute postoperative pain is limited. This study investigated the effect of tDCS vs. sham stimulation on postoperative morphine consumption and pain intensity after thoracotomy. METHODS: This is a single-center, prospective, randomized, double-blind, sham-controlled trial in lung cancer patients undergoing thoracotomy under general anesthesia. All patients received patient-controlled (PCA) intravenous morphine and intercostal nerve blocks at the end of surgery. The intervention group (a-tDCS, n = 31) received anodal tDCS over the left primary motor cortex (C3-Fp2) for 20 min at 1.2 mA, on five consecutive days; the control group (n = 31) received sham stimulation. Morphine consumption, number of analgesia demands, and pain intensity at rest, with movement and with cough were recorded at the following intervals: immediately before (T1), immediately after intervention (T2), then every hour for 4 h (Т3-Т6), then every 6 h (Т7-Т31) for 5 days. We recorded outcomes on postoperative days 1 and 5 and conducted a phone interview inquiring about chronic pain 1 year later (NCT03005548). RESULTS: A total of 62 patients enrolled, but tDCS was prematurely stopped in six patients. Fifty-five patients (27 a-tDCS, 28 sham) had three or more tDCS applications and were included in the analysis. Cumulative morphine dose in the first 120 h after surgery was significantly lower in the tDCS [77.00 (54.00-123.00) mg] compared to sham group [112.00 (79.97-173.35) mg, p = 0.043, Cohen's d = 0.42]. On postoperative day 5, maximum visual analog scale (VAS) pain score with cough was significantly lower in the tDCS group [29.00 (20.00-39.00) vs. 44.50 (30.00-61.75) mm, p = 0.018], and pain interference with cough was 80% lower [10.00 (0.00-30.00) vs. 50.00 (0.00-70.00), p = 0.013]. One year after surgery, there was no significant difference between groups with regard to chronic pain and analgesic use. CONCLUSION: In lung cancer patients undergoing thoracotomy, three to five tDCS sessions significantly reduced cumulative postoperative morphine use, maximum VAS pain scores with cough, and pain interference with cough on postoperative day 5, but there was no obvious long-term benefit from tDCS.

Patient-Controlled Intravenous Morphine Analgesia Combined with Transcranial Direct Current Stimulation for Post-Thoracotomy Pain: A Cost-Effectiveness Study and A Feasibility For Its Future Implementation.

This prospective randomized study aims to evaluate the feasibility and cost-effectiveness of combining transcranial direct current stimulation (tDCS) with patient controlled intravenous morphine analgesia (PCA-IV) as part of multimodal analgesia after thoracotomy. Patients assigned to the active treatment group (a-tDCS, n = 27) received tDCS over the left primary motor cortex for five days, whereas patients assigned to the control group (sham-tDCS, n = 28) received sham tDCS stimulations. All patients received postoperative PCA-IV morphine. For cost-effectiveness analysis we used data about total amount of PCA-IV morphine and maximum visual analog pain scale with cough (VASP-Cmax). Direct costs of hospitalization were assumed as equal for both groups. Cost-effectiveness analysis was performed with the incremental cost-effectiveness ratio (ICER), expressed as the incremental cost (RSD or US$) per incremental gain in mm of VASP-Cmax reduction. Calculated ICER was 510.87 RSD per VASP-Cmax 1 mm reduction. Conversion on USA market (USA data 1.325 US$ for 1 mg of morphine) revealed ICER of 189.08 US$ or 18960.39 RSD/1 VASP-Cmax 1 mm reduction. Cost-effectiveness expressed through ICER showed significant reduction of PCA-IV morphine costs in the tDCS group. Further investigation of tDCS benefits with regards to reduction of postoperative pain treatment costs should also include the long-term benefits of reduced morphine use.

Increased plasma phosphatidylcholine/lysophosphatidylcholine ratios in patients with Parkinson's disease.

RATIONALE: Changes in lipid composition might be associated with the onset and progression of various neurodegenerative diseases. Herein, we investigated the changes in the plasma phosphatidylcholine (PC)/lysophosphatidylcholine (LPC) ratios in patients with Parkinson's disease (PD) in comparison with healthy subjects and their correlation with clinico-pathological features. METHODS: The study included 10 controls and 25 patients with PD. All patients were assigned to groups based on clinico-pathological characteristics (gender, age at examination, duration of disease and Hoehn and Yahr (H&Y) stage). The analysis of the PC/LPC intensity ratios in plasma lipid extracts was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: PD patients exhibited an increased PC/LPC intensity ratio in comparison with the control group of healthy subjects. Furthermore, the investigated ratio was shown to be correlated with clinico-pathological parameters, in particular with H&Y stage and disease duration. The PC/LPC intensity ratio in plasma samples of PD patients was found to be elevated in all examined H&Y stages and throughout the disease duration. CONCLUSIONS: To our knowledge, this is the first study examining the PC/LPC ratios in plasma of patients with PD and illustrating their correlation with clinico-pathological features. Although the presented results may be considered as preliminary due to the limited number of participants, the observed alterations of PC/LPC ratios in plasma might be a first step in the characterization of plasma lipid changes in PD patients and an indicator of lipid reconfiguration.

Prooxidant-antioxidant balance, advanced oxidation protein products and lipid peroxidation in Serbian patients with Parkinson's disease.

BACKGROUND: Biomarkers of oxidative stress are relevant in the evaluation of the disease status and prooxidant-antioxidant balance, advanced oxidation protein products and lipid peroxidation products (malondialdehyde and 4-hydroxynonenal) are being extensively evaluated regarding their relationship with clinical presentation and disease severity. AIM OF THE STUDY: The aim of this study was to evaluate the levels of the above-mentioned parameters in plasma of 39 men and 17 women with Parkinson's disease, originated from the Republic of Serbia and their relation to clinicopathological characteristics (gender, age at examination, duration of the disease, and Hoehn and Yahr score) and oxidative status. RESULTS: The incidence of disease was 2:1 towards males. The investigated oxidative parameters were gender and Hoehn and Yahr related. Significant association of higher Hoehn and Yahr scores was observed for malondialdehyde (p = 0.01) and prooxidant-antioxidant balance (p = 0.02). Relation between oxidant-antioxidant status was further supported by observed positive correlation between 4-hydroxynonenal (p = 0.04) and prooxidant-antioxidant balance (p = 0.03). Finally, the multivariate analysis indicated that prooxidant-antioxidant balance and malondialdehyde were partially determined by gender (10.6% and 7.6%) and Hoehn and Yahr scores (13.6% and 18.8%), while Hoehn and Yahr scores contributed to the variance of advanced oxidation protein products with 13.2%. CONCLUSION: Our results indicate the higher level of oxidative stress (oxidant-antioxidant imbalance) and possible relation of several markers with gender and disease stage in patients with Parkinson's disease. The analyzed markers could be used to specify the severity of oxidative stress; however, their potential value should be analyzed in further studies.

Quantitative Assessment of the Arm/Hand Movements in Parkinson's Disease Using a Wireless Armband Device.

We present an approach for quantitative assessment of the arm/hand movements in patients with Parkinson's disease (PD), from sensor data acquired with a wearable, wireless armband device (Myo sensor). We propose new Movement Performance Indicators that can be adopted by practitioners for the quantitative evaluation of motor performance and support their clinical evaluations. In addition, specific Movement Performance Indicators can indicate the presence of the bradykinesia symptom. The study includes seventeen PD patients and sixteen age-matched controls. A set of representative arm/hand movements is defined under the supervision of movement disorder specialist. In order to assist the evaluations, and for progress monitoring purposes, as well as for assessing the amount of bradykinesia in PD, a total set of 84 Movement Performance Indicators are computed from the sensor readings. Subsequently, we investigate whether wireless armband device, with the use of the proposed Movement Performance Indicators can be utilized: (1) for objective and precise quantitative evaluation of the arm/hand movements of Parkinson's patients, (2) for assessment of the bradykinesia motor symptom, and (3) as an adequate low-cost alternative for the sensor glove. We conducted extensive analysis of proposed Movement Performance Indicators and results are indicating following clinically relevant characteristics: (i) adequate reliability as measured by ICC; (ii) high accuracy in discrimination between the patients and controls, and between the disease stages (support to disease diagnosis and progress monitoring, respectively); (iii) substantial difference in comparison between the left-hand and the right-hand movements across controls and patients, as well as between disease stage groups; (iv) statistically significant correlation with clinical scales (tapping test and UPDRS-III Motor Score); and (v) quantitative evaluation of bradykinesia symptom. Results suggest that the proposed approach has a potential to be adopted by physicians, to afford them with quantitative, objective and precise methods and data during clinical evaluations and support the assessment of bradykinesia.

Combined Vision and Wearable Sensors-based System for Movement Analysis in Rehabilitation.

BACKGROUND: Traditional rehabilitation sessions are often a slow, tedious, disempowering and non-motivational process, supported by clinical assessment tools, i.e. evaluation scales that are prone to subjective rating and imprecise interpretation of patient's performance. Poor patient motivation and insufficient accuracy are thus critical factors that can be improved by new sensing / processing technologies. OBJECTIVES: We aim to develop a portable and affordable system, suitable for home rehabilitation, which combines vision-based and wearable sensors. We introduce a novel approach for examining and characterizing the rehabilitation movements, using quantitative descriptors. We propose new Movement Performance Indicators (MPIs) that are extracted directly from sensor data and quantify the symmetry, velocity, and acceleration of the movement of different body/hand parts, and that can potentially be used by therapists for diagnosis and progress assessment. METHODS: First, a set of rehabilitation exercises is defined, with the supervision of neurologists and therapists for the specific case of Parkinson's disease. It comprises full-body movements measured with a Kinect device and fine hand movements, acquired with a data glove. Then, the sensor data is used to compute 25 Movement Performance Indicators, to assist the diagnosis and progress monitoring (assessing the disease stage) in Parkinson's disease. A kinematic hand model is developed for data verification and as an additional resource for extracting supplementary movement information. RESULTS: Our results show that the proposed Movement Performance Indicators are relevant for the Parkinson's disease assessment. This is further confirmed by correlation of the proposed indicators with clinical tapping test and UPDRS clinical scale. Classification results showed the potential of these indicators to discriminate between the patients and controls, as well as between the stages that characterize the evolution of the disease. CONCLUSIONS: The proposed sensor system, along with the developed approach for rehabilitation movement analysis have a significant potential to support and advance traditional rehabilitation therapy. The main impact of our work is two-fold: (i) the proposition of an approach for supporting the therapists during the diagnosis and monitoring evaluations by reducing subjectivity and imprecision, and (ii) offering the possibility of the system to be used at home for rehabilitation exercises in between sessions with doctors and therapists.

Effects of anodal tDCS and occupational therapy on fine motor skill deficits in patients with chronic stroke.

BACKGROUND: A growing body of evidence supports the effectiveness of using transcranial direct current stimulation (tDCS) in patients with chronic hand motor impairment resulting from stroke. OBJECTIVE: In this study, we investigate and compare the combined effects of anodal tDCS and occupational therapy (OT) to sham stimulation with OT (control) on fine motor skill deficits of chronic stroke patients. METHODS: A total of 26 stroke patients (at ≥ 9 months) were randomly assigned to an active treatment or a control group in a double-blinded, sham-controlled, parallel design study. Each group received OT for 45 min/day (10 sessions for 2 weeks). Treatment was preceded by either 20 minutes of 2 mA anodal tDCS over ipsilesional M1 or sham tDCS. A modified Jebsen-Taylor Hand Function Test (mJTHFT) was administered as primary outcome measure, and handgrip dynamometer and upper limb Fugl-Meyer (ULFM) assessments were performed as secondary outcomes. The assessment was done at baseline (T0), after the interventions on day 1(T1), day 10 (T2) and day 40 (T3). RESULTS: We observed a statistically significant effect in the tDCS group when the results were compared to the sham group. The mJTHFT times were significantly shorter immediately after treatment and at day 40. The intervention had no effect on handgrip strength or ULFM score. CONCLUSION: Fine motor skill deficits in chronic stroke survivors can be improved when intensive OT is primed with anodal tDCS over the ipsilesional hemisphere.

Transcranial theta-burst stimulation alters GLT-1 and vGluT1 expression in rat cerebellar cortex.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in expression of proteins engaged in activity of excitatory and inhibitory systems as well as redox homeostasis. Our aim was to investigate the effect of single (SS) and repeated session (RS) of intermittent and continuous theta-burst stimulation (iTBS; cTBS) on the expression of vesicular and plasmatic glutamate transporters 1 (vGluT1 and GLT-1), glial fibrillary acidic protein (GFAP) and influence on oxidative status in rats cerebellar tissue and plasma. Redox state parameters in cerebellar tissue and plasma were assessed 24 h after single and 48 h after the last TBS session. Molecular changes were examined by immunofluorescence. Stimulation significantly increased thiol groups (SH) in tissue of SS iTBS group, and decreased in iTBS RS. Activity of glucose-6-phosphate-dehydrogenase (G6PD) was increased markedly in cTBS RS. Immunoreactivity of vGluT1 in cTBS RS decreased, while GLT-1 increased in cTBS SS and cTBS RS, compared to control. Present study gives insight in molecular and biochemical mechanisms by which iTBS and cTBS exerts its effects on rats cerebellar cortex.

Opportunities for Guided Multichannel Non-invasive Transcranial Current Stimulation in Poststroke Rehabilitation.

Stroke is a leading cause of serious long-term disability worldwide. Functional outcome depends on stroke location, severity, and early intervention. Conventional rehabilitation strategies have limited effectiveness, and new treatments still fail to keep pace, in part due to a lack of understanding of the different stages in brain recovery and the vast heterogeneity in the poststroke population. Innovative methodologies for restorative neurorehabilitation are required to reduce long-term disability and socioeconomic burden. Neuroplasticity is involved in poststroke functional disturbances and also during rehabilitation. Tackling poststroke neuroplasticity by non-invasive brain stimulation is regarded as promising, but efficacy might be limited because of rather uniform application across patients despite individual heterogeneity of lesions, symptoms, and other factors. Transcranial direct current stimulation (tDCS) induces and modulates neuroplasticity, and has been shown to be able to improve motor and cognitive functions. tDCS is suited to improve poststroke rehabilitation outcomes, but effect sizes are often moderate and suffer from variability. Indeed, the location, extent, and pattern of functional network connectivity disruption should be considered when determining the optimal location sites for tDCS therapies. Here, we present potential opportunities for neuroimaging-guided tDCS-based rehabilitation strategies after stroke that could be personalized. We introduce innovative multimodal intervention protocols based on multichannel tDCS montages, neuroimaging methods, and real-time closed-loop systems to guide therapy. This might help to overcome current treatment limitations in poststroke rehabilitation and increase our general understanding of adaptive neuroplasticity leading to neural reorganization after stroke.

Diagnostic value of combined magnetic resonance imaging examination of brachial plexus and electrophysiological studies in multifocal motor neuropathy.

BACKGROUND/AIM: Multifocal motor neuropathy (MMN) is an immune-mediated disorder characterised by slowly progressive asymetrical weakness of limbs without sensory loss. The objective of this study was to investigate the involvement of brachial plexus using combined cervical magnetic stimulation and magnetic resonance imaging (MRI) of plexus brachialis in patients with MMN. We payed special attention to the nerve roots forming nerves inervating weak muscles, but without detectable conduction block (CB) using conventional nerve conduction studies. METHODS: Nine patients with proven MMN were included in the study. In all of them MRI of the cervical spine and brachial plexus was performed using a Siemens Avanto 1.5 T unit, applying T1 and turbo spin-echo T1 sequence, axial turbo spin-echo T2 sequence and a coronal fat-saturated turbo spin-echo T2 sequence. RESULTS: In all the patients severe asymmetric distal weakness of muscles inervated by radial, ulnar, median and peroneal nerves was observed and the most striking presentation was bilateral wrist and finger drop. Three of them had additional proximal weakness of muscles inervated by axillar and femoral nerves. The majority of the patients had slightly increased cerebrospinal fluid (CSF) protein content. Six of the patients had positive serum polyclonal IgM anti-GM1 antibodies. Electromyoneurography (EMG) showed neurogenic changes, the most severe in distal muscles inervated by radial nerves. All the patients had persistent partial CBs outside the usual sites of nerve compression in radial, ulnar, median and peroneal nerves. In three of the patients cervical magnetic stimulation suggested proximal CBs between cervical root emergence and Erb's point (prolonged motor root conduction time). In all the patients T2-weighted MRI revealed increased signal intensity in at least one cervical root, truncus or fasciculus of brachial plexus. CONCLUSION: We found clinical correlation between muscle weakness, prolonged motor root conduction time and MRI abnormalities of the brachial plexus, which was of the greatest importance in the nerves without CB inervating weak muscles.

Low-frequency repetitive transcranial magnetic stimulation in the right prefrontal cortex combined with partial sleep deprivation in treatment-resistant depression: a randomized sham-controlled trial.

INTRODUCTION: Sham-controlled low-frequency repetitive transcranial magnetic stimulation (rTMS) was used in patients with pharmacoresistant major depression as an added treatment along with partial sleep deprivation (PSD). In addition, the potential predictive role of brain-derived neurotrophic factor genetic polymorphism on treatment response was analyzed. METHODS: We recruited 19 female patients (48.3 ± 8.6 years old) with treatment-resistant unipolar major depression (Hamilton Depression Rating Scale [HDRS] score ≥20) who were on a stable antidepressant treatment. They received either 1-Hz rTMS or sham stimulation over the right dorsolateral prefrontal cortex (intensity of 110% of the threshold; 3000 stimuli per protocol; and 10 daily sessions). Additionally, PSD was applied once per week during the treatment. The patients were evaluated (HDRS and Clinical Global Impression Scale) by a blind rater at baseline (B) and after 2 and 3 weeks (W2 and W3) of treatment for short-term outcome. Long-term evaluations were performed after 12 (W12) and 24 weeks (W24) for patients who received active stimulation. RESULTS: Eleven patients in the active group showed a significant HDRS score reduction from 30.09 ± 3.53 (B) to 16.73 ± 5.71 (W3) compared to the lack of therapeutic response in the sham-treated patients. The long-term follow-up for the active group included 64% of the responders at W12 and 55% at W24. Full remission (HDRS ≤10) was achieved in 5 of 11 patients. Four of these 5 patients with long-term sustained remission expressed the Val66Val genotype. CONCLUSION: Our study suggests a clinically relevant response, persisting for up to 6 months, from 1-Hz rTMS over the right dorsolateral prefrontal cortex and PSD in patients with pharmacoresistant major depression. The brain-derived neurotrophic factor Val66Val homozygous genotype may be related to a better treatment outcome.

Switch to hypomania induced by repetitive transcranial magnetic stimulation and partial sleep deprivation added to antidepressant: a case report.

INTRODUCTION: Bipolar depression is often unrecognized and difficult to treat because of two opposite problems: treatment resistance and risk of manic switch. CASE REPORT: A 53-year-old female was suffering from unipolar depressive disorder since the age of 36. During a recent major depressive episode pervasive feelings of sadness, lost of interest in activities, severe insomnia and highly expressed somatic anxiety dominated 7 months. After unsuccessful tries with two different antidepressants of adequate doses and duration, slow rate repetitive trascranial magnetic stimulation (rTMS) was started, but the patient stayed at the fixed dose of antidepressant. Partial sleep deprivation (PSD) was additionally applied twice during these 2 weeks with the idea to boost up, or enhance rTMS treatment response. At the last two rTMS sessions depression obviously meliorated, but the patient also expressed symptoms of hypomania. The therapy of rTMS was stopped, hypomanic symptoms gradually vanished and two weeks after the rTMS treatment the patient was euthymic. Antidepressant was kept on. In a follow-up period of 2 years the diagnose of bipolar affective disorder was definitely established. CONCLUSION: This case report shows that a combination of slow rate rTMS and partial sleep deprivation in the patient at the fixed dose of antidepressants, have strong synergistic effect even with potential to induce hypomanic switch, that is the first description in the literature to our knowledge.