Background Reduced excitability of the right prefrontal cortex (rPFC) has been implicated in attention deficit/hyperactivity disorder (ADHD). Despite its high prevalence, chronic treatments for ADHD ...are not tolerable by many patients. Modulation of the rPFC with rTMS may become a novel treatment alternative. Methods Drug-free adults with ADHD ( n = 53) received 15 daily sessions of high-frequency repetitive TMS directed to the rPFC, using either deep (H-6r, dTMS), standard (Figure-8, 8TMS), or sham coils. Standard ADHD questionnaires were administered, and EEG recordings were taken before, during, and after the first and the last days of treatment. In addition, EEG was recorded during a Stop Signal task (SST), following single TMS pulses over the rPFC, and during the treatment session itself. Additional comparison group of healthy subjects ( n = 41) was recorded under the same conditions, but did not undergo the chronic rTMS treatment. Results At baseline, amplitudes of TMS evoked potential (TEP) and the SST’s N200 and P300 components, were significantly lower in subjects with ADHD than those of healthy controls. Moreover, the TEP and SST amplitudes correlated with ADHD symptoms and with the behavioral inhibition measures. Following treatment, improvement in ADHD total symptoms was only evident in the dTMS group. Moreover, TEP was enhanced following the first treatment session with either 8TMS or dTMS, but long-term cumulative enhancement was evident only in the dTMS group. Finally, specific EEG bands recorded at rest and during the first treatment session were highly correlated with dTMS outcomes; yielding a prognostic marker that explains 90% of variance in therapeutic outcome. Discussion These findings suggest that 3 weeks high frequency dTMS treatment can serve as a novel treatment for ADHD in adults, possibly by enhancing excitability of the rPFC. Furthermore, electrophysiological activity elicited during the first treatment session can serve as a high quality prognostic marker. This predictor may promote superior treatment response rates under proper selection of patients and is a first step towards the development of personalized dTMS treatment.
Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal ...neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.
Several psychiatric disorders involve impaired excitability and function of reward-related circuitries. Repeated stimulation of these circuitries can enhance neuroplasticity and induce long-lasting ...alterations in excitability and function, thereby becoming a novel therapeutic approach. Our animal studies revealed that multiple sessions of localized stimulation of the prefrontal cortex unilaterally or bilaterally can alter molecular and behavioral features of depression or addiction, respectively. In order to affect the relevant circuitries without a surgery, we have designed special transcranial magnetic stimulation (TMS) coils that enable stimulation of deeper and larger regions relative to those directly affected by standard TMS. These coils, termed H-coils, were tested for their safety and ability to reach deeper brain regions, and evaluation of their antidepressant potential when applied over the prefrontal cortex of medication-resistant depressive patients showed high rates of remission in a large multi-center study. The therapeutic potential of other versions of the H-coils are evaluated in several psychiatric disorders including addiction. We have recently completed a study in heavy smokers in which the effectiveness of several stimulation parameters were evaluated in combination with or without cue-induced craving. It was found that high-frequency stimulation of the prefrontal cortex and the insular cortex combined with craving induction causes significant lasting reductions in cigarette consumption, urine cotinine levels and cigarette craving. Such effect was not observed when stimulation did not follow psychological activation of craving or when stimulation was applied at low frequency. The choice of coil and target in TMS studies may be critical in both psychiatric and basic brain research. The ability to induce direct stimulation of deeper brain regions opens a wide range of therapeutic and research options. Optimization of stimulation parameters requires further investigation into mechanisms utilizing imaging and electrophysiological techniques.
The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain ...disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders.
In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.
Background
Painful neuropathy is associated with plasticity changes in the nervous system. Standard repetitive transcranial magnetic stimulation (rTMS) is a non‐invasive technique used to study ...changes in cortical excitability and to inhibit pain perception. Deep rTMS is a newer development that allows direct activation of deeper neuronal populations, by a unique coil design termed the H‐coil. This study was designed to assess whether deep rTMS applied over the motor cortical lower‐limb representation relieves pain in patients with diabetic neuropathy.
Methods
Patients were randomly assigned to receive daily real or sham H‐coil rTMS for 5 consecutive days. After a 5‐week washout period, they crossed over to the alternative treatment for additional 5 days (according to a crossover study design). Outcome measures were changes in the visual analogue scale (VAS) for pain and in area and threshold of RIII nociceptive flexion reflex (RIII reflex).
Results
Of the 25 patients randomized, 23 completed the study. After real rTMS, the VAS scores decreased significantly (p = 0.01), and so did RIII reflex area (p < 0.01), while no significant effects in these variables were induced by the sham rTMS treatment. The rTMS‐induced changes in the outcome measures disappeared about 3 weeks after stimulation. All patients tolerated stimulation well.
Conclusions
Deep H‐coil rTMS provides pain relief in patients with diabetic neuropathy. This innovative technique can induce a therapeutic effect on brain areas that otherwise remain difficult to target. rTMS may produce its analgesic effects, inducing motor cortex plasticity and activating descending inhibitory pain control systems.
Well-functioning error monitoring of the inner and outer environments is essential for adaptively altering behavior, while malfunction characterizes conditions such as obsessive–compulsive disorder ...(OCD). The underlying brain processing is manifested as Error-Related Negativity (ERN) signal elicited following error comission, and Perceived Error Related Theta Activity (PERTA) signal elicited following detection of discrepancy in the environment. Yet, while enhanced ERN was repeatedly demonstrated in OCD patients and was found to be potentiated among their unaffected first degree relatives, no comparable observations were reported with regard to PERTA. We recorded EEG activity while OCD patients, OCD patients’ siblings (Family), and healthy controls (HC) performed computerized tasks. For the examination of ERN we used the Stroop task and for the examination of PERTA we presented correct and incorrect mathematical equations. Increased ERN (0–120 ms post response) was observed in both the OCD and Family groups, but only the OCD patients’ signal significantly differed from that of HC's. Similarly, modified PERTA activity was observed in both the OCD and Family groups in the N1 peak (65–125 ms post perceived error), but only for the OCD group this activity significantly differed from that of HC. Both ERN and PERTA's N1 are fast occurring peaks, which suggests that OCD is associate with a constantly over-activated detection system that monitors the inner and outer environment and reacts promptly following detection of a mistake. Furthermore, the modified but non-significantly different activity of the Family group suggests that the pathological condition evolves in vulnerable individuals with neuronal predisposition.
•A TMS questionnaire, TMSens_Q, was developed to report secondary effects following TMS application.•A Delphi procedure was used to reach a consensus on items among international TMS experts.•The TMS ...questionnaire could improve the quality of data reporting in TMS studies.
Transcranial magnetic stimulation (TMS) has been widely used in both clinical and research practice. However, TMS might induce unintended sensations and undesired effects as well as serious adverse effects. To date, no shared forms are available to report such unintended effects. This study aimed at developing a questionnaire enabling reporting of TMS unintended effects. A Delphi procedure was applied which allowed consensus among TMS experts. A steering committee nominated a number of experts to be involved in the Delphi procedure. Three rounds were conducted before reaching a consensus. Afterwards, the questionnaire was publicized on the International Federation of Clinical Neurophysiology website to collect further suggestions by the wider scientific community. A last Delphi round was then conducted to obtain consensus on the suggestions collected during the publicization and integrate them in the questionnaire. The procedure resulted in a questionnaire, that is the TMSens_Q, applicable in clinical and research settings. Routine use of the structured TMS questionnaire and standard reporting of unintended TMS effects will help to monitor the safety of TMS, particularly when applying new protocols. It will also improve the quality of data collection as well as the interpretation of experimental findings.
Two Brain Sites for Cannabinoid Reward Zangen, Abraham; Solinas, Marcello; Ikemoto, Satoshi ...
The Journal of neuroscience,
05/2006, Letnik:
26, Številka:
18
Journal Article
Recenzirano
Odprti dostop
The recent findings that Delta9tetrahydrocannabinol (Delta9THC), the active agent in marijuana and hashish, (1) is self-administered intravenously, (2) potentiates the rewarding effects of electrical ...brain stimulation, and (3) can establish conditioned place preferences in laboratory animals, suggest that these drugs activate biologically primitive brain reward mechanisms. Here, we identify two chemical trigger zones for stimulant and rewarding actions of Delta9THC. Microinjections of Delta9THC into the posterior ventral tegmental area (VTA) or into the shell of the nucleus accumbens (NAS) increased locomotion, and rats learned to lever-press for injections of Delta9THC into each of these regions. Substitution of vehicle for drug or treatment with a cannabinoid CB1 receptor antagonist caused response cessation. Microinjections of Delta9THC into the posterior VTA and into the posterior shell of NAS established conditioned place preferences. Injections into the core of the NAS, the anterior VTA, or dorsal to the VTA were ineffective. These findings link the sites of rewarding action of Delta9THC to brain regions where such drugs as amphetamines, cocaine, heroin, and nicotine are also thought to have their sites of rewarding action.
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