Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington's disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies. As a number of studies have reported tau pathology in HD patients, we investigated whether HD pathology may promote tau hyperphosphorylation and if so tackle some of its underlying mechanisms. For that purpose, we used the R6/2 mouse, a well-characterized model of HD, and analyzed tau phosphorylation before and after the onset of HD-like symptoms. We found a significant increase in tau hyperphosphorylation at the PHF-1 epitope in pre-symptomatic R6/2 mice, whereas symptomatic mice displayed tau hyperphosphorylation at multiple tau phosphoepitopes (AT8, CP13, PT205 and PHF-1). There was no activation of major tau kinases that could explain this observation. However, when we examined tau phosphatases, we found that calcineurin/PP2B was downregulated by 30% in pre-symptomatic and 50% in symptomatic R6/2 mice, respectively. We observed similar changes in tau phosphorylation and calcineurin expression in Q175 mice, another HD model. Calcineurin was also reduced in Q111 compared with Q7 cells. Finally, pharmacological or genetic inhibition of endogenous calcineurin was sufficient to promote tau hyperphosphorylation in neuronal cells. Taken together, our data suggest that mutant huntingtin can induce abnormal tau hyperphosphorylation in vivo, via the deregulation of calcineurin.

Does abnormal interhemispheric inhibition play a role in mirror dystonia?

The presence of mirror dystonia (dystonic movement induced by a specific task performed by the unaffected hand) in the dominant hand of writer's cramp patients when the nondominant hand is moved suggests an abnormal interaction between the 2 hemispheres. In this study we compare the level of interhemispheric inhibition (IHI) in 2 groups of patients with writer's cramp, one with the presence of a mirror dystonia and the other without as well as a control group. The level of bidirectional IHI was measured in wrist muscles with dual-site transcranial magnetic stimulation with a 10-millisecond (short IHI) and a 40-millisecond (long IHI) interstimulus interval during rest and while holding a pen in 9 patients with mirror dystonia 7 without mirror dystonia, and 13 controls. The group of patients without mirror dystonia did not differ from the controls in their IHI level. In contrast, IHI was significantly decreased in the group of patients with mirror dystonia in comparison with the group without mirror dystonia and the controls in both wrist muscles of both the dystonic and unaffected hand whatever the resting or active condition (P = 0.001). The decrease of IHI level in the group of patients with mirror dystonia was negatively correlated with the severity and the duration of the disease: the weaker the level of IHI, the more severe was the disease and the longer its duration. Interhemispheric inhibition disturbances are most likely involved in the occurrence of mirror dystonia. This bilateral deficient inhibition further suggests the involvement of the unaffected hemisphere in the pathophysiology of unilateral dystonia.

Concurrent Transcranial Direct Current Stimulation and Resting-State Functional Magnetic Resonance Imaging in Patients with Gambling Disorder.

Background/Introduction: Transcranial direct current stimulation (tDCS) delivered over the dorsolateral prefrontal cortex (DLPFC) while patients are at rest can decrease craving in patients with substance-related and addictive disorders. Yet, the effects of tDCS on resting-state brain activity remain unknown in this population. This study examined the effects of tDCS on resting-state functional connectivity (rsFC) with concurrent stimulation and functional magnetic resonance imaging in patients with gambling disorder. Methods: This was a randomized, sham-controlled, double-blind, crossover study. The anodal and cathodal electrodes were applied over the right and left DLPFC, respectively. Patients received 30 min of active and sham stimulation on separate days. rsFC was assessed before and during stimulation with seed-based analyses. Results: There was a significant increase of rsFC between the right DLPFC seed and the right superior parietal lobule during active stimulation as compared to during sham stimulation (p = 0.0059, corrected for multiple comparisons). There was also a positive correlation between rsFC change of this frontoparietal network and brain volume of the right DLPFC (p = 0.0042, corrected for multiple comparisons). Discussion: A single session of tDCS targeting the DLPFC strengthened functional connectivity in a frontoparietal circuit, known to be implicated in cognitive control, especially in patients with a greater volume of the region under the anode electrode. Impact statement Transcranial direct current stimulation increased the functional connectivity of a frontoparietal circuit in patients with gambling disorder. These changes were larger in patients with greater volume of the dorsolateral prefrontal cortex. Transcranial direct current stimulation strengthened the connectivity of a brain network known to be associated with cognitive control.

Brain morphometry in adults with gambling disorder.

Little is known regarding the brain substrates of Gambling Disorder, including surface brain morphometry, and whether these are linked to the clinical profile. A better understanding of the brain substrates will likely help determine targets to treat patients. Hence, the aim of this study was two-fold, that is to examine surface-based morphometry in 17 patients with gambling disorder as compared to norms of healthy individuals (2713 and 2790 subjects for cortical and subcortical anatomical scans, respectively) and to assess the clinical relevance of morphometry in patients with Gambling Disorder. This study measured brain volume, surface and thickness in Gambling Disorder. We compared these measures to those of a normative database that controlled for factors such as age and sex. We also tested for correlations with gambling-related behaviors, such as gambling severity and duration, impulsivity, and depressive symptoms (assessed using the South Oaks Gambling Screen, years of gambling, Barratt Impulsiveness Scale, and Beck Depression Inventory, respectively). Patients displayed thinner prefrontal and parietal cortices, greater volume and thickness of the occipital and the entorhinal cortices, and greater volume of subcortical regions as compared to the norms of healthy individuals. There were positive correlations between surface area of occipital regions and depressive symptoms. This work contributes to better characterize the brain substrates of Gambling Disorder, which appear to resemble those of substance use disorders and Internet Gaming Disorder.

Online effects of transcranial direct current stimulation on prefrontal metabolites in gambling disorder.

Gambling disorder is characterized by persistent maladaptive gambling behaviors and is now considered among substance-related and addictive disorders. There is still unmet therapeutic need for these clinical populations, however recent advances indicate that interventions targeting the Glutamatergic/GABAergic system hold promise in reducing symptoms in substance-related and addictive disorders, including gambling disorder. There is some data indicating that transcranial direct current stimulation may hold clinical benefits in substance use disorders and modulate levels of brain metabolites including glutamate and GABA. The goal of the present work was to test whether this non-invasive neurostimulation method modulates key metabolites in gambling disorder. We conducted a sham-controlled, crossover, randomized study, blinded at two levels in order to characterize the effects of transcranial direct current stimulation over the dorsolateral prefrontal cortex on neural metabolites levels in sixteen patients with gambling disorder. Metabolite levels were measured with magnetic resonance spectroscopy from the right dorsolateral prefrontal cortex and the right striatum during active and sham stimulation. Active as compared to sham stimulation elevated prefrontal GABA levels. There were no significant changes between stimulation conditions in prefrontal glutamate + glutamine and N-acetyl Aspartate, or in striatal metabolite levels. Results also indicated positive correlations between metabolite levels during active, but not sham, stimulation and levels of risk taking, impulsivity and craving. Our findings suggest that transcranial direct current stimulation can modulate GABA levels in patients with gambling disorder which may represent an interesting future therapeutic avenue.

Cortical Excitability During Passive Action Observation in Hospitalized Adults With Subacute Moderate to Severe Traumatic Brain Injury: A Preliminary TMS Study.

Studies indicate that motor functions in patients with traumatic brain injury (TBI) can be improved with action observation. It has been hypothesized that this clinical practice relies on modulation of motor cortical excitability elicited by passive action observation in patients with TBI, a phenomenon shown thus far only in normal controls. The purpose of this work was to test this hypothesis and characterize the modulation of motor cortex excitability during passive action observation in patients with subacute moderate to severe TBI. We measured motor evoked potentials induced by single-pulse transcranial magnetic stimulation to the left primary motor cortex and recorded from the contralateral first dorsal interosseus while 20 participants observed videos of static and moving right index finger. Results were compared with those of 20 age-and gender-matched healthy controls. As expected, greater excitability was elicited during moving than static stimuli in healthy subjects. However, this was not observed in patients with TBI. Modulation of motor excitability during action observation is impaired in patients with TBI depending on motor dysfunction, lesion site, and number of days postinjury. These preliminary results suggest a strategy to identify patients in whom action observation might be a valuable neurorehabilitative strategy.

Anesthesia and tau pathology.

Alzheimer's disease (AD) is the most common form of dementia and remains a growing worldwide health problem. As life expectancy continues to increase, the number of AD patients presenting for surgery and anesthesia will steadily rise. The etiology of sporadic AD is thought to be multifactorial, with environmental, biological and genetic factors interacting together to influence AD pathogenesis. Recent reports suggest that general anesthetics may be such a factor and may contribute to the development and exacerbation of this neurodegenerative disorder. Intra-neuronal neurofibrillary tangles (NFT), composed of hyperphosphorylated and aggregated tau protein are one of the main neuropathological hallmarks of AD. Tau pathology is important in AD as it correlates very well with cognitive dysfunction. Lately, several studies have begun to elucidate the mechanisms by which anesthetic exposure might affect the phosphorylation, aggregation and function of this microtubule-associated protein. Here, we specifically review the literature detailing the impact of anesthetic administration on aberrant tau hyperphosphorylation as well as the subsequent development of neurofibrillary pathology and degeneration.