Elevated iron concentration in putamen and cortical speech motor network in developmental stuttering.

Theoretical accounts of developmental stuttering implicate dysfunctional cortico-striatal-thalamo-cortical motor loops through the putamen. However, the analysis of conventional MRI brain scans in individuals who stutter has failed to yield strong support for this theory in terms of reliable differences in the structure or function of the basal ganglia. Here, we performed quantitative mapping of brain tissue, which can be used to measure iron content alongside markers sensitive to myelin and thereby offers particular sensitivity to the measurement of iron-rich structures such as the basal ganglia. Analysis of these quantitative maps in 41 men and women who stutter and 32 individuals who are typically fluent revealed significant group differences in maps of R2*, indicative of higher iron content in individuals who stutter in the left putamen and in left hemisphere cortical regions important for speech motor control. Higher iron levels in brain tissue in individuals who stutter could reflect elevated dopamine levels or lysosomal dysfunction, both of which are implicated in stuttering. This study represents the first use of these quantitative measures in developmental stuttering and provides new evidence of microstructural differences in the basal ganglia and connected frontal cortical regions.

Propofol rather than Isoflurane Accelerates the Interstitial Fluid Drainage in the Deep Rat Brain.

Objective: Different anesthetics have distinct effects on the interstitial fluid (ISF) drainage in the extracellular space (ECS) of the superficial rat brain, while their effects on ISF drainage in the ECS of the deep rat brain still remain unknown. Herein, we attempt to investigate and compare the effects of propofol and isoflurane on ECS structure and ISF drainage in the caudate-putamen (CPu) and thalamus (Tha) of the deep rat brain. Methods: Adult Sprague-Dawley rats were anesthetized with propofol or isoflurane, respectively. Twenty-four anesthetized rats were randomly divided into the propofol-CPu, isoflurane-CPu, propofol-Tha, and isoflurane-Tha groups. Tracer-based magnetic resonance imaging (MRI) and fluorescent-labeled tracer assay were utilized to quantify ISF drainage in the deep brain. Results: The half-life of ISF in the propofol-CPu and propofol-Tha groups was shorter than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. The ECS volume fraction in the propofol-CPu and propofol-Tha groups was much higher than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. However, the ECS tortuosity in the propofol-CPu and propofol-Tha groups was much smaller than that in isoflurane-CPu and isoflurane-Tha groups, respectively. Conclusions: Our results demonstrate that propofol rather than isoflurane accelerates the ISF drainage in the deep rat brain, which provides novel insights into the selective control of ISF drainage and guides selection of anesthetic agents in different clinical settings, and unravels the mechanism of how general anesthetics function.

Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder - A PET study.

INTRODUCTION: Noradrenergic denervation is thought to aggravate motor dysfunction in Parkinson's disease (PD). In a previous PET study with the norepinephrine transporter (NART) ligand 11C-MeNER, we detected reduced NART binding in primary sensorimotor cortex (M1S1) of PD patients. Idiopathic rapid-eye-movement sleep behaviour disorder (iRBD) is a phenotype of prodromal PD. Using 11C-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether 11C-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with 18F-DOPA PET were correlated. METHODS: 17 iRBD patients, 16 PD patients with (PDRBD+) and 14 without RBD (PDRBD-), and 25 control subjects underwent 11C-MeNER PET. iRBD patients also had 18F-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed. RESULTS: Partial-volume corrected 11C-MeNER binding potential (BPND) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PDRBD+ groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PDRBD+P = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 11C-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal 18F-DOPA uptake and thalamic 11C-MeNER binding in iRBD patients (r2 = 0.343, P = 0.013). CONCLUSIONS: This study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 11C-MeNER binding in iRBD may represent noradrenergic terminal degeneration or physiological down-regulation of NARTs in this prodromal phenotype of PD. The correlation between thalamic 11C-MeNER binding and putaminal 18F-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD.

Effectiveness of QSM over R2* in assessment of parkinson's disease - A systematic review.

The incidence and prevalence of Parkinson's (PD) are increasing rapidly in developing countries. PD is difficult to diagnose based on clinical assessment. Presently, magnetic resonance imaging (MRI) methods such as R2* and Quantitative Susceptibility Mapping (QSM) were found to be useful in diagnosing the PD based on the iron deposition in different regions of the brain. The objective of this review was to evaluate the efficacy of QSM over R2* in assessment of PD. A comprehensive literature search was made on PubMed-Medline, CINAHL, Science Direct, Scopus, Web of Science, and the Cochrane library databases for original research articles published between 2000 and 2018. Original articles that reported the efficacy of QSM and R2* in assessment of PD were included. A total of 327 studies were identified in the literature search. However, only ten studies were eligible for analysis. Of the ten studies, five studies compared the accuracy of QSM over R2* in measuring the iron deposition in different regions of brain in PD. Our review found that QSM has better accuracy in identifying iron deposition in PD patients compared to R2*. However, there is discrepancy in the results between MRI Imaging methods and Postmortem studies. Additional longitudinal research studies are needed to provide a strong evidence base for the use of MRI imaging methods such as R2*and QSM in accurately measuring iron deposition in different regions of brain and serve as biomarkers in PD.

Vector-mediated l-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson's disease.

Ever since its introduction 40 years ago l-3,4-dihydroxyphenylalanine (l-DOPA) therapy has retained its role as the leading standard medication for patients with Parkinson's disease. With time, however, the shortcomings of oral l-DOPA treatment have become apparent, particularly the motor fluctuations and troublesome dyskinetic side effects. These side effects, which are caused by the excessive swings in striatal dopamine caused by intermittent oral delivery, can be avoided by delivering l-DOPA in a more continuous manner. Local gene delivery of the l-DOPA synthesizing enzymes, tyrosine hydroxylase and guanosine-tri-phosphate-cyclohydrolase-1, offers a new approach to a more refined dopaminergic therapy where l-DOPA is delivered continuously at the site where it is needed i.e. the striatum. In this study we have explored the therapeutic efficacy of adeno-associated viral vector-mediated l-DOPA delivery to the putamen in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys, the standard non-human primate model of Parkinson's disease. Viral vector delivery of the two enzymes, tyrosine hydroxylase and guanosine-5'-tri-phosphate-cyclohydrolase-1, bilaterally into the dopamine-depleted putamen, induced a significant, dose-dependent improvement of motor behaviour up to a level identical to that obtained with the optimal dose of peripheral l-DOPA. Importantly, this improvement in motor function was obtained without any adverse dyskinetic effects. These results provide proof-of-principle for continuous vector-mediated l-DOPA synthesis as a novel therapeutic strategy for Parkinson's disease. The constant, local supply of l-DOPA obtained with this approach holds promise as an efficient one-time treatment that can provide long-lasting clinical improvement and at the same time prevent the appearance of motor fluctuations and dyskinetic side effects associated with standard oral dopaminergic medication.

Regulation of Brain DNA Methylation Factors and of the Orexinergic System by Cocaine and Food Self-Administration.

Inhibitors of DNA methylation and orexin type-1 receptor antagonists modulate the neurobiological effects driving drugs of abuse and natural reinforcers by activating common brain structures of the mesolimbic reward system. In this study, we applied a self-administration paradigm to assess the involvement of factors regulating DNA methylation processes and satiety or appetite signals. These factors include Dnmts and Tets, miR-212/132, orexins, and orx-R1 genes. The study focused on dopamine projection areas such as the prefrontal cortex (PFCx) and caudate putamen (CPu) and in the hypothalamus (HP) that is interconnected with the reward system. Striking changes were observed in response to both reinforcers, but differed depending on contingent and non-contingent delivery. Expression also differed in the PFCx and the CPu. Cocaine and food induced opposite effects on Dnmt3a expression in both brain structures, whereas they repressed both miRs to a different extent, without affecting their primary transcript in the CPu. Unexpectedly, orexin mRNAs were found in the CPu, suggesting a transport from their transcription site in the HP. The orexin receptor1 gene was found to be induced by cocaine in the PFCx, consistent with a regulation by DNA methylation. Global levels of 5-methylcytosines in the PFCx were not significantly altered by cocaine, suggesting that it is rather their distribution that contributes to long-lasting behaviors. Together, our data demonstrate that DNA methylation regulating factors are differentially altered by cocaine and food. At the molecular level, they support the idea that neural circuits activated by both reinforcers do not completely overlap.

Pre-conditioning with Remote Photobiomodulation Modulates the Brain Transcriptome and Protects Against MPTP Insult in Mice.

Transcranial photobiomodulation (PBM), which involves the application of low-intensity red to near-infrared light (600-1100 nm) to the head, provides neuroprotection in animal models of various neurodegenerative diseases. However, the absorption of light energy by the human scalp and skull may limit the utility of transcranial PBM in clinical contexts. We have previously shown that targeting light at peripheral tissues (i.e. "remote PBM") also provides protection of the brain in an MPTP mouse model of Parkinson's disease, suggesting remote PBM might be a viable alternative strategy for overcoming penetration issues associated with transcranial PBM. This present study aimed to determine an effective pre-conditioning regimen of remote PBM for inducing neuroprotection and elucidate the molecular mechanisms by which remote PBM enhances the resilience of brain tissue. Balb/c mice were irradiated with 670-nm light (4 J/cm2 per day) targeting dorsum and hindlimbs for 2, 5 or 10 days, followed by injection of the parkinsonian neurotoxin MPTP (50 mg/kg) over two consecutive days. Despite no direct irradiation of the head, 10 days of pre-conditioning with remote PBM significantly attenuated MPTP-induced loss of midbrain tyrosine hydroxylase-positive dopaminergic cells and mitigated the increase in FOS-positive neurons in the caudate-putamen complex. Interrogation of the midbrain transcriptome by RNA microarray and pathway enrichment analysis suggested upregulation of cell signaling and migration (including CXCR4+ stem cell and adipocytokine signaling), oxidative stress response pathways and modulation of the blood-brain barrier following remote PBM. These findings establish remote PBM preconditioning as a viable neuroprotective intervention and provide insights into the mechanisms underlying this phenomenon.

Auditory stimulation by exposure to melodic music increases dopamine and serotonin activities in rat forebrain areas linked to reward and motor control.

Listening to melodic music is regarded as a non-pharmacological intervention that ameliorates various disease symptoms, likely by changing the activity of brain monoaminergic systems. Here, we investigated the effects of exposure to melodic music on the concentrations of dopamine (DA), serotonin (5-HT) and their respective metabolites in the caudate-putamen (CPu) and nucleus accumbens (NAcc), areas linked to reward and motor control. Male adult Wistar rats were randomly assigned to a control group or a group exposed to music. The music group was submitted to 8 music sessions [Mozart's sonata for two pianos (K. 488) at an average sound pressure of 65 dB]. The control rats were handled in the same way but were not exposed to music. Immediately after the last exposure or control session, the rats were euthanized, and their brains were quickly removed to analyze the concentrations of 5-HT, DA, 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the CPu and NAcc. Auditory stimuli affected the monoaminergic system in these two brain structures. In the CPu, auditory stimuli increased the concentrations of DA and 5-HIAA but did not change the DOPAC or 5-HT levels. In the NAcc, music markedly increased the DOPAC/DA ratio, suggesting an increase in DA turnover. Our data indicate that auditory stimuli, such as exposure to melodic music, increase DA levels and the release of 5-HT in the CPu as well as DA turnover in the NAcc, suggesting that the music had a direct impact on monoamine activity in these brain areas.

Regional Variations of Spontaneous, Transient Adenosine Release in Brain Slices.

Transient adenosine signaling has been recently discovered in vivo, where the concentration is on average 180 nM and the duration only 3-4 s. In order to rapidly screen different brain regions and mechanisms of formation and regulation, here we develop a rat brain slice model to study adenosine transients. The frequency, concentration, and duration of transient adenosine events were compared in the prefrontal cortex (PFC), hippocampus (CA1), and thalamus. Adenosine transients in the PFC were similar to those in vivo, with a concentration of 160 ± 10 nM, and occurred frequently, averaging one every 50 ± 5 s. In the thalamus, transients were infrequent, occurring every 280 ± 40 s, and lower concentration (110 ± 10 nM), but lasted twice as long as in the PFC. In the hippocampus, adenosine transients were less frequent than those in the PFC, occurring every 79 ± 7 s, but the average concentration (240 ± 20 nM) was significantly higher. Adenosine transients are largely maintained after applying 200 nM tetrodotoxin, implying they are not activity dependent. The response to adenosine A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) differed by region; DPCPX had no significant effects in the PFC, but increased the average transient concentration in the thalamus and both the transient frequency and concentration in the hippocampus. Thus, the amount of adenosine available to activate receptors, and the ability to upregulate adenosine signaling with DPCPX, varies by brain region. This is an important consideration for designing treatments that modulate adenosine in order to cause neuroprotective effects.

Photobiomodulation-induced changes in a monkey model of Parkinson's disease: changes in tyrosine hydroxylase cells and GDNF expression in the striatum.

Intracranial application of red to infrared light, known also as photobiomodulation (PBM), has been shown to improve locomotor activity and to neuroprotect midbrain dopaminergic cells in rodent and monkey models of Parkinson's disease. In this study, we explored whether PBM has any influence on the number of tyrosine hydroxylase (TH)+cells and the expression of GDNF (glial-derived neurotrophic factor) in the striatum. Striatal sections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice and monkeys and 6-hydroxydopamine (6OHDA)-lesioned rats that had PBM optical fibres implanted intracranially (or not) were processed for immunohistochemistry (all species) or western blot analysis (monkeys). In our MPTP monkey model, which showed a clear loss in striatal dopaminergic terminations, PBM generated a striking increase in striatal TH+ cell number, 60% higher compared to MPTP monkeys not treated with PBM and 80% higher than controls. This increase was not evident in our MPTP mouse and 6OHDA rat models, both of which showed minimal loss in striatal terminations. In monkeys, the increase in striatal TH+ cell number in MPTP-PBM cases was accompanied by similar increases in GDNF expression, as determined from western blots, from MPTP and control cases. In summary, these results offer insights into the mechanisms by which PBM generates its beneficial effects, potentially with the use of trophic factors, such as GDNF.

BDNF val66met association with serotonin transporter binding in healthy humans.

The serotonin transporter (5-HTT) is a key feature of the serotonin system, which is involved in behavior, cognition and personality and implicated in neuropsychiatric illnesses including depression. The brain-derived neurotrophic factor (BDNF) val66met and 5-HTTLPR polymorphisms have predicted differences in 5-HTT levels in humans but with equivocal results, possibly due to limited sample sizes. Within the current study we evaluated these genetic predictors of 5-HTT binding with [11C]DASB positron emission tomography (PET) in a comparatively large cohort of 144 healthy individuals. We used a latent variable model to determine genetic effects on a latent variable (5-HTTLV), reflecting shared correlation across regional 5-HTT binding (amygdala, caudate, hippocampus, midbrain, neocortex, putamen and thalamus). Our data supported a significant BDNF val66met effect on 5-HTTLV such that met-carriers showed 2-7% higher subcortical 5-HTT binding compared with val/val individuals (P=0.042). Our data did not support a BDNF val66met effect in neocortex and 5-HTTLPR did not significantly predict 5-HTTLV. We did not observe evidence for an interaction between genotypes. Our findings indicate that met-carriers have increased subcortical 5-HTT binding. The small difference suggests limited statistical power may explain previously reported null effects. Our finding adds to emerging evidence that BDNF val66met contributes to differences in the human brain serotonin system, informing how variability in the 5-HTT level emerges and may represent an important molecular mediator of BDNF val66met effects on behavior and related risk for neuropsychiatric illness.

[11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome: A pilot study.

Complex regional pain syndrome (CRPS) is characterized by severe and chronic pain, but the pathophysiology of this disease are not clearly understood. The primary aim of our case-control study was to explore neuroinflammation in patients with CRPS using positron emission tomography (PET), with an 18-kDa translocator protein specific radioligand [C]-(R)-PK11195. [C]-(R)-PK11195 PET scans were acquired for 11 patients with CRPS (30-55 years) and 12 control subjects (30-52 years). Parametric image of distribution volume ratio (DVR) for each participant was generated by applying a relative equilibrium-based graphical analysis. The DVR of [C]-(R)-PK11195 in the caudate nucleus (t(21) = -3.209, P = 0.004), putamen (t(21) = -2.492, P = 0.022), nucleus accumbens (t(21) = -2.218, P = 0.040), and thalamus (t(21) = -2.395, P = 0.026) were significantly higher in CRPS patients than in healthy controls. Those of globus pallidus (t(21) = -2.045, P = 0.054) tended to be higher in CRPS patients than in healthy controls. In patients with CRPS, there was a positive correlation between the DVR of [C]-(R)-PK11195 in the caudate nucleus and the pain score, the visual analog scale (r = 0.661, P = 0.026, R = 0.408) and affective subscales of McGill Pain Questionnaire (r = 0.604, P = 0.049, R = 0.364). We demonstrated that neuroinflammation of CRPS patients in basal ganglia. Our results suggest that microglial pathology can be an important pathophysiology of CRPS. Association between the level of caudate nucleus and pain severity indicated that neuroinflammation in this region might play a key role. These results may be essential for developing effective medical treatments.

Lifetime methamphetamine dependence is associated with cerebral microgliosis in HIV-1-infected adults.

Methamphetamine (Meth) use is common among HIV-infected persons. It remains unclear whether Meth dependence is associated with long-lasting degenerative changes in the brain parenchyma and microvasculature of HIV-infected individuals. We examined the postmortem brains of 78 HIV-infected adults, twenty of whom were diagnosed with lifetime Meth dependence (18 past and two current at the final follow-up visit). Using logistic regression models, we analyzed associations of Meth with cerebral gliosis (immunohistochemistry for ionized calcium-binding adapter molecule-1 (Iba1) and glial fibrillary acidic protein (GFAP) in frontal, temporo-parietal, and putamen-internal capsule regions), synaptodendritic loss (confocal microscopy for synaptophysin (SYP) and microtubule-associated protein-2 (MAP2) in frontal cortex), ß-amyloid plaque deposition (immunohistochemistry in frontal and temporo-parietal cortex and putamen), and arteriolosclerosis (histopathology in forebrain white matter). We found that Meth was associated with marked Iba1 gliosis in the temporo-parietal region (odds ratio, 4.42 (95 % confidence interval, 1.36, 14.39), p = 0.014, n = 62), which remained statistically significant after adjusting for HIV encephalitis, white matter lesions, and opportunistic diseases (n = 61); hepatitis C virus seropositivity (n = 54); and lifetime dependence on alcohol, opiates, and cannabis (n = 62). There was no significant association of Meth with GFAP gliosis, SYP or MAP2 loss, ß-amyloid plaque deposition, or arteriolosclerosis. In conclusion, we found lifetime Meth dependence to be associated with focal cerebral microgliosis among HIV-infected adults, but not with other brain degenerative changes examined. Some of the changes in select brain regions might be reversible following extended Meth abstinence or, alternatively, might have not been induced by Meth initially.

Altered serotonin transporter binding potential in patients with obsessive-compulsive disorder under escitalopram treatment: [11C]DASB PET study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic, relapsing mental illness. Selective serotonin reuptake inhibitors block serotonin transporters (SERTs) and are the mainstay of treatment for OCD. SERT abnormalities are reported in drug-free patients with OCD, but it is not known what happens to SERT levels during treatment. This is important as alterations in SERT levels in patients under treatment could underlie poor response, or relapse during or after treatment. The aim of the present study was first to validate a novel approach to measuring SERT levels in people taking treatment and then to investigate SERT binding potential (BP) using [11C]DASB PET in patients with OCD currently treated with escitalopram in comparison with healthy controls. METHOD: Twelve patients and age- and sex-matched healthy controls were enrolled. The patients and healthy controls underwent serial PET scans after administration of escitalopram and blood samples for drug concentrations were collected simultaneously with the scans. Drug-free BPs were obtained by using an inhibitory E max model we developed previously. RESULTS: The inhibitory E max model was able to accurately predict drug-free SERT BP in people taking drug treatment. The drug-free BP in patients with OCD currently treated with escitalopram was significantly different from those in healthy volunteers [Cohen's d = 0.03 (caudate), 1.16 (putamen), 1.46 (thalamus), -5.67 (dorsal raphe nucleus)]. CONCLUSIONS: This result extends previous findings showing SERT abnormalities in drug-free patients with OCD by indicating that altered SERT availability is seen in OCD despite treatment. This could account for poor response and the high risk of relapse in OCD.

Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition.

BACKGROUND: Manganese, an essential metal for normal growth and development, is neurotoxic on excessive exposure. Standard trace element-supplemented neonatal parenteral nutrition (PN) has a high manganese content and bypasses normal gastrointestinal absorptive control mechanisms, which places infants at risk of manganese neurotoxicity. Magnetic resonance (MR) relaxometry demonstrating short T1 relaxation time (T1R) in the basal ganglia reflects excessive brain manganese accumulation. OBJECTIVE: This study tested the hypothesis that infants with greater parenteral manganese exposure have higher brain manganese accumulation, as measured by MR imaging, than do infants with lower parenteral manganese exposure. DESIGN: Infants exposed to parenteral manganese were enrolled in a prospective cohort study. Infants classified as having high manganese exposure received >75% of their nutrition in the preceding 4 wk as PN. All others were classified as having low exposure. Daily parenteral and enteral manganese intakes were calculated. Whole-blood manganese was measured by high-resolution inductively coupled plasma mass spectrometry. Brain MR relaxometry was interpreted by a masked reviewer. Linear regression models, adjusted for gestational age (GA) at birth, estimated the association of relaxometry indexes with total and parenteral manganese exposures. RESULTS: Seventy-three infants were enrolled. High-quality MR images were available for 58 infants, 39 with high and 19 with low manganese exposure. Four infants with a high exposure had blood manganese concentrations >30 µg/L. After controlling for GA, higher parenteral and total manganese intakes were associated with a lower T1R (P = 0.01) in the globus pallidus and putamen but were not associated with whole-blood manganese (range: 3.6-56.6 µg/L). Elevated conjugated bilirubin magnified the association between parenteral manganese and decreasing T1R. CONCLUSION: A short T1R for GA identifies infants at risk of increased brain manganese deposition associated with PN solutions commonly used to nourish critically ill infants. These trials were registered at clinicaltrials.gov as NCT00392977 and NCT00392730.

Quantitative assessment of brain iron by R2* relaxometry in patients with cervical dystonia.

BACKGROUND: The pathophysiology of cervical dystonia is poorly understood. Increased brain iron deposition has been described in different movement disorders. Our aim was to investigate brain iron content in patients with cervical dystonia, using R2* relaxation rate, a validated MRI marker of brain iron level. METHODS: Twelve female patients with primary focal cervical dystonia (mean age: 45.4 ± 8.0 years) and 12 age-matched healthy female subjects (mean age: 45.0 ± 8.0 years) underwent 3T MRI to obtain regional R2* relaxation rates of the thalamus, caudate nucleus, putamen, and globus pallidus (GP). Regions of interest were delineated automatically on T1-weighted MRIs. RESULTS: R2* values in the putamen were positively correlated with age. Patients with cervical dystonia showed elevated R2* values in the GP. CONCLUSIONS: This pilot study provides the first quantitative support for increased brain iron deposition in cervical dystonia. Further studies are needed to explore the implications of this finding.

Neural correlates associated with symptom provocation in pediatric obsessive compulsive disorder after a single session of sham-controlled repetitive transcranial magnetic stimulation.

Treatments for pediatric obsessive-compulsive disorder (OCD) could be enhanced if the physiological changes engendered by treatment were known. This study examined neural correlates of a provocation task in youth with OCD, before and after sham-controlled repetitive transcranial magnetic stimulation (rTMS). We hypothesized that rTMS to the right dorsolateral prefrontal cortex would inhibit activity in cortico-striato-thalamic (CST) circuits associated with OCD to a greater extent than sham rTMS. After baseline (Time 1) functional magnetic resonance imaging (fMRI) during a provocation task, subjects received one session of either fMRI-guided sham (SG; n=8) or active (AG; n=10) 1-Hz rTMS over the rDLPFC for 30min. During rTMS, subjects were presented with personalized images that evoked OCD-related anxiety. Following stimulation, fMRI and the provocation task were repeated (Time 2). Contrary to our prediction for the provocation task, the AG was associated with no changes in BOLD response from Times 1 to 2. In contrast, the SG had a significant increase at Time 2 in BOLD response in the right inferior frontal gyrus and right putamen, which persisted after adjusting for age, gender, and time to scanner as covariates. This study provides an initial framework for TMS interrogation of the CST circuit in pediatric OCD.

Topography of primitive reflexes in dementia: an F-18 fluorodeoxyglucose positron emission tomography study.

BACKGROUND AND PURPOSE: Although primitive reflexes (PRs) are inhibited during the first years of childhood, they may reappear with brain injury. PRs have been linked to frontal lobe dysfunction, but their precise topography has not yet been defined. The purpose of this study was to map which regions of the brain display a reduced glucose metabolism in patients with cognitive impairment and PRs. METHODS: A prospective study was conducted to evaluate PRs in a group of patients assessed due to suspected cognitive decline. Neurological and neuropsychological examinations and (18) F-fluorodeoxyglucose positron emission tomography fused with computerized tomography were performed. Voxel-based brain mapping analysis by means of statistical parametric mapping was used to compare patients with and without PRs. RESULTS: The study included 99 patients (33 diagnosed with Alzheimer's disease, 33 on the frontotemporal dementia spectrum and 33 with other diagnoses). Mean age was 71 ± 9.7 years; time since symptom onset was 3.6 ± 2.9 years. At least one PR was observed in 43 cases (43.4% of the whole sample; 48.5% in the Alzheimer disease group, 63.6% in frontotemporal dementia and 18.2% in the group with other diagnoses). The group of patients with PRs exhibited a decreased cerebral metabolism in the bilateral superior frontal gyri (Brodmann area 6), bilateral putamina and thalami. CONCLUSIONS: The presence of PRs was associated with hypometabolism at the superior frontal gyrus and putamen. This suggests that dysfunction in the corticostriatal motor circuit (supplementary motor area-putamen-thalamus) may constitute the anatomical basis of the recurrence of PRs.

The utility of susceptibility-weighted imaging for differentiating Parkinsonism-predominant multiple system atrophy from Parkinson's disease: correlation with 18F-flurodeoxyglucose positron-emission tomography.

Our study was intended to demonstrate the different signal intensity (SI) pattern of the putamen seen on susceptibility-weighted imaging (SWI) between that of Parkinson's disease (PD) and Parkinsonism-predominant multiple system atrophy (MSA-P), and to correlate it with (18)F-flurodeoxyglucose positron-emission tomography ((18)F-FDG PET). Thirty patients with PD and 17 with MSA-P underwent SWI, and (18)F-FDG PET were included. The SI was measured on SWI in the anterior and posterior halves of the putamen using a region-of-interest (ROI) on both sides. The normalized regional glucose metabolism (standardized uptake value ratio, SUVR) was measured on co-registered (18)F-FDG PET images using the ROI obtained with SWI. Analysis included a group-level comparison of the SI values obtained on SWI, and these results were correlated with the SUVR on (18)F-FDG PET. The SIs of the bilateral posterior, dominant-side of the posterior, mean values of the bilateral anterior and posterior halves of the putamen on SWI, differed significantly between the two groups (P < 0.001, respectively). The SUVR of the all locations also differed significantly between PD and MSA-P (P < 0.001, respectively). There was a moderate degree of positive correlation between the SI and the SUVR of the left posterior half, and mean value of the bilateral posterior putamen in MSA-P (r = 0.634, P = 0.006, r = 0.492, P = 0.045). In conclusion, the low SI seen on the posterior putamen may differentiate MSA-P from PD. Furthermore, low SI in the putamen correlated with hypometabolism on (18)F-FDG PET. Therefore, SWI could be a potential complementary diagnostic tool to (18)F-FDG PET for differentiating these conditions.

Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial.

INTRODUCTION: Parkinson's disease (PD) has a progressive course and is characterized by the degeneration of dopaminergic neurons. Although no neuroprotective treatments for PD have been found to date, the endocannabinoid system has emerged as a promising target. METHODS: From a sample of 119 patients consecutively evaluated in a specialized movement disorders outpatient clinic, we selected 21 PD patients without dementia or comorbid psychiatric conditions. Participants were assigned to three groups of seven subjects each who were treated with placebo, cannabidiol (CBD) 75 mg/day or CBD 300 mg/day. One week before the trial and in the last week of treatment participants were assessed in respect to (i) motor and general symptoms score (UPDRS); (ii) well-being and quality of life (PDQ-39); and (iii) possible neuroprotective effects (BDNF and H(1)-MRS). RESULTS: We found no statistically significant differences in UPDRS scores, plasma BDNF levels or H(1)-MRS measures. However, the groups treated with placebo and CBD 300 mg/day had significantly different mean total scores in the PDQ-39 (p = 0.05). CONCLUSIONS: Our findings point to a possible effect of CBD in improving quality of life measures in PD patients with no psychiatric comorbidities; however, studies with larger samples and specific objectives are required before definitive conclusions can be drawn.