Beyond the caudate nucleus: Early atypical neuroimaging findings in biotin-thiamine- responsive basal ganglia disease.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a treatable neurometabolic disease caused by variants in SLC19A3. Typical imaging features include symmetrical involvement of the caudate nuclei and putamina. OBJECTIVE: The study sought to explore classical BTBGD without caudate nucleus involvement, to highlight the importance of recognizing this new pattern early in the disease. METHODS: Individuals with genetically confirmed BTBGD who harbored the same homozygous variant: NM_025243.4 (SLC19A3): c.1264A > G (p.Thr422Ala) and had atypical neuroimaging were recruited. RESULTS: Nine patients with BTBGD had atypical neuroimaging findings on the first MRI scan. The median age at symptom onset was 3 years. All patients presented with classical clinical features of subacute encephalopathy, dystonia, ataxia, and seizures. During the acute crisis, MRI revealed bilateral and symmetric involvement of the putamina in all patients; one showed small caudate nuclei involvement. In addition, the thalami, cerebellum, and brain stem were involved in six patients, seven patients, and three patients, respectively. Treatment included a combination of high doses of thiamine and biotin. One patient died; he did not receive any vitamin supplementation. Two patients who were treated late had severe neurological sequelae, including generalized dystonia and quadriplegia. Six patients treated early had good outcomes with minimal sequelae, including mild dystonia and dysarthria. Two patients showed the classical chronic atrophic and necrotic changes already described. CONCLUSION: The early atypical neuroimaging pattern of BTBGD described here, particularly the lack of caudate nucleus involvement, should not dissuade the clinician and radiologist from considering a diagnosis of BTBGD.

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.

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.

Brain interstitial fluid drainage and extracellular space affected by inhalational isoflurane: in comparison with intravenous sedative dexmedetomidine and pentobarbital sodium.

Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain. Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular space but these still remain unknown. Herein, effects of the inhalational isoflurane, intravenous sedative dexmedetomidine and pentobarbital sodium on deep brain matters' interstitial fluid drainage and extracellular space and underlying mechanisms were investigated. When compared to intravenous anesthetic dexmedetomidine or pentobarbital sodium, inhalational isoflurane induced a restricted diffusion of extracellular space, a decreased extracellular space volume fraction, and an increased norepinephrine level in the caudate nucleus or thalamus with the slowdown of brain interstitial fluid drainage. A local administration of norepinephrine receptor antagonists, propranolol, atipamezole and prazosin into extracellular space increased diffusion of extracellular space and interstitial fluid drainage whilst norepinephrine decreased diffusion of extracellular space and interstitial fluid drainage. These findings suggested that restricted diffusion in brain extracellular space can cause slowdown of interstitial fluid drainage, which may contribute to the neurotoxicity following the waste accumulation in extracellular space under inhaled anesthesia per se.

Resolvin D1 suppresses inflammation-induced hyperexcitability of nociceptive trigeminal neurons associated with mechanical hyperalgesia.

7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid (resolvin D1 [RvD1]) is biosynthesized from docosahexaenoic acid (DHA), and belongs to a novel family of lipid mediators showing remarkable anti-inflammatory effects; however, the effect of RvD1 on inflammation-induced hyperexcitability of nociceptive neurons under in vivo conditions remains to be determined. The present study, therefore, investigated whether under in vivo conditions, systemic administration of RvD1 could attenuate the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis (SpVc) wide-dynamic range (WDR) neurons associated with hyperalgesia in rats. The threshold of escape from mechanical stimulation applied to the orofacial area in rats with complete Freund's adjuvant-induced inflammation was significantly lower than in naïve rats. The lowered mechanical threshold in rats with inflammation was returned to control levels following administration of RvD1 (3 ng/kg, i.p.) for 3 days. The mean discharge frequency of SpVc WDR neurons in rats with inflammation was significantly decreased after RvD1 administration for both non-noxious and noxious mechanical stimuli. Increased spontaneous discharge of SpVc WDR neurons in rats with inflammation was also significantly decreased after RvD1 administration. Noxious pinch-evoked afterdischarge frequency and occurrence in rats with inflammation was significantly diminished after RvD1 administration. Expansion of the receptive field in rats with inflammation also returned to control levels after RvD1 administration. These results suggest that administration of RvD1 attenuates inflammation-induced hyperexcitability of SpVc WDR neurons associated with inflammatory hyperalgesia. These findings support the idea that RvD1, derived from DHA, as well as DHA itself, are potential complementary or alternative therapeutic agents for the alleviation of inflammatory hyperalgesia.

Impact of chronic migraine attacks and their severity on the endogenous µ-opioid neurotransmission in the limbic system.

OBJECTIVE: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous µ-opioid neurotransmission. BACKGROUND: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. METHODS: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the µ-opioid receptor availability and the clinical data. RESULTS: µOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower µOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower µOR BPND values indicate either a decrease in µOR concentration or an increase in endogenous µ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in µOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R2 = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R2 = 0.08). CONCLUSIONS: Increased endogenous µ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous µ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313.

Brain neurochemistry in unmedicated obsessive-compulsive disorder patients and effects of 12-week escitalopram treatment: 1 H-magnetic resonance spectroscopy study.

AIM: The purpose of this study was to examine treatment-related neurochemical changes in 28 unmedicated obsessive-compulsive disorder (OCD) patients using 1 H-magnetic resonance spectroscopy (1 H-MRS). METHODS: We included subjects diagnosed with OCD (n = 28), each with a total duration of illness of less than 5 years, as a study group and age- and sex-matched healthy controls (n = 26). The inclusion criteria for the OCD group were right-handed individuals aged 18 years or older who had not been on any specific treatment for OCD for the last at least 8 weeks and who had no other psychiatric comorbidity. A pre-post and case-control design was employed in which OCD patients underwent 1 H-MRS at baseline and 12 weeks after treatment with escitalopram (n = 21). Clinical assessment was carried out using a semi-structured pro forma Yale-Brown Obsessive Compulsive Scale and the World Health Organization Disability Assessment Scale 2.0 before and after treatment. Volume-localized 1 H-MRS was carried out with a 3-Tesla Philips MR scanner. RESULTS: Our data suggested higher levels of myoinositol (mI), total choline (tCho), and glutamate+glutamine (Glx) in the medial thalamus at pre-assessment in OCD subjects as compared to healthy controls and a significant reduction in tCho and Glx after treatment in OCD subjects. The mI levels in the caudate nucleus and Glx levels in the anterior cingulate cortex were significantly correlated with disease severity on the Yale-Brown Obsessive Compulsive Scale. CONCLUSION: Our study supports the hypothesis of a hyper-glutaminergic state (as suggested by increased Glx levels) and neurodegeneration (as suggested by increased tCho and mI in the thalamus) in cortico-striato-thalamocortical circuitry in OCD patients as suggested by previous studies using MRS as well as other functional imaging studies.

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.

Cerebral dopaminergic and glutamatergic transmission relate to different subjective responses of acute alcohol intake: an in vivo multimodal imaging study.

Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [18 F]fallypride and [18 F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [18 F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P < 0.05, corrected for multiple comparisons). Dopamine release in the ACC and orbitofrontal and ventromedial PFCs were correlated with subjective 'liking' and 'wanting' effects (P < 0.05). In contrast, baseline mGluR5 availability was positively correlated with the 'high' effect of alcohol in dorsolateral, ventrolateral and ventromedial PFCs and in the medial temporal lobe, thalamus and caudate nucleus (P < 0.05). Although neither proton-magnetic resonance spectroscopy glutamate nor glutamine levels were affected by alcohol, baseline ACC glutamate levels were negatively associated with the alcohol 'liking' effect (P < 0.003). These data reveal new mechanistic understanding and differential neurobiological underpinnings of the effects of acute alcohol consumption on human behavior. Specifically, prefrontal dopamine release may encode alcohol 'liking' and 'wanting' effects in specific areas underlying value processing and motivation, whereas mGluR5 availability in distinct prefrontal-temporal-subcortical regions is more related to the alcohol 'high' effect.

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.

Monoamine Release during Unihemispheric Sleep and Unihemispheric Waking in the Fur Seal.

STUDY OBJECTIVES: Our understanding of the role of neurotransmitters in the control of the electroencephalogram (EEG) has been entirely based on studies of animals with bilateral sleep. The study of animals with unihemispheric sleep presents the opportunity of separating the neurochemical substrates of waking and sleep EEG from the systemic, bilateral correlates of sleep and waking states. METHODS: The release of histamine (HI), norepinephrine (NE), and serotonin (5HT) in cortical and subcortical areas (hypothalamus, thalamus and caudate nucleus) was measured in unrestrained northern fur seals (Callorhinus ursinus) using in vivo microdialysis, in combination with, polygraphic recording of EEG, electrooculogram, and neck electromyogram. RESULTS: The pattern of cortical and subcortical HI, NE, and 5HT release in fur seals is similar during bilaterally symmetrical states: highest in active waking, reduced in quiet waking and bilateral slow wave sleep, and lowest in rapid eye movement (REM) sleep. Cortical and subcortical HI, NE, and 5HT release in seals is highly elevated during certain waking stimuli and behaviors, such as being sprayed with water and feeding. However, in contrast to acetylcholine (ACh), which we have previously studied, the release of HI, NE, and 5HT during unihemispheric sleep is not lateralized in the fur seal. CONCLUSIONS: Among the studied neurotransmitters most strongly implicated in waking control, only ACh release is asymmetric in unihemispheric sleep and waking, being greatly increased on the activated side of the brain. COMMENTARY: A commentary on this article appears in this issue on page 491.

Biophysical changes in subcortical nuclei: the impact of diabetes and major depression.

Magnetization transfer (MT) is a neuroimaging technique that is frequently used to characterize the biophysical abnormalities in both gray and white matter regions of the brain. In our study, we used MT to examine the integrity of key nodes in frontal-subcortical circuits in four subject groups: patients diagnosed with type 2 diabetes with and without major depression (MDD), a healthy control group, and a group diagnosed with MDD without diabetes. In the MDD group, MT studies demonstrated lower magnetization transfer ratios (MTR), a marker of abnormalities in the macromolecular protein pool, in the thalami when compared with the control groups. The group with diabetes and MDD showed lower MTR in the globus pallidus when compared with the group with MDD. Biophysical measures, in subcortical nuclei, correlated inversely with measures of glycemic control, cerebrovascular burden and depression scores. These findings have broad implications for the underlying neuronal circuitry and neurobiology of mood disorders.

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.

Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides.

There is mounting evidence to suggest aberrant astrocytic function in depression and suicide. Independent studies have reported astrocytic abnormalities in certain brain regions, but it remains unclear whether this is a brain-wide phenomenon. The present study examined this question by measuring glial fibrillary acidic protein (GFAP) expression in postmortem brain samples from suicide completers and matched non-psychiatric controls. Suicide completers were selected based on their recent characterization as low GFAP expressors in the prefrontal cortex, (Brodmann areas 8/9 and 10). Real-time PCR and immunoblotting were used to measure GFAP gene expression and protein levels in BA4 (primary motor cortex), BA17 (primary visual cortex), cerebellar cortex, mediodorsal thalamus and caudate nucleus. We found downregulation of GFAP mRNA and protein in the mediodorsal thalamus and caudate nucleus of depressed suicides compared with controls, whereas GFAP expression in other brain regions was similar between groups. Furthermore, a regional comparison including all samples revealed that GFAP expression in both subcortical regions was, on average, between 11- and 15-fold greater than in cerebellum and neocortex. Examining astrocyte morphology by immunohistochemistry showed that astrocytes in both thalamus and caudate displayed larger cell bodies and extended more ramified processes across larger domains than the previously described cortical astrocytes. This study reveals that astrocytic abnormalities are not brain wide and suggests that they are restricted to cortical and subcortical networks known to be affected in mood disorders. Additionally, our results show a greater diversity in human astrocytic phenotypes than previously thought.

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.

Blood-brain barrier breakdown in the aging human hippocampus.

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.

Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury.

OBJECTIVE: To obtain quantitative neurometabolite measurements, specifically myoinositol (mI) and glutamate plus glutamine (Glx), markers of glial and neuronal excitation, in deep gray matter structures after mild traumatic brain injury (mTBI) using proton magnetic resonance spectroscopy ((1)H-MRS) and to compare these measurements against normal healthy control subjects. METHODS: This study approved by the institutional review board is Health Insurance Portability and Accountability Act compliant. T1-weighted MRI and multi-voxel (1)H-MRS imaging were acquired at 3 tesla from 26 patients with mTBI an average of 22 days postinjury and from 13 age-matched healthy controls. Two-way analysis of variance was used to compare patients and controls for mean N-acetylaspartate, choline, creatine (Cr), Glx, and mI levels as well as the respective ratios to Cr within the caudate, globus pallidus, putamen, and thalamus. RESULTS: Quantitative putaminal mI was higher in patients with mTBI compared with controls (p = 0.02). Quantitative neurometabolite ratios of putaminal mI and Glx relative to Cr, mI/Cr, and Glx/Cr were also higher among patients with mTBI compared with controls (p = 0.01 and 0.02, respectively). No other differences in neurometabolite levels or ratios were observed in any other brain region evaluated. CONCLUSION: Increased putaminal mI, mI/Cr, and Glx/Cr in patients after mTBI compared with control subjects supports the notion of a complex glial and excitatory response to injury without concomitant neuronal loss, evidenced by preserved N-acetylaspartate levels in this region.