Deep brain stimulation alleviates tics in Tourette syndrome via striatal dopamine transmission.

Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome.

The Influence of Frequency Bands and Brain Region on ECoG-Based BMI Learning Performance.

Numerous brain-machine interface (BMI) studies have shown that various frequency bands (alpha, beta, and gamma bands) can be utilized in BMI experiments and modulated as neural information for machine control after several BMI learning trial sessions. In addition to frequency range as a neural feature, various areas of the brain, such as the motor cortex or parietal cortex, have been selected as BMI target brain regions. However, although the selection of target frequency and brain region appears to be crucial in obtaining optimal BMI performance, the direct comparison of BMI learning performance as it relates to various brain regions and frequency bands has not been examined in detail. In this study, ECoG-based BMI learning performances were compared using alpha, beta, and gamma bands, respectively, in a single rodent model. Brain area dependence of learning performance was also evaluated in the frontal cortex, the motor cortex, and the parietal cortex. The findings indicated that BMI learning performance was best in the case of the gamma frequency band and worst in the alpha band (one-way ANOVA, F = 4.41, p < 0.05). In brain area dependence experiments, better BMI learning performance appears to be shown in the primary motor cortex (one-way ANOVA, F = 4.36, p < 0.05). In the frontal cortex, two out of four animals failed to learn the feeding tube control even after a maximum of 10 sessions. In conclusion, the findings reported in this study suggest that the selection of target frequency and brain region should be carefully considered when planning BMI protocols and for performing optimized BMI.

Cocaine-Induced Changes in Tonic Dopamine Concentrations Measured Using Multiple-Cyclic Square Wave Voltammetry in vivo.

For over 40 years, in vivo microdialysis techniques have been at the forefront in measuring the effects of illicit substances on brain tonic extracellular levels of dopamine that underlie many aspects of drug addiction. However, the size of microdialysis probes and sampling rate may limit this technique's ability to provide an accurate assessment of drug effects in microneural environments. A novel electrochemical method known as multiple-cyclic square wave voltammetry (M-CSWV), was recently developed to measure second-to-second changes in tonic dopamine levels at microelectrodes, providing spatiotemporal resolution superior to microdialysis. Here, we utilized M-CSWV and fast-scan cyclic voltammetry (FSCV) to measure changes in tonic or phasic dopamine release in the nucleus accumbens core (NAcc) after acute cocaine administration. Carbon-fiber microelectrodes (CFM) and stimulating electrodes were implanted into the NAcc and medial forebrain bundle (MFB) of urethane anesthetized (1.5 g/kg i.p.) Sprague-Dawley rats, respectively. Using FSCV, depths of each electrode were optimized by determining maximal MFB electrical stimulation-evoked phasic dopamine release. Changes in phasic responses were measured after a single dose of intravenous saline or cocaine hydrochloride (3 mg/kg; n = 4). In a separate group, changes in tonic dopamine levels were measured using M-CSWV after intravenous saline and after cocaine hydrochloride (3 mg/kg; n = 5). Both the phasic and tonic dopamine responses in the NAcc were augmented by the injection of cocaine compared to saline control. The phasic and tonic levels changed by approximately x2.4 and x1.9, respectively. These increases were largely consistent with previous studies using FSCV and microdialysis. However, the minimal disruption/disturbance of neuronal tissue by the CFM may explain why the baseline tonic dopamine values (134 ± 32 nM) measured by M-CSWV were found to be 10-fold higher when compared to conventional microdialysis. In this study, we demonstrated phasic dopamine dynamics in the NAcc with acute cocaine administration. M-CSWV was able to record rapid changes in tonic levels of dopamine, which cannot be achieved with other current voltammetric techniques. Taken together, M-CSWV has the potential to provide an unprecedented level of physiologic insight into dopamine signaling, both in vitro and in vivo, which will significantly enhance our understanding of neurochemical mechanisms underlying psychiatric conditions.

Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis.

Monoamine oxidase (MAO) is believed to mediate the degradation of monoamine neurotransmitters, including dopamine, in the brain. Between the two types of MAO, MAO-B has been believed to be involved in dopamine degradation, which supports the idea that the therapeutic efficacy of MAO-B inhibitors in Parkinson's disease can be attributed to an increase in extracellular dopamine concentration. However, this belief has been controversial. Here, by utilizing in vivo phasic and basal electrochemical monitoring of extracellular dopamine with fast-scan cyclic voltammetry and multiple-cyclic square wave voltammetry and ex vivo fluorescence imaging of dopamine with GRABDA2m, we demonstrate that MAO-A, but not MAO-B, mainly contributes to striatal dopamine degradation. In contrast, our whole-cell patch-clamp results demonstrated that MAO-B, but not MAO-A, was responsible for astrocytic GABA-mediated tonic inhibitory currents in the rat striatum. We conclude that, in contrast to the traditional belief, MAO-A and MAO-B have profoundly different roles: MAO-A regulates dopamine levels, whereas MAO-B controls tonic GABA levels.

Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson's Disease.

Current pharmacological treatments for Parkinson's disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.

Diminished Frontal Theta Activity During Gaming in Young Adults With Internet Gaming Disorder.

Cognitive control is essential for flexible, top-down, goal-directed behavior. Individuals with Internet gaming disorder (IGD) are characterized by impaired prefrontal cortex function and cognitive control. This results in an increase in stimulus-driven habitual behavior, particularly related to pathological gaming. In the present study, we investigated the electroencephalographic (EEG) activity in individuals with IGD. Twenty-four individuals with IGD and 35 healthy control (HC) subjects were recruited. We analyzed their EEG activity while the subjects played their favorite game (30-40 min duration). We compared the band power between the two groups. During gaming, the left frontal theta, alpha, and beta band activities were lower in subjects with IGD than in HCs. Moreover, the left frontal theta power negatively correlated with IGD severity. These results indicate that left frontal theta power could be used as a neurophysiological biomarker for the detection of diminished cognitive control patterns in individuals with IGD.

Touch stimulated pulse generation in biomimetic single-layer graphene.

Detecting variation in contact pressure is a separate sensing mode in the human somatosensory system that differs from the detection of pressure magnitude. If pressure magnitude and variation sensing can be achieved simultaneously, an advanced biomimetic tactile system that better emulates human senses may be developed. We report on a novel single-layer graphene based artificial mechanoreceptor that generates a resistance pulse as the contact stimulus passes a specific threshold pressure, mimicking the generation of action potentials in a biological fast-adapting mechanoreceptor. The electric field from a flexible membrane gate electrode placed above a graphene channel raises the Fermi level from the valence band as pressure deflects the membrane. The threshold pressure is reached when the Fermi level crosses the Dirac point in the graphene energy band, which generates a sharp peak in the measured resistance. We found that by changing the gate potential it was possible to modulate the threshold pressure and using a series of graphene channels, a train of pulses were generated during a transient pressurizing stimulus demonstrating biomimetic behaviour.

Involvement of the dorsolateral prefrontal cortex and superior temporal sulcus in impaired social perception in schizophrenia.

BACKGROUND: Schizophrenia is a mental disorder characterized by impairments in diverse thinking and emotional responses, which are related to social perception dysfunction. This fMRI study was designed to investigate a neurobiological basis of social perception deficits of patients with schizophrenia in various social situations of daily life and their relationship with clinical symptoms and social dysfunction. METHODS: Seventeen patients and 19 controls underwent functional magnetic resonance imaging, during which participants performed a virtual social perception task, containing an avatar's speech with positive, negative or neutral emotion in a virtual reality space. Participants were asked to determine whether or not the avatar's speech was appropriate to each situation. RESULTS: The significant group×appropriateness interaction was seen in the left dorsolateral prefrontal cortex (DLPFC), resulting from lower activity in patients in the inappropriate condition, and left DLPFC activity was negatively correlated with the severity of negative symptoms and positively correlated with the level of social functioning. The significant appropriateness×emotion interaction observed in the left superior temporal sulcus (STS) was present in controls, but absent in patients, resulting from the existence and absence of a difference between the inappropriate positive and negative conditions, respectively. CONCLUSIONS: These findings indicate that dysfunction of the DLPFC-STS network may underlie patients' abnormal social perception in various social situations of daily life. Abnormal functioning of this network may contribute to increases of negative symptoms and decreases of social functioning.

Deficient gaze pattern during virtual multiparty conversation in patients with schizophrenia.

Virtual reality has been used to measure abnormal social characteristics, particularly in one-to-one situations. In real life, however, conversations with multiple companions are common and more complicated than two-party conversations. In this study, we explored the features of social behaviors in patients with schizophrenia during virtual multiparty conversations. Twenty-three patients with schizophrenia and 22 healthy controls performed the virtual three-party conversation task, which included leading and aiding avatars, positive- and negative-emotion-laden situations, and listening and speaking phases. Patients showed a significant negative correlation in the listening phase between the amount of gaze on the between-avatar space and reasoning ability, and demonstrated increased gaze on the between-avatar space in the speaking phase that was uncorrelated with attentional ability. These results suggest that patients with schizophrenia have active avoidance of eye contact during three-party conversations. Virtual reality may provide a useful way to measure abnormal social characteristics during multiparty conversations in schizophrenia.

Aberrant neural responses to social rejection in patients with schizophrenia.

Patients with schizophrenia often show abnormal social interactions, which may explain their social exclusion behaviors. This study aimed to elucidate patients' brain responses to social rejection in an interactive situation. Fifteen patients with schizophrenia and 16 healthy controls participated in the functional magnetic resonance imaging experiment with the virtual handshake task, in which socially interacting contents such as acceptance and refusal of handshaking were implemented. Responses to the refusal versus acceptance conditions were evaluated and compared between the two groups. Controls revealed higher activity in the refusal condition compared to the acceptance condition in the right superior temporal sulcus, whereas patients showed higher activity in the prefrontal regions, including the frontopolar cortex. In patients, contrast activities of the right superior temporal sulcus were inversely correlated with the severity of schizophrenic symptoms, whereas contrast activities of the left frontopolar cortex were positively correlated with the current anxiety scores. The superior temporal sulcus hypoactivity and frontopolar hyperactivity of patients with schizophrenia in social rejection situations may suggest the presence of mentalizing deficits in negative social situations and inefficient processes of socially aberrant stimuli, respectively. These abnormalities may be one of the neural bases of distorted or paranoid beliefs in schizophrenia.

Measurements of RF heating during 3.0-T MRI of a pig implanted with deep brain stimulator.

PURPOSE: To present preliminary, in vivo temperature measurements during MRI of a pig implanted with a deep brain stimulation (DBS) system. MATERIALS AND METHODS: DBS system (Medtronic Inc., Minneapolis, MN) was implanted in the brain of an anesthetized pig. 3.0-T MRI was performed with a T/R head coil using the low-SAR GRE EPI and IR-prepped GRE sequences (SAR: 0.42 and 0.39 W/kg, respectively), and the high-SAR 4-echo RF spin echo (SAR: 2.9 W/kg). Fluoroptic thermometry was used to directly measure RF-related heating at the DBS electrodes, and at the implantable pulse generator (IPG). For reference the measurements were repeated in the same pig at 1.5 T and, at both field strengths, in a phantom. RESULTS: At 3.0T, the maximal temperature elevations at DBS electrodes were 0.46 °C and 2.3 °C, for the low- and high-SAR sequences, respectively. No heating was observed on the implanted IPG during any of the measurements. Measurements of in vivo heating differed from those obtained in the phantom. CONCLUSION: The 3.0-T MRI using GRE EPI and IR-prepped GRE sequences resulted in local temperature elevations at DBS electrodes of no more than 0.46 °C. Although no extrapolation should be made to human exams and much further study will be needed, these preliminary data are encouraging for the future use 3.0-T MRI in patients with DBS.

Involvement of the anterior thalamic radiation in boys with high functioning autism spectrum disorders: a Diffusion Tensor Imaging study.

BACKGROUND: Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the key thalamic relay nuclei and cortico-thalamic connectivity in the pathophysiology of autism. Accordingly, we aimed to focus on evaluating the integrity of the thalamic radiation and sought to replicate prior white matter findings in Korean boys with high-functioning autism spectrum disorders (ASD) using Diffusion Tensor Imaging (DTI). METHODS: We compared fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 17 boys with ASD and 17 typically developing controls in the anterior thalamic radiation (ATR), superior thalamic radiation (STR), posterior thalamic radiation (PTR), corpus callosum (CC), uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF). RESULTS: The two groups were group-matched on age, IQ, handedness and head circumference. In whole-brain voxel-wise analyses, FA was significantly reduced and MD was significantly increased in the right ATR, CC, and left UF in subjects with ASD (p<0.05, corrected). We found significantly lower FA in right and left ATR, CC, left UF and right and left ILF and significantly higher MD values of the CC in the ASD group in region of interest-based analyses. We also observed significantly higher RD values of right and left ATR, CC, left UF, left ILF in subjects with ASD compared to typically developing boys and significantly lower AD values of both ILF. Right ATR and right UF FA was significantly negatively correlated with total SRS score within the ASD group (r=-.56, p=.02). CONCLUSIONS: Our preliminary findings support evidence implicating disturbances in the thalamo-frontal connections in autism. These findings highlight the role of hypoconnectivity between the frontal cortex and thalamus in ASD.

Spatial distribution of glucose hypometabolism induced by intracerebroventricular streptozotocin in monkeys.

Intracerebroventricular injection of streptozotocin (icv-STZ) in rodents induces cellular and behavioral features mimicking Alzheimer's disease (AD). However, the effect of icv-STZ in terms of regional cerebral glucose metabolism has not yet been examined in vivo. Given that regionally specific hypometabolism of glucose is a consistent neuroimaging marker in early AD, we monitored 18F-deoxyglucose uptake using a high-resolution micro-PET after icv-STZ in non-human primates. Two cynomolgus monkeys (Macaca fascicularis) received STZ (2 mg/kg), and another two were given normal saline as controls, at the cerebellomedullary cistern (CM) three times (day 1, 7, and 14). FDG-PET, as well as MRI for structural evaluation, was performed immediately before, six weeks after, and 12 weeks after the first icv injection. In the STZ group, FDG uptake decreased significantly in comparison to the pre-injection baseline, at the precuneus, the posterior cingulate, and medial temporal cortices. Increase in sulcal markings suggesting brain atrophy was observed by MRI at six weeks post-injection. The structural changes normalized at 12 weeks, but the reduced FDG uptake persisted at the same loci. The cortical distribution of glucose hypometabolism was similar to that at early stages of AD patients. The findings demonstrate that the effect of icv-STZ is regionally specific, lending further support for the method as a model of AD pathogenesis.

Carbon nanofiber electrode array for electrochemical detection of dopamine using fast scan cyclic voltammetry.

A carbon nanofiber (CNF) electrode array was integrated with the Wireless Instantaneous Neurotransmitter Concentration Sensor System (WINCS) for the detection of dopamine using fast scan cyclic voltammetry (FSCV). Dopamine detection performance by CNF arrays was comparable to that of traditional carbon fiber microelectrodes (CFMs), demonstrating that CNF arrays can be utilized as an alternative carbon electrode for neurochemical monitoring.

Emerging techniques for elucidating mechanism of action of deep brain stimulation.

Deep brain stimulation (DBS) within the basal ganglia complex is an effective neurosurgical approach for treating symptoms of Parkinson's disease (PD), Essential Tremor, Dystonia, Depression, Obssessive Compulsive Disorder, and Tourette's Syndrome, among others. Elucidating DBS mechanism has become a critical clinical and research goal in stereotactic and functional neurosurgery and in neural engineering. Along with electro-physiological and microdialysis techniques, two additional powerful technologies, notably functional Magnetic Resonance Imaging (fMRI) and in vivo neurochemical monitoring have recently been used to investigate DBS-mediated activation of basal ganglia network circuitry. For this purpose, we have previously developed WINCS (Wireless Instantaneous Neurotransmitter Concentration Sensor System), which is an MRI-compatible wireless monitoring device to obtain chemically resolved neurotransmitter measurements at implanted microsensors in a large mammalian model (pig) as well as in human patients. This device supports an array of electrochemical measurements that includes fast-scan cyclic voltammetry (FSCV) for real-time simultaneous in vivo monitoring of dopamine and adenosine release at carbon-fiber microelectrodes as well as fixed potential amperometry for monitoring of glutamate at enzyme-linked biosensors. In addition, we have utilized fMRI to investigate subthalamic nucleus (STN) DBS activation in the pig with 3Tesla MR scanner. We demonstrate the activation of specific basal ganglia circuitry during STN DBS using both fMRI and FSCV in the pig model. Our results suggest that fMRI and electrochemistry are important emerging techniques for use in elucidating mechanism of action of DBS.

Correlation between fluorodeoxyglucose positron emission tomography and magnetic resonance imaging findings of non-suppurative meningoencephalitis in 5 dogs.

This study characterized the [(18)F]2-deoxy-2-fluoro-D-glucose positron emission tomography (FDG-PET) findings of encephalitis in dogs and assessed the role of FDG-PET in the diagnosis of meningoencephalitis. The medical records, magnetic resonance (MR), and FDG-PET images of 3 dogs with necrotizing meningoencephalitis (NME), 1 dog with granulomatous meningoencephalitis (GME), and 1 dog with meningoencephalitis of unknown etiology (MUE) were reviewed. On the FDG-PET, glucose hypometabolism was identified in the dog with NME, whereas hypermetabolism was noted in the dog with GME. The T2-weighted images (WI) and fluid attenuated inversion recovery (FLAIR) images were characterized by hyperintensity, whereas the signal intensity of the lesions on the T1-WI images was variable. The metabolic changes on the brain FDG-PET corresponded well to the hyper- and hypointense lesions seen on the MR imaging. This type of tomography (FDG-PET) aided in the differentiation of different types of inflammatory meningoencephalitis when the metabolic data was combined with clinical and MR findings.

Canine hippocampal formation composited into three-dimensional structure using MPRAGE.

This study was performed to anatomically illustrate the living canine hippocampal formation in three-dimensions (3D), and to evaluate its relationship to surrounding brain structures. Three normal beagle dogs were scanned on a MR scanner with inversion recovery segmented 3D gradient echo sequence (known as MP-RAGE: Magnetization Prepared Rapid Gradient Echo). The MRI data was manually segmented and reconstructed into a 3D model using the 3D slicer software tool. From the 3D model, the spatial relationships between hippocampal formation and surrounding structures were evaluated. With the increased spatial resolution and contrast of the MPRAGE, the canine hippocampal formation was easily depicted. The reconstructed 3D image allows easy understanding of the hippocampal contour and demonstrates the structural relationship of the hippocampal formation to surrounding structures in vivo.

Magnetic resonance imaging of the canine brain at 7 T.

The purpose of this study was to describe relevant canine brain structures as seen on T2-weighted images following magnetic resonance (MR) imaging at 7 T and to compare the results with imaging at 1.5 T. Imaging was performed on five healthy laboratory beagle dogs using 1.5 and 7 T clinical scanners. At 1.5 T, spin echo images were acquired, while gradient echo images were acquired at 3 T. Image quality and conspicuity of anatomic structures were evaluated qualitatively by direct comparison of the images obtained from the two different magnetic fields. The signal-to-nose ratio (SNR) and contrast-to-noise ratio (CNR) were calculated and compared between 1.5 and 7 T. The T2-weighted images at 7 T provided good spatial and contrast resolution for the identification of clinically relevant brain anatomy; these images provided better delineation and conspicuity of the brain stem and cerebellar structures, which were difficult to unequivocally identify at 1.5 T. However, frontal and parietal lobe and the trigeminal nerve were difficult to identify at 7 T due to susceptibility artifact. The SNR and CNR of the images at 7 T were significantly increased up to 318% and 715% compared with the 1.5 T images. If some disadvantages of 7 T imaging, such as susceptibility artifacts, technical difficulties, and high cost, can be improved, 7 T clinical MR imaging could provide a good experimental and diagnostic tool for the evaluation of canine brain disorders.

18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging findings of primary intracranial histiocytic sarcoma in a dog.

A 10-year-old, neutered male, Maltese dog presented with a three week history of intention tremor, right hind limb rigidity, poor coordination, and occasional circling to the left. On magnetic resonance imaging (MRI) of the brain, a mass was identified in the right occipital lobe and cerebellum. Three weeks after the initial MRI scan, we performed an (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) of the brain. The FDG-PET demonstrated areas of hypermetabolism in the right occipital lobe, cerebellum, pons, and medulla oblongata. When the standardized uptake value was calculated, the hypermetabolic lesion was higher than the gray matter values. The anatomical location of the hypermetabolic lesion was more precisely identified by the PET-MRI fusion images. The dog was definitively diagnosed as a primary histiocytic sarcoma of the brain. This is the first report of PET findings of an intracranial histiocytic sarcoma in a dog.

MRI features in a canine model of ischemic stroke: correlation between lesion volume and neurobehavioral status during the subacute stage.

The purpose of this study was to evaluate the diagnostic value of magnetic resonance imaging (MRI) and assess the correlation between the volume of the ischemic lesion and neurobehavioral status during the subacute stage of ischemic stroke. Ischemic stroke was induced in 6 healthy laboratory beagles through permanent occlusion of the middle cerebral artery (MCAO). T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging, diffusion-weighted imaging (DWI), measurement of the apparent diffusion coefficient (ADC) ratio, and neurobehavioral evaluation were performed 3 times serially by using a 1.5-T MR system: before and 3 and 10 d after MCAO. Ischemic lesions demonstrated T2 hyperintensity, FLAIR hyperintensity, and DWI hyperintensity. The ADC ratio was decreased initially but then was increased at 10 d after MCAO. Ischemic lesion volumes on T2-weighted and FLAIR imaging were not significantly different from those on DWI. The lesion volume and neurobehavioral score showed strong correlation. Our results suggest that conventional MRI may be a reliable diagnostic tool during the subacute stage of canine ischemic stroke.