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.

A Diagonal-Steering-Based Binaural Beamforming Algorithm Incorporating a Diagonal Speech Localizer for Persons With Bilateral Hearing Impairment.

Previously suggested diagonal-steering algorithms for binaural hearing support devices have commonly assumed that the direction of the speech signal is known in advance, which is not always the case in many real circumstances. In this study, a new diagonal-steering-based binaural speech localization (BSL) algorithm is proposed, and the performances of the BSL algorithm and the binaural beamforming algorithm, which integrates the BSL and diagonal-steering algorithms, were evaluated using actual speech-in-noise signals in several simulated listening scenarios. Testing sounds were recorded in a KEMAR mannequin setup and two objective indices, improvements in signal-to-noise ratio (SNRi ) and segmental SNR (segSNRi ), were utilized for performance evaluation. Experimental results demonstrated that the accuracy of the BSL was in the 90-100% range when input SNR was -10 to +5 dB range. The average differences between the γ-adjusted and γ-fixed diagonal-steering algorithms (for -15 to +5 dB input SNR) in the talking in the restaurant scenario were 0.203-0.937 dB for SNRi and 0.052-0.437 dB for segSNRi , and in the listening while car driving scenario, the differences were 0.387-0.835 dB for SNRi and 0.259-1.175 dB for segSNRi . In addition, the average difference between the BSL-turned-on and the BSL-turned-off cases for the binaural beamforming algorithm in the listening while car driving scenario was 1.631-4.246 dB for SNRi and 0.574-2.784 dB for segSNRi . In all testing conditions, the γ-adjusted diagonal-steering and BSL algorithm improved the values of the indices more than the conventional algorithms. The binaural beamforming algorithm, which integrates the proposed BSL and diagonal-steering algorithm, is expected to improve the performance of the binaural hearing support devices in noisy situations.

Development of virtual reality proprioceptive rehabilitation system for stroke patients.

In this study, the virtual reality (VR) proprioception rehabilitation system was developed for stroke patients to use proprioception feedback in upper limb rehabilitation by blocking visual feedback. To evaluate its therapeutic effect, 10 stroke patients (onset>3 month) trained proprioception feedback rehabilitation for one week and visual feedback rehabilitation for another week in random order. Proprioception functions were checked before, a week after, and at the end of training. The results show the click count, error distance and total error distance among proprioception evaluation factors were significantly reduced after proprioception feedback training compared to visual feedback training (respectively, p=0.005, p=0.001, and p=0.007). In addition, subjects were significantly improved in conventional behavioral tests after training. In conclusion, we showed the effectiveness and possible use of the VR to recover the proprioception of stroke patients.

Auditory adaptation to sound intensity in conscious rats: 2-[F-18]-fluoro-2-deoxy-D-glucose PET study.

Despite the importance of the adaptive process for discriminating the broad range of sound intensity, there have been few systemic investigations targeting the auditory mechanisms. In this study, the adaptation effect of sound intensity on the change in glucose metabolism in rat brains was examined using a PET technique. In the first experiment, broadband white noise sound (40, 60, 80, or 100 dB sound pressure level) was given for 30 min after an 2-[F-18]-fluoro-2-deoxy-D-glucose injection in an awake condition. In the second experiment, sound stimuli with an intensity modulation of 0, 0.5, and 5.0 Hz in frequency and at three intensity levels were used for examining the metabolism change according to the short time scale variation of the sound intensity. As a result, the metabolic activities in the bilateral cochlear nucleus, superior olivary complexes, and inferior colliculus were proportional to the sound intensity level, whereas the bilateral auditory cortical areas unexpectedly decreased as the sound intensity level increased in the first experiment. In the second experiment, the glucose metabolism in the auditory cortex was higher at 0.5 and 5.0 Hz modulation frequency than the 0.0 Hz modulation frequency, while retaining an inverse relationship with the sound intensity. The metabolism in inferior colliculus was higher at 5.0 Hz modulation frequency than 0.0 and 0.5 Hz modulation frequencies. Taken together, the auditory cortex metabolism seemed to be actively adapted to the average sound intensity, which indicates that it plays an important role in processing the broad range to sound intensity more than the other nucleus of the auditory pathway. Especially, this study demonstrated that the sound intensity-dependent glucose metabolism can be seen in a small rodent's brain stem level using 2-[F-18]-fluoro-2-deoxy-D-glucose PET functional neuroimaging.

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.

Proton magnetic resonance spectroscopy in subjects with high genetic risk of schizophrenia: investigation of anterior cingulate, dorsolateral prefrontal cortex and thalamus.

OBJECTIVE: Reduced N-acetylaspartate levels in regions of the frontal cortex, including the anterior cingulate cortex, dorsolateral prefrontal cortex, and thalamus, involved in the pathophysiology of schizophrenia suggest that brain metabolite abnormalities may be a marker of genetic vulnerability to schizophrenia. We used proton magnetic resonance spectroscopy (H-MRS) to acquire absolute concentrations of brain metabolites in subjects with a high genetic risk of schizophrenia to investigate the potential relationship between unexpressed genetic liability to schizophrenia and neuronal dysfunction. METHOD: Included in the study were 22 subjects who had at least two relatives with schizophrenia (high genetic risk group) and 22 controls with no second-degree relatives with schizophrenia. Absolute concentrations of N-acetylaspartate, creatine, choline, glutamate/glutamine, and myo-inositol and the ratios of metabolites in the anterior cingulate cortex, left dorsolateral prefrontal cortex, and left thalamus were measured using H-MRS at 1.5 Tesla. RESULTS: Relative to the controls, the high genetic risk group showed significant differences in absolute metabolite levels in the spectra of the regions of the left thalamus, including significant decreases in N-acetylaspartate, creatine, and choline concentrations. CONCLUSIONS: The study points to neuronal dysfunction, and in particular thalamic dysfunction, as a key region of the vulnerability marker of schizophrenia. Further studies should examine the nature of the thalamus more intensively to further our understanding of thalamic dysfunction as a vulnerability marker.

BT-11 improves stress-induced memory impairments through increment of glucose utilization and total neural cell adhesion molecule levels in rat brains.

In Oriental medicine, roots of Polygala tenuifolia Willdenow have been known to be an important herb that exhibits sedative effects in insomnia, palpitation with anxiety, restlessness, and disorientation in humans. We previously reported that BT-11, extracted from those roots, improved scopolamine-induced amnesia in rats and inhibited acetylcholinesterase activities in vitro. Therefore, we proposed that BT-11 could remedy stress-induced memory deficits in rats. In this study, the stress-induced memory impairments in rats were significantly reversed almost to the control level by BT-11 treatment. To seek an active component of BT-11 that plays an important role in antipsychotic effects, we compared BT-11 with 3,4,5-trimethoxycinnamic acid (TMCA), which is a constituent of those root extracts. However, the effects of TMCA were less or were not consistent with those of BT-11 in some of tests. In particular, BT-11 reversed the stress-induced reduction of glucose utilization by [(18)fluorodeoxyglucose]FDG-PET and the levels of neural cell adhesion molecule (NCAM) in rat brains to the control levels, whereas TMCA did not. Therefore, BT-11 improved stress-induced memory impairments through increment of glucose utilization and total NCAM levels in rat brains. In conclusion, BT-11 may be strongly effective against stress-induced amnesia in rats, through the combined effects of TMCA and other active components of BT-11.

Neural responses in rat brain during acute immobilization stress: a [F-18]FDG micro PET imaging study.

We used the [F-18]FDG micro PET neuroimaging technique to investigate changes in brain activity induced by acute stress in rats. Animals were given immobilization stress for 1 or 2 h, or 1-h stress followed by 1-h recovery, after which their brains were scanned. Plasma corticosterone levels measured at various time points in separate groups of rats showed a rapid increase during stress and slower decrease after termination of the stress. Immobilization stress given for an hour activated the hypothalamus, entorhinal and insular/piriform cortices, and raphe pallidus nucleus. At the same time, the dorsal hippocampus, thalamus, other cortical areas (motor, somatosensory and barrel field), striatum, superior colliculus and cerebellum were deactivated. With 2-h immobilization stress, the activity of the hypothalamus, various cortical areas and dorsal hippocampus habituated during the second hour while that of the thalamus and cerebellum did not. During 1-h recovery, the hypothalamic activation and widespread cortical deactivation disappeared, but the dorsal hippocampus, thalamus and cerebellum still remained significantly deactivated. Additional brain areas such as the septum and prelimbic cortex now showed deactivation during recovery. Changes in glucose metabolism in the dorsal hippocampus and hypothalamus exhibited a highly significant negative correlation, supporting the view that the hippocampus is involved in regulating the stress response of the hypothalamo-pituitary-adrenal axis. The advantages and limitations of the [F-18]FDG micro PET used in this study are discussed.

A proton MRSI study of brain N-acetylaspartate level after 12 weeks of citalopram treatment in drug-naive patients with obsessive-compulsive disorder.

OBJECTIVE: Reductions in the level of N-acetylaspartate within subcortical structures of patients with obsessive-compulsive disorder (OCD) have been reported in several studies. However, there have been, as yet, no reports regarding N-acetylaspartate levels in the prefrontal cortex of adult drug-naive OCD patients. The authors used proton magnetic resonance spectroscopic imaging ((1)H-MRSI) to investigate regional N-acetylaspartate level abnormalities and changes after 12 weeks of pharmacotherapy with citalopram in drug-naive OCD patients. METHOD: Thirteen drug-naive OCD patients and 13 age- and sex-matched healthy comparison subjects were included in this study. N-acetylaspartate levels (obtained from ratios of N-acetylaspartate with creatine, choline, and creatine plus choline) in the prefrontal cortex, parietal cortex, anterior cingulate, posterior cingulate, frontal white matter, and parietal white matter were measured by (1)H-MRSI. In OCD patients, measurements were taken before and after 12 weeks of citalopram treatment. Correlations between N-acetylaspartate concentrations in regions of interest and clinical measures were also assessed. RESULTS: Drug-naive OCD patients exhibited significantly lower N-acetylaspartate levels in the prefrontal cortex, frontal white matter, and anterior cingulate at baseline than did comparison subjects. Significant increases in N-acetylaspartate level were detected in the prefrontal cortex and frontal white matter in OCD patients after 12 weeks of citalopram treatment. CONCLUSIONS: These data suggest that reductions in neuronal viability occur in the frontal region of OCD patients and that these reductions may be partly reversible.