Explore the vast range of titles available.

Anatomical and functional analyses reveal the existence of two types of globus pallidus externus neurons that directly control cortex, suggesting a pathway by which dopaminergic drugs used to treat neuropsychiatric disorders may act in the basal ganglia to modulate cortex. Basal ganglia/frontal cortex linkage Current models postulate that the basal ganglia — nerve cells clustered in the caudate nucleus, putamen and globus pallidus at the base of the forebrain in vertebrates — exert their effects on the cerebral cortex indirectly via inhibition of thalamus, and that this circuitry controls movement and reward learning. Bernardo Sabatini and colleagues now describe a previously unrecognized direct anatomical connection from the globus pallidus externus to the frontal cortex, and show that it functionally modulates cortical activity. The activity of this pathway is sensitive to dopamine receptor signalling, suggesting a potentially novel mechanism for the action of dopaminergic drugs used to treat neuropsychiatric disorders. The basal ganglia are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning 1 . Current models postulate that the basal ganglia modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by direct- and indirect-pathway striatal projection neurons (dSPNs and iSPNs, respectively) 2 , 3 , 4 . The basal ganglia thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems 5 . Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the basal ganglia, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP–FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT + cells, which have been historically identified as an extension of the nucleus basalis, as well as ChAT − cells, release the inhibitory neurotransmitter GABA (γ-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus, GP–FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo . Furthermore, iSPN inhibition of GP–FC cells is sensitive to dopamine 2 receptor signalling, revealing a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the basal ganglia to modulate frontal cortices.

Quantitative susceptibility mapping (QSM) and R2* relaxation rate mapping have demonstrated increased iron deposition in the substantia nigra of patients with idiopathic Parkinson's disease (PD). However, the findings in other subcortical deep gray matter nuclei are converse and the sensitivity of QSM and R2* for morphological changes and their relation to clinical measures of disease severity has so far been investigated only sparsely. The local ethics committee approved this study and all subjects gave written informed consent. 66 patients with idiopathic Parkinson's disease and 58 control subjects underwent quantitative MRI at 3T. Susceptibility and R2* maps were reconstructed from a spoiled multi-echo 3D gradient echo sequence. Mean susceptibilities and R2* rates were measured in subcortical deep gray matter nuclei and compared between patients with PD and controls as well as related to clinical variables. Compared to control subjects, patients with PD had increased R2* values in the substantia nigra. QSM also showed higher susceptibilities in patients with PD in substantia nigra, in the nucleus ruber, thalamus, and globus pallidus. Magnetic susceptibility of several of these structures was correlated with the levodopa-equivalent daily dose (LEDD) and clinical markers of motor and non-motor disease severity (total MDS-UPDRS, MDS-UPDRS-I and II). Disease severity as assessed by the Hoehn & Yahr scale was correlated with magnetic susceptibility in the substantia nigra. The established finding of higher R2* rates in the substantia nigra was extended by QSM showing superior sensitivity for PD-related tissue changes in nigrostriatal dopaminergic pathways. QSM additionally reflected the levodopa-dosage and disease severity. These results suggest a more widespread pathologic involvement and QSM as a novel means for its investigation, more sensitive than current MRI techniques.

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34–97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM.

Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease, a group of untreatable and usually fatal disorders. Refractory epileptic events are a common neurological presentation of mitochondrial disease, including Leigh syndrome, a severe form of mitochondrial disease associated with epilepsy. However, the neuronal substrates and circuits for mitochondrial disease-induced epilepsy remain unclear. Here, using mouse models of Leigh syndrome that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrated that mitochondrial dysfunction leads to a reduction of GABAergic neurons in the rostral external globus pallidus (GPe) and identified a specific affectation of pallidal Lhx6-expressing inhibitory neurons contributing to altered GPe excitability. Our findings revealed that viral vector-mediated Ndufs4 reexpression in the GPe effectively prevented seizures and improved survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a role for pallido-subthalamic projections in epilepsy development in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with mitochondrial disease, providing promising leads in the quest to identify effective treatments.

Background Patients with Parkinson’s disease (PD) have elevated levels of brain iron, especially in the nigrostriatal dopaminergic system. The purpose of this study was to evaluate the iron deposition in the substantia nigra (SN) and other deep gray matter nuclei of PD patients using quantitative susceptibility mapping (QSM) and its clinical relationship, and to explore whether there is a gradient of iron deposition pattern in globus pallidus (GP)–fascicula nigrale (FN)–SN pathway. Methods Thirty-three PD patients and 26 age- and sex-matched healthy volunteers (HVs) were included in this study. Subjects underwent brain MRI and constructed QSM data. The differences in iron accumulation in the deep gray matter nuclei of the subjects were compared, including the PD group and the control group, the early-stage PD (EPD) group and the late-stage PD (LPD) group. The iron deposition pattern of the GP–FN–SN pathway was analyzed. Results The PD group showed increased susceptibility values in the FN, substantia nigra pars compacta (SNc), internal globus pallidus (GPi), red nucleus (RN), putamen and caudate nucleus compared with the HV group (P < 0.05). In both PD and HV group, iron deposition along the GP–FN–SN pathway did not show an increasing gradient pattern. The SNc, substantia nigra pars reticulata (SNr) and RN showed significantly increased susceptibility values in the LPD patients compared with the EPD patients. Conclusion PD is closely related to iron deposition in the SNc. The condition of PD patients is related to the SNc and the SNr. There is not an increasing iron deposition gradient along the GP–FN–SN pathway. The source and mechanism of iron deposition in the SN need to be further explored, as does the relationship between the iron deposition in the RN and PD.

•Enhanced and broader detection Capability: the APART-QSM demonstrated a greater ability to identify significant changes overlooked by conventional QSM.•Reduced iron and myelin contents in ASD: the APART-QSM revealed significantly reduced iron contents in several brain regions, and a significant reduction in myelin content of the globus pallidus. The change in brain iron content may precede the change in myelin content in ASD.•Clinically relevant Correlations: the iron and myelin contents in the globus pallidum and iron content in the substantia nigra were negatively correlated with ASD symptom severity. Autism spectrum disorder (ASD) may have both brain iron and myelin changes, but traditional methods fail to differentiate them. This study utilized an advanced susceptibility source separation technique, APART-QSM (iterAtive magnetic suscePtibility sources sepARaTion), to investigate brain iron and myelination alterations in children with ASD and link neuroimaging findings to clinical symptom severity. Sixty-five school-aged children with ASD and Sixty age- and sex-matched typically developing children were included. By providing enhanced and broader detection capabilities compared to conventional QSM, APART-QSM uncovered reduced iron content across multiple deep gray matters and decreased myelin content in the globus pallidum in ASD. The iron and myelin contents in the globus pallidum and iron content in the substantia nigra were significantly negatively correlated with ASD symptom severity. Coexisting abnormal brain iron and myelin contents in ASD, particularly in the globus pallidus, offer innovative and promising insights into ASD pathology and potential biomarkers. [Display omitted]

The role of the striatum in motor control is commonly assumed to be mediated by the two striatal efferent pathways characterized by striatal projection neurons (SPNs) expressing dopamine (DA) D1 receptors or D2 receptors (D1-SPNs and D2-SPNs, respectively), without regard to SPNs coexpressing both receptors (D1/D2-SPNs). Here we developed an approach to target these hybrid SPNs in mice and demonstrate that, although these SPNs are less abundant, they have a major role in guiding the motor function of the other two populations. D1/D2-SPNs project exclusively to the external globus pallidus and have specific electrophysiological features with distinctive integration of DA signals. Gain- and loss-of-function experiments indicate that D1/D2-SPNs potentiate the prokinetic and antikinetic functions of D1-SPNs and D2-SPNs, respectively, and restrain the integrated motor response to psychostimulants. Overall, our findings demonstrate the essential role of this population of D1/D2-coexpressing neurons in orchestrating the fine-tuning of DA regulation in thalamo-cortico-striatal loops. Bonnavion, Varin and colleagues show that striatal projection neurons that coexpress dopamine D1 and D2 receptors have unique physiological properties and serve as a crucial third output in the striatum for motor control and dopaminergic signal integration.

High-frequency deep brain stimulation (DBS) at subthalamic nucleus (STN) is an effective therapy for Parkinson’s disease (PD), but the underlying mechanisms remain unclear. Here we find an important role of asynchronous release (AR) of GABA induced by high-frequency stimulation (HFS) in alleviating motor functions of dopamine-depleted male mice. Electrophysiological recordings reveal that 130-Hz HFS causes an initial inhibition followed by desynchronization of STN neurons, largely attributable to presynaptic GABA release. Low-frequency stimulation at 20 Hz, however, produces much weaker AR and negligible effects on neuronal firing. Further optogenetic and cell-ablation experiments demonstrate that activation of parvalbumin axons, but not non-parvalbumin axons, from external globus pallidus (GPe) is both necessary and sufficient for DBS effects. Reducing AR diminishes the high-frequency DBS effect, while increasing AR allows low-frequency DBS to achieve a therapeutic benefit. Therefore, asynchronous GABA release from GPe PV neurons may contribute significantly to the therapeutic effects of high-frequency DBS. Subthalamic nucleus (STN) deep brain stimulation (DBS) treats Parkinson’s disease effectively only at high frequencies. Authors show high- (not low-) frequency DBS desynchronizes GABA release and STN neuron firing, suggesting a therapeutic mechanism.

The globus pallidus externus (GP) is a nucleus of the basal ganglia (BG), containing GABAergic projection neurons that arborize widely throughout the BG, thalamus and cortex. Ongoing work seeks to map axonal projection patterns from GP cell types, as defined by their electrophysiological and molecular properties. Here we use transgenic mice and recombinant viruses to characterize parvalbumin expressing (PV+) GP neurons within the BG circuit. We confirm that PV+ neurons 1) make up ~40% of the GP neurons 2) exhibit fast-firing spontaneous activity and 3) provide the major axonal arborization to the STN and substantia nigra reticulata/compacta (SNr/c). PV+ neurons also innervate the striatum. Retrograde labeling identifies ~17% of pallidostriatal neurons as PV+, at least a subset of which also innervate the STN and SNr. Optogenetic experiments in acute brain slices demonstrate that the PV+ pallidostriatal axons make potent inhibitory synapses on low threshold spiking (LTS) and fast-spiking interneurons (FS) in the striatum, but rarely on spiny projection neurons (SPNs). Thus PV+ GP neurons are synaptically positioned to directly coordinate activity between BG input nuclei, the striatum and STN, and thalamic-output from the SNr.

Abstract Background and Hypothesis The dopamine theory of schizophrenia suggests that antipsychotics alleviate symptoms by blocking dopamine D2/3 receptors, yet a significant subset of patients does not respond adequately to treatment. To investigate potential predictors, we evaluated d-amphetamine-induced dopamine release and 1-year clinical outcomes in 21 antipsychotic-naive patients with first-episode schizophrenia. Study Design Twenty-one antipsychotic-naive patients (6 female) underwent dopamine D2/3 receptor radioligand [11C]-(+)-PHNO positron emission tomography. For estimating dopamine release, scans were performed with and without d-amphetamine pretreatment. The Positive and Negative Syndrome Scale was performed at regular intervals over 1 year while receiving treatment in a naturalistic setting (Clinical Trial Registry: EUDRACT 2010-019586-29). Study Results A group analysis revealed no significant differences in d-amphetamine-induced dopamine release between patients with or without clinically significant improvement. However, d-amphetamine-induced dopamine release in ventral striatum was significantly associated with reductions in positive symptoms (r = 0.54, P = .04; uncorrected P-values); release in globus pallidus correlated with a decrease in PANSS negative (r = 0.58, P = .02), general (r = 0.53, P = .04), and total symptom scores (r = 0.063, P = .01). Higher dopamine release in substantia nigra/ventral tegmental area predicted larger reductions in general symptoms (r = 0.51, P = .05). Post-amphetamine binding in putamen correlated positively with negative symptom scores at baseline (r = 0.66, P = .005) and throughout all follow-up visits. Conclusions These exploratory results support a relationship between d-amphetamine-induced dopamine release and the severity and persistence of symptoms during the first year of psychosis.