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Circadian rhythms have been shown in the subthalamic nucleus (STN) in Parkinsons disease (PD), but only a few studies have focused on the globus pallidus internus (GPi). This retrospective study investigates GPi circadian rhythms in a large cohort of subjects with PD (130 recordings from 93 subjects) with GPi activity chronically recorded in their home environment. We found a significant change in GPi activity between daytime and nighttime in most subjects (82.4%), with a reduction in GPi activity at nighttime in 56.2% of recordings and an increase in activity in 26.2%. GPi activity in higher frequency bands ( > 20 Hz) was more likely to decrease at night and in patients taking extended-release levodopa medication. Our results suggest that circadian fluctuations in the GPi vary across individuals and that increased power at night might be due to the reemergence of pathological neural activity. These findings should be considered to ensure successful implementation of adaptive neurostimulation paradigms in the real-world.

Basal ganglia (BG) circuits help guide and invigorate actions using predictions of future rewards (values). Within the BG, the globus pallidus pars externa (GPe) may play an essential role in aggregating and distributing value information. We recorded from the GPe in unrestrained rats performing both Pavlovian and instrumental tasks to obtain rewards and distinguished neuronal subtypes by their firing properties across the wake/sleep cycle and optogenetic tagging. In both tasks, the parvalbumin-positive (PV+), faster-firing prototypical neurons showed strong, sustained modulation by value, unlike other subtypes, including the arkypallidal cells that project back to striatum. Furthermore, we discovered that a distinct minority (7%) of GP cells display slower, pacemaker-like firing and encode reward prediction errors (RPEs) almost identically to midbrain dopamine neurons. These cell-specific forms of GPe value representation help define the circuit mechanisms by which the BG contribute to motivation and reinforcement learning.

BackgroundDeep brain stimulation (DBS) of the globus pallidus interna (GPi) is an effective therapy for select patients with primary dystonia. DBS programming for dystonia is often challenging due to variable time to symptomatic improvement or stimulation induced side effects (SISE) such as capsular or optic tract activation which can prolong device optimization.ObjectiveTo characterize the safety and tolerability of active recharge biphasic DBS (bDBS) in primary dystonia and to compare it to conventional clinical DBS (clinDBS).MethodsTen subjects with primary dystonia and GPi DBS underwent a single center, double blind, nonrandomized crossover study comparing clinDBS versus bDBS. The testing occurred over two-days. bDBS and clinDBS were administered on separate days and each was activated for 6 h. Rating scales were collected by video recording and scored by four blinded movement disorders trained neurologists.ResultsThe bDBS paradigm was safe and well-tolerated in all ten subjects. There were no persistent SISE reported. The mean change in the Unified Dystonia Rating Scale after 4 h of stimulation was greater in bDBS when compared to clinDBS (-6.5 vs 0.3, p < 0.04).ConclusionIn this pilot study, we demonstrated that biphasic DBS is a novel stimulation paradigm which can be administered safely. The biphasic waveform revealed a greater immediate improvement. Further studies are needed to determine whether this immediate improvement persists with chronic stimulation or if clinDBS will eventually achieve similar levels of improvement to bDBS over time.

BackgroundFragile X premutation carriers (55-200 CGG triplets) may develop a progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), after the age of 50. The neuroradiologic markers of FXTAS are hyperintense T2-signals in the middle cerebellar peduncle-the MCP sign. We recently noticed abnormal T2-signals in the globus pallidus in male premutation carriers and controls but the prevalence and clinical significance were unknown.MethodsWe estimated the prevalence of the MCP sign and pallidal T2-abnormalities in 230 male premutation carriers and 144 controls (aged 8-86), and examined the associations with FXTAS symptoms, CGG repeat length, and iron content in the cerebellar dentate nucleus and globus pallidus.ResultsAmong participants aged ≥45 years (175 premutation carriers and 82 controls), MCP sign was observed only in premutation carriers (52 vs. 0%) whereas the prevalence of pallidal T2-abnormalities approached significance in premutation carriers compared with controls after age-adjustment (25.1 vs. 13.4%, p = 0.069). MCP sign was associated with impaired motor and executive functioning, and the additional presence of pallidal T2-abnormalities was associated with greater impaired executive functioning. Among premutation carriers, significant iron accumulation was observed in the dentate nucleus, and neither pallidal or MCP T2-abnormalities affected measures of the dentate nucleus. While the MCP sign was associated with CGG repeat length >75 and dentate nucleus volume correlated negatively with CGG repeat length, pallidal T2-abnormalities did not correlate with CGG repeat length. However, pallidal signal changes were associated with age-related accelerated iron depletion and variability and having both MCP and pallidal signs further increased iron variability in the globus pallidus.ConclusionsOnly the MCP sign, not pallidal abnormalities, revealed independent associations with motor and cognitive impairment; however, the occu

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.

BackgroundFragile X premutation carriers (55-200 CGG triplets) may develop a progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), after the age of 50. The neuroradiologic markers of FXTAS are hyperintense T2-signals in the middle cerebellar peduncle-the MCP sign. We recently noticed abnormal T2-signals in the globus pallidus in male premutation carriers and controls but the prevalence and clinical significance were unknown.MethodsWe estimated the prevalence of the MCP sign and pallidal T2-abnormalities in 230 male premutation carriers and 144 controls (aged 8-86), and examined the associations with FXTAS symptoms, CGG repeat length, and iron content in the cerebellar dentate nucleus and globus pallidus.ResultsAmong participants aged ≥45 years (175 premutation carriers and 82 controls), MCP sign was observed only in premutation carriers (52 vs. 0%) whereas the prevalence of pallidal T2-abnormalities approached significance in premutation carriers compared with controls after age-adjustment (25.1 vs. 13.4%, p = 0.069). MCP sign was associated with impaired motor and executive functioning, and the additional presence of pallidal T2-abnormalities was associated with greater impaired executive functioning. Among premutation carriers, significant iron accumulation was observed in the dentate nucleus, and neither pallidal or MCP T2-abnormalities affected measures of the dentate nucleus. While the MCP sign was associated with CGG repeat length >75 and dentate nucleus volume correlated negatively with CGG repeat length, pallidal T2-abnormalities did not correlate with CGG repeat length. However, pallidal signal changes were associated with age-related accelerated iron depletion and variability and having both MCP and pallidal signs further increased iron variability in the globus pallidus.ConclusionsOnly the MCP sign, not pallidal abnormalities, revealed independent associations with motor and cognitive impairment; however, the occu

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.

Parkinson's disease (PD) is a progressive neurodegenerative illness with both motor and nonmotor symptoms. Deep brain stimulation (DBS) is an established safe neurosurgical symptomatic therapy for eligible patients with advanced disease in whom medical treatment fails to provide adequate symptom control and good quality of life, or in whom dopaminergic medications induce severe side effects such as dyskinesias. DBS can be tailored to the patient's symptoms and targeted to various nodes along the basal ganglia-thalamus circuitry, which mediates the various symptoms of the illness; DBS in the thalamus is most efficient for tremors, and DBS in the pallidum most efficient for rigidity and dyskinesias, whereas DBS in the subthalamic nucleus (STN) can treat both tremors, akinesia, rigidity and dyskinesias, and allows for decrease in doses of medications even in patients with advanced stages of the disease, which makes it the preferred target for DBS. However, DBS in the STN assumes that the patient is not too old, with no cognitive decline or relevant depression, and does not exhibit severe and medically resistant axial symptoms such as balance and gait disturbances, and falls. Dysarthria is the most common side effect of DBS, regardless of the brain target. DBS has a long-lasting effect on appendicular symptoms, but with progression of disease, nondopaminergic axial features become less responsive to DBS. DBS for PD is highly specialised; to enable adequate selection and follow-up of patients, DBS requires dedicated multidisciplinary teams of movement disorder neurologists, functional neurosurgeons, specialised DBS nurses and neuropsychologists.

Parkinson's disease (PD) is a progressive neurodegenerative illness with both motor and nonmotor symptoms. Deep brain stimulation (DBS) is an established safe neurosurgical symptomatic therapy for eligible patients with advanced disease in whom medical treatment fails to provide adequate symptom control and good quality of life, or in whom dopaminergic medications induce severe side effects such as dyskinesias. DBS can be tailored to the patient's symptoms and targeted to various nodes along the basal ganglia-thalamus circuitry, which mediates the various symptoms of the illness; DBS in the thalamus is most efficient for tremors, and DBS in the pallidum most efficient for rigidity and dyskinesias, whereas DBS in the subthalamic nucleus (STN) can treat both tremors, akinesia, rigidity and dyskinesias, and allows for decrease in doses of medications even in patients with advanced stages of the disease, which makes it the preferred target for DBS. However, DBS in the STN assumes that the patient is not too old, with no cognitive decline or relevant depression, and does not exhibit severe and medically resistant axial symptoms such as balance and gait disturbances, and falls. Dysarthria is the most common side effect of DBS, regardless of the brain target. DBS has a long-lasting effect on appendicular symptoms, but with progression of disease, nondopaminergic axial features become less responsive to DBS. DBS for PD is highly specialised; to enable adequate selection and follow-up of patients, DBS requires dedicated multidisciplinary teams of movement disorder neurologists, functional neurosurgeons, specialised DBS nurses and neuropsychologists.

Parkinson's disease (PD) is a progressive neurodegenerative illness with both motor and nonmotor symptoms. Deep brain stimulation (DBS) is an established safe neurosurgical symptomatic therapy for eligible patients with advanced disease in whom medical treatment fails to provide adequate symptom control and good quality of life, or in whom dopaminergic medications induce severe side effects such as dyskinesias. DBS can be tailored to the patient's symptoms and targeted to various nodes along the basal ganglia-thalamus circuitry, which mediates the various symptoms of the illness; DBS in the thalamus is most efficient for tremors, and DBS in the pallidum most efficient for rigidity and dyskinesias, whereas DBS in the subthalamic nucleus (STN) can treat both tremors, akinesia, rigidity and dyskinesias, and allows for decrease in doses of medications even in patients with advanced stages of the disease, which makes it the preferred target for DBS. However, DBS in the STN assumes that the patient is not too old, with no cognitive decline or relevant depression, and does not exhibit severe and medically resistant axial symptoms such as balance and gait disturbances, and falls. Dysarthria is the most common side effect of DBS, regardless of the brain target. DBS has a long-lasting effect on appendicular symptoms, but with progression of disease, nondopaminergic axial features become less responsive to DBS. DBS for PD is highly specialised; to enable adequate selection and follow-up of patients, DBS requires dedicated multidisciplinary teams of movement disorder neurologists, functional neurosurgeons, specialised DBS nurses and neuropsychologists.

Parkinson's disease (PD) is a progressive neurodegenerative illness with both motor and nonmotor symptoms. Deep brain stimulation (DBS) is an established safe neurosurgical symptomatic therapy for eligible patients with advanced disease in whom medical treatment fails to provide adequate symptom control and good quality of life, or in whom dopaminergic medications induce severe side effects such as dyskinesias. DBS can be tailored to the patient's symptoms and targeted to various nodes along the basal ganglia-thalamus circuitry, which mediates the various symptoms of the illness; DBS in the thalamus is most efficient for tremors, and DBS in the pallidum most efficient for rigidity and dyskinesias, whereas DBS in the subthalamic nucleus (STN) can treat both tremors, akinesia, rigidity and dyskinesias, and allows for decrease in doses of medications even in patients with advanced stages of the disease, which makes it the preferred target for DBS. However, DBS in the STN assumes that the patient is not too old, with no cognitive decline or relevant depression, and does not exhibit severe and medically resistant axial symptoms such as balance and gait disturbances, and falls. Dysarthria is the most common side effect of DBS, regardless of the brain target. DBS has a long-lasting effect on appendicular symptoms, but with progression of disease, nondopaminergic axial features become less responsive to DBS. DBS for PD is highly specialised; to enable adequate selection and follow-up of patients, DBS requires dedicated multidisciplinary teams of movement disorder neurologists, functional neurosurgeons, specialised DBS nurses and neuropsychologists.

Parkinson's disease (PD) is a progressive neurodegenerative illness with both motor and nonmotor symptoms. Deep brain stimulation (DBS) is an established safe neurosurgical symptomatic therapy for eligible patients with advanced disease in whom medical treatment fails to provide adequate symptom control and good quality of life, or in whom dopaminergic medications induce severe side effects such as dyskinesias. DBS can be tailored to the patient's symptoms and targeted to various nodes along the basal ganglia-thalamus circuitry, which mediates the various symptoms of the illness; DBS in the thalamus is most efficient for tremors, and DBS in the pallidum most efficient for rigidity and dyskinesias, whereas DBS in the subthalamic nucleus (STN) can treat both tremors, akinesia, rigidity and dyskinesias, and allows for decrease in doses of medications even in patients with advanced stages of the disease, which makes it the preferred target for DBS. However, DBS in the STN assumes that the patient is not too old, with no cognitive decline or relevant depression, and does not exhibit severe and medically resistant axial symptoms such as balance and gait disturbances, and falls. Dysarthria is the most common side effect of DBS, regardless of the brain target. DBS has a long-lasting effect on appendicular symptoms, but with progression of disease, nondopaminergic axial features become less responsive to DBS. DBS for PD is highly specialised; to enable adequate selection and follow-up of patients, DBS requires dedicated multidisciplinary teams of movement disorder neurologists, functional neurosurgeons, specialised DBS nurses and neuropsychologists.

Thesis Abstract Numerous actions in sequence are often required to meet our demands, though the precise number and timing of these actions may not initially be evident; in such cases, adaptive learning processes must be implemented to discover appropriate solutions. By training mice in a revised tandem lever-press protocol and implementing novel behavioural analysis methods, the number of constituent actions and the timing of action sequences were quantified and categorised according to their successful or unsuccessful outcomes. Successful adaptations to action sequences following failed attempts reliably involved the addition of multiple constituent actions over less time. We next sought to investigate the neurobiological basis of these adaptive action sequences, focusing on motor cortical targets to the dorsal striatum (DStr) and external segment of the globus pallidus (GPe). Guided by the subthalamic nucleus' comparable motor cortex afferents of the hyperdirect pathway, we identified accessory projections of the hyperdirect pathway that densely innervate the DStr and GPe. Based on this newly characterized circuitry, we addressed the function of the post-synaptic DLS and GPe target structures using pathway-specific genetic ablation according to: motor cortical connectivity, DLS and GPe interconnectivity, and intra-striatal sub-circuitry. This revealed a unique relationship between post-synaptic targets of the motor cortex in the DLS and the timing of rewarded sequences, while further downstream reciprocal DLS-GPe connections and indirect pathway striatal neurons appear to modulate preparatory action sequence timing. This project revealed key adaptive strategies used by mice to successfully update the number and timing of actions in sequence.

Deep brain nuclei are integral components of large-scale circuits mediating important cognitive and sensorimotor functions. However, because they fall outside the domain of conventional non-invasive neuromodulatory techniques, their study has been primarily based on neuropsychological models, limiting the ability to fully characterize their role and to develop interventions in cases where they are damaged. To address this gap, we used the emerging technology of non-invasive low-intensity focused ultrasound (LIFU) to directly modulate left lateralized basal ganglia structures in healthy volunteers. During sonication, we observed local and distal decreases in blood oxygenation level dependent (BOLD) signal in the targeted left globus pallidus (GP) and in large-scale cortical networks. We also observed a generalized decrease in relative perfusion throughout the cerebrum following sonication. These results show, for the first time using functional MRI data, the ability to modulate deep-brain nuclei using LIFU while measuring its local and global consequences, opening the door for future applications of subcortical LIFU.

Aging entails a multifaceted complex of changes in macro- and micro-structural properties of human brain gray matter (GM) and white matter (WM) tissues, as well as in intellectual abilities. To better capture tissue-specific brain aging, we combined volume and distribution properties of diffusivity indices to derive subject-specific age scores for each tissue. We compared age-related variance between younger and older adults for GM and WM age scores, and tested whether tissue-specific age scores could explain different effects of aging on fluid (Gf) and crystalized (Gc) intelligence in younger and older adults. Chronological age was strongly associated with GM (R2 = 0.73) and WM (R2 = 0.57) age scores. The GM age score accounted for significantly more variance in chronological age in younger relative to older adults (p < 0.001), whereas the WM age score accounted for significantly more variance in chronological age in older compared to younger adults (p < 0.025). Consistent with existing literature, younger adults outperformed older adults in Gf while older adults outperformed younger adults in Gc. The GM age score was negatively associated with Gf in younger adults (p < 0.02), whereas the WM age score was negatively associated with Gc in older adults (p < 0.02). Our results provide evidence for differences in the effects of age on GM and WM in younger versus older adults that may contribute to age-related differences in Gf and Gc.

Activation of cannabinoid 1 receptors (CB1 R) modulates multiple behaviours, including exploration, motor coordination and response to psychostimulants. It is known that CB1 R expressed by either excitatory or inhibitory neurons mediates different behavioural responses to CB1 R activation, yet the involvement of CB1 R expressed by medium spiny neurons (MSNs), the neuronal subpopulation that expresses the highest level of CB1 R in the CNS, remains unknown. We report a new genetically modified mouse line that expresses functional CB1 R in MSN on a CB1 R knockout (KO) background (CB1 R(MSN) mice). The absence of cannabimimetic responses measured in CB1 R KO mice was not rescued in CB1 R(MSN) mice, nor was decreased spontaneous locomotion, impaired instrumental behaviour or reduced amphetamine-triggered hyperlocomotion measured in CB1 R KO mice. Significantly, reduced novel environment exploration of an open field and absence of amphetamine sensitization (AS) measured in CB1 R KO mice were fully rescued in CB1 R(MSN) mice. Impaired motor coordination in CB1 R KO mice measured on the Rotarod was partially rescued in CB1 R(MSN) mice. Thus, CB1 R expressed by MSN control exploration, motor coordination, and AS. Our study demonstrates a new functional roles for cell specific CB1 R expression and their causal link in the control of specific behaviors.

BACKGROUND: Substantial evidence indicates that a microdeletion on human chromosome 16p11.2 is linked to neurodevelopmental disorders, including autism spectrum disorder (ASD). Carriers of this deletion show divergent symptoms besides the core features of autism spectrum disorder, such as anxiety and emotional symptoms. The neural mechanisms underlying these symptoms are poorly understood. METHODS: We used mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) and their sex-matched wild-type littermates for the study and examined their anxiety-related behaviors, auditory perception, and central amygdala circuit function using behavioral, circuit tracing, and electrophysiological techniques. RESULTS: Mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) had sex-specific anxiety-related behavioral and neural circuit changes. Specifically, we found that female, but not male, 16p11.2 del/+ mice showed enhanced fear generalization-a hallmark of anxiety disorders-after auditory fear conditioning and displayed increased anxiety-like behaviors after physical restraint stress. Notably, such sex-specific behavioral changes were paralleled by an increase in activity in central amygdala neurons projecting to the globus pallidus in female, but not male, 16p11.2 del/+ mice. CONCLUSIONS: Together, these results reveal female-specific anxiety phenotypes related to 16p11.2 microdeletion syndrome and a potential underlying neural circuit mechanism. Our study therefore identifies previously underappreciated sex-specific behavioral and neural changes in a genetic model of 16p11.2 microdeletion syndrome and highlights the importance of investigating female-specific aspects of this syndrome for targeted treatment strategies.

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson's disease (PD). Interleukin-1beta (IL-1 beta), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1 beta was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1 beta neutralization are still poorly understood. The present study investigated the role of IL-1 beta on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1 beta neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1 beta attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson's disease (PD). Interleukin-1beta (IL-1 beta), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1 beta was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1 beta neutralization are still poorly understood. The present study investigated the role of IL-1 beta on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1 beta neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1 beta attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson's disease (PD). Interleukin-1beta (IL-1 beta), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1 beta was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1 beta neutralization are still poorly understood. The present study investigated the role of IL-1 beta on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1 beta neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1 beta attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.

Dystonia is a movement disorder characterised by involuntary muscle contractions resulting in abnormal movements, postures and tremor. The pathophysiology of dystonia is not fully understood but loss of neuronal inhibition, excessive sensorimotor plasticity and defective sensory processing are thought to contribute to network dysfunction underlying the disorder. Neurophysiology studies have been important in furthering our understanding of dystonia and have provided insights into the mechanism of effective dystonia treatment with pallidal deep brain stimulation. In this article we review neurophysiology studies in dystonia and its treatment with Deep Brain Stimulation, including Transcranial magnetic stimulation studies, studies of reflexes and sensory processing, and oscillatory activity recordings including local field potentials, micro-recordings, EEG and evoked potentials.

BackgroundPost-hypoxic myoclonus (PHM) is characterized by generalized myoclonus after hypoxic brain injury. Myoclonus is often functionally impairing and refractory to medical therapies. Deep brain stimulation (DBS) has been used to treat myoclonus-dystonia, but few cases of PHM have been described.Case reportA 33-year-old woman developed severe, refractory generalized myoclonus after cardiopulmonary arrest from drowning. We performed MRI-guided asleep bilateral pallidal DBS placement, resulting in improvement in action myoclonus at one year.DiscussionOur case contributes to growing evidence for DBS for PHM. Interventional MRI guided DBS technique can be used for safe and accurate lead placement.HighlightsWe report a case of a patient who developed post-hypoxic myoclonus after cardiopulmonary arrest from drowning, who later underwent deep brain stimulation to treat refractory myoclonus. This is the first case to describe asleep, interventional MRI-guided technique for implanting DBS leads in post-hypoxic myoclonus.

ObjectiveThe aim of this study was to evaluate the feasibility and preliminary efficacy and safety of combined bilateral ventralis oralis posterior/ventralis intermedius (Vop/Vim) deep brain stimulation (DBS) for the treatment of acquired dystonia in children and young adults. Pallidal DBS is efficacious for severe, medication-refractory isolated dystonia, providing 50%-60% long-term improvement. Unfortunately, pallidal stimulation response rates in acquired dystonia are modest and unpredictable, with frequent nonresponders. Acquired dystonia, most commonly caused by cerebral palsy, is more common than isolated dystonia in pediatric populations and is more recalcitrant to standard treatments. Given the limitations of pallidal DBS in acquired dystonia, there is a need to explore alternative brain targets. Preliminary evidence has suggested that thalamic stimulation may be efficacious for acquired dystonia.MethodsFour participants, 3 with perinatal brain injuries and 1 with postencephalitic symptomatic dystonia, underwent bilateral Vop/Vim DBS and bimonthly evaluations for 12 months. The primary efficacy outcome was the change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Barry-Albright Dystonia Scale (BADS) scores between the baseline and 12-month assessments. Video documentation was used for blinded ratings. Secondary outcomes included evaluation of spasticity (Modified Ashworth Scale score), quality of life (Pediatric Quality of Life Inventory [PedsQL] and modified Unified Parkinson's Disease Rating Scale Part II [UPDRS-II] scores), and neuropsychological assessments. Adverse events were monitored for safety.ResultsAll participants tolerated the procedure well, and there were no safety concerns or serious adverse events. There was an average improvement of 21.5% in the BFMDRS motor subscale score, but the improvement was only 1.6% according to the BADS score. Following blinded video review, dystonia severity ratings were even more modest. Secondary outco

Despite the harm caused by binge drinking, the neural mechanisms leading to risky and disinhibited intoxication-related behaviors are not well understood. Evidence suggests that the globus pallidus externus (GPe), a substructure within the basal ganglia, participates in inhibitory control processes, as examined in stop-signaling tasks. In fact, studies in rodents have revealed that alcohol can change GPe activity by decreasing neuronal firing rates, suggesting that the GPe may have a central role in explaining impulsive behaviors and failures of inhibition that occur during binge drinking. In this study, twenty-five healthy volunteers underwent intravenous alcohol infusion to achieve a blood alcohol level of 0.08 g/dl, which is equivalent to a binge drinking episode. A resting state functional magnetic resonance imaging scan was collected prior to the infusion and at binge-level exposure. Functional connectivity analysis was used to investigate the association between alcohol-induced changes in GPe connectivity, drinking behaviors, and impulsivity traits. We found that individuals with greater number of drinks or heavy drinking days in the recent past had greater alcohol-induced deficits in GPe connectivity, particularly to the striatum. Our data also indicated an association between impulsivity and alcohol-induced deficits in GPe-frontal/precentral connectivity. Moreover, alcohol induced changes in GPe-amygdala circuitry suggested greater vulnerabilities to stress-related drinking in some individuals. Taken together, these findings suggest that alcohol may interact with impulsive personality traits and drinking patterns to drive alterations in GPe circuitry associated with behavioral inhibition, possibly indicating a neural mechanism by which binge drinking could lead to impulsive behaviors.

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson's disease (PD). Interleukin-1beta (IL-1 beta), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1 beta was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1 beta neutralization are still poorly understood. The present study investigated the role of IL-1 beta on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1 beta neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1 beta attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.

The central amygdala (CeA) is critically involved in a range of adaptive behaviors, including defensive behaviors. Neurons in the CeA send long-range projections to a number of extra-amygdala targets, but the functions of these projections remain elusive. Here, we report that a previously neglected CeA-to-globus pallidus external segment (GPe) circuit plays an essential role in classical fear conditioning. By anatomic tracing, in situ hybridization and channelrhodopsin (ChR2)-assisted circuit mapping in both male and female mice, we found that a subset of CeA neurons send projections to the GPe, and the majority of these GPe-projecting CeA neurons express the neuropeptide somatostatin. Notably, chronic inhibition of GPe-projecting CeA neurons with the tetanus toxin light chain (TeLC) completely blocks auditory fear conditioning. In vivo fiber photometry revealed that these neurons are selectively excited by the unconditioned stimulus (US) during fear conditioning. Furthermore, transient optogenetic inactivation or activation of these neurons selectively during US presentation impairs or promotes, respectively, fear learning. Our results suggest that a major function of GPe-projecting CeA neurons is to represent and convey US-related information through the CeA-GPe circuit, thereby regulating learning in fear conditioning.SIGNIFICANCE STATEMENT The central amygdala (CeA) has been implicated in the establishment of defensive behaviors toward threats, but the underlying circuit mechanisms remain unclear. Here, we found that a subpopulation of neurons in the CeA, which are mainly those that express the neuropeptide somatostatin, send projections to the globus pallidus external segment (GPe), and this CeA-GPe circuit conveys unconditioned stimulus (US)-related information during classical fear conditioning, thereby having an indispensable role in learning. Our results reveal a previously unknown circuit mechanism for fear learning.

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson's disease (PD). Interleukin-1beta (IL-1 beta), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1 beta was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1 beta neutralization are still poorly understood. The present study investigated the role of IL-1 beta on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1 beta neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1 beta attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.

Striatal medium spiny neurons (MSNs) play a crucial role in various motor and cognitive functions. They are separated into those belonging to the direct pathway (dMSNs) and the indirect pathway (iMSNs) of the basal ganglia, depending on whether they express D1 or D2 type dopamine receptors, respectively. In this thesis I investigated the input processing of both MSN types, the characteristics of dMSN outputs, and the effect that aberrant iMSN activity has on the subthalamic nucleus-globus pallidus externa (STN-GPe) network.In order to verify a previous result from a computational study claiming that dMSNs should receive either more or stronger total input than iMSNs, I performed an analysis of in vivo whole-cell MSN recordings in healthy and dopamine (DA) depleted (6OHDA) anesthetized mice. To test this prediction, I compared subthreshold membrane potential fluctuations and spike-triggered average membrane potentials of the two MSN types. I found that dMSNs in healthy mice exhibited considerably larger fluctuations over a wide frequency range, as well as significantly faster depolarization towards the spiking threshold than iMSNs. However, these effects were not present in recordings from 6OHDA animals. Together, these findings strongly suggest that dMSNs do receive stronger total input than iMSNs in healthy condition.I also examined how different concentrations of dopamine affect neural trial-by-trial (or response) variability in a biophysically detailed compartmental model of a direct-pathway MSN. Some of the sources of trial-by-trial variability include synaptic noise, neural refractory period, and ongoing neural activity. The focus of this study was on the effects of two particular properties of the synaptic input: correlations of synaptic input rates, and the balance between excitatory and inhibitory inputs (E-I balance). The model demonstrates that dopamine is in general a significant diminisher of trial-by-trial variability, but that its efficacy depends, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

Striatal medium spiny neurons (MSNs) play a crucial role in various motor and cognitive functions. They are separated into those belonging to the direct pathway (dMSNs) and the indirect pathway (iMSNs) of the basal ganglia, depending on whether they express D1 or D2 type dopamine receptors, respectively. In this thesis I investigated the input processing of both MSN types, the characteristics of dMSN outputs, and the effect that aberrant iMSN activity has on the subthalamic nucleus-globus pallidus externa (STN-GPe) network.In order to verify a previous result from a computational study claiming that dMSNs should receive either more or stronger total input than iMSNs, I performed an analysis of in vivo whole-cell MSN recordings in healthy and dopamine (DA) depleted (6OHDA) anesthetized mice. To test this prediction, I compared subthreshold membrane potential fluctuations and spike-triggered average membrane potentials of the two MSN types. I found that dMSNs in healthy mice exhibited considerably larger fluctuations over a wide frequency range, as well as significantly faster depolarization towards the spiking threshold than iMSNs. However, these effects were not present in recordings from 6OHDA animals. Together, these findings strongly suggest that dMSNs do receive stronger total input than iMSNs in healthy condition.I also examined how different concentrations of dopamine affect neural trial-by-trial (or response) variability in a biophysically detailed compartmental model of a direct-pathway MSN. Some of the sources of trial-by-trial variability include synaptic noise, neural refractory period, and ongoing neural activity. The focus of this study was on the effects of two particular properties of the synaptic input: correlations of synaptic input rates, and the balance between excitatory and inhibitory inputs (E-I balance). The model demonstrates that dopamine is in general a significant diminisher of trial-by-trial variability, but that its efficacy depends, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

Introduction: In a double-blind randomized crossover trial, we previously established that bilateral deep brain stimulation of the anteromedial globus pallidus internus (GPiam-DBS) is effective in significantly reducing tic severity in patients with refractory Tourette syndrome (TS). Here, we report the effects of bilateral GPiam-DBS on cognitive function in 11 of the 13 patients who had participated in our double-blind cross-over trial of GPi-DBS. Methods: Patients were assessed at baseline (4 weeks prior to surgery) and at the end of each of the three-month blinded periods, with stimulation either ON or OFF. The patients were evaluated on tests of memory (California Verbal Learning Test-II (CVLT-II); Corsi blocks; Short Recognition Memory for Faces), executive function (D-KEFS Stroop color-word interference, verbal fluency, Trail-making test, Hayling Sentence Completion test), and attention (Paced Auditory Serial Addition Test, Numbers and Letters Test). Results: GPiam-DBS did not produce any significant change in global cognition. Relative to pre-operative baseline assessment verbal episodic memory on the CVLT-II and set-shifting on the Trail-making Test were improved with DBS OFF. Performance on the cognitive tests were not different with DBS ON versus DBS OFF. GPiam-DBS did not alter aspects of cognition that are impaired in TS such as inhibition on the Stroop interference task or the Hayling Sentence Completion test. Conclusions: This study extends previous findings providing data showing that GPiam-DBS does not adversely affect cognitive domains such as memory, executive function, verbal fluency, attention, psychomotor speed, and information processing. These results indicate that GPiam-DBS does not produce any cognitive deficits in TS.

The external segment of the globus pallidus (GPe), a subcortical nucleus centrally located in the indirect pathway of the basal ganglia, plays a pivotal role in processing and broadcasting information received from the striatum and the subthalamic nucleus through its widespread projections across major basal ganglia nuclei. One of the largest neuronal populations of the GPe expresses the Ca2+-binding protein parvalbumin (PV) and projects to multiple nuclei of the basal ganglia and the thalamus and has been shown to be involved in movement disability in Parkinson’s disease (PD). However, most studies to date considered GPe PV neurons as a homogeneous population. We found that the GPe PV neurons can be further subdivided into two non-overlapping populations based on their projections to either the substantia nigra pars reticulata (SNr) or the parafascicular thalamus (PF) and their intrinsic electrophysiological properties. We further investigated the circuit-specific roles of these subpopulations in locomotion and reversal learning as well as their contributions to the impairments of motor and cognitive flexibility in a PD mouse model. Our findings establish the behavioral significance of two distinct GPe PV neuronal populations embedded in discrete neural pathways and their differential contributions to specific subdomains of Parkinsonian-like behaviors.

BackgroundDeep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting.MethodsWe collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases.ResultsTics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi.ConclusionThe results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was th

The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of midbrain dopaminergic neurons localized in the substantia nigra pars compacta (SNc). This degeneration causes cellular and synaptic dysfunctions in the BG network, which are responsible for the appearance of the motor symptoms of Parkinson's disease. Dopamine (DA) modulation and the consequences of its loss on the striatal microcircuit have been extensively studied, and because of the discrete nature of DA innervation of other BG nuclei, its action outside the striatum has been considered negligible. However, there is a growing body of evidence supporting functional extrastriatal DA modulation of both cellular excitability and synaptic transmission. In this review, the functional relevance of DA modulation outside the striatum in both normal and pathological conditions will be discussed.

The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of midbrain dopaminergic neurons localized in the substantia nigra pars compacta (SNc). This degeneration causes cellular and synaptic dysfunctions in the BG network, which are responsible for the appearance of the motor symptoms of Parkinson's disease. Dopamine (DA) modulation and the consequences of its loss on the striatal microcircuit have been extensively studied, and because of the discrete nature of DA innervation of other BG nuclei, its action outside the striatum has been considered negligible. However, there is a growing body of evidence supporting functional extrastriatal DA modulation of both cellular excitability and synaptic transmission. In this review, the functional relevance of DA modulation outside the striatum in both normal and pathological conditions will be discussed.

Introduction: In a double-blind randomized crossover trial, we previously established that bilateral deep brain stimulation of the anteromedial globus pallidus internus (GPiam-DBS) is effective in significantly reducing tic severity in patients with refractory Tourette syndrome (TS). Here, we report the effects of bilateral GPiam-DBS on cognitive function in 11 of the 13 patients who had participated in our double-blind cross-over trial of GPi-DBS. Methods: Patients were assessed at baseline (4 weeks prior to surgery) and at the end of each of the three-month blinded periods, with stimulation either ON or OFF. The patients were evaluated on tests of memory (California Verbal Learning Test-II (CVLT-II); Corsi blocks; Short Recognition Memory for Faces), executive function (D-KEFS Stroop color-word interference, verbal fluency, Trail-making test, Hayling Sentence Completion test), and attention (Paced Auditory Serial Addition Test, Numbers and Letters Test). Results: GPiam-DBS did not produce any significant change in global cognition. Relative to pre-operative baseline assessment verbal episodic memory on the CVLT-II and set-shifting on the Trail-making Test were improved with DBS OFF. Performance on the cognitive tests were not different with DBS ON versus DBS OFF. GPiam-DBS did not alter aspects of cognition that are impaired in TS such as inhibition on the Stroop interference task or the Hayling Sentence Completion test. Conclusions: This study extends previous findings providing data showing that GPiam-DBS does not adversely affect cognitive domains such as memory, executive function, verbal fluency, attention, psychomotor speed, and information processing. These results indicate that GPiam-DBS does not produce any cognitive deficits in TS.

The external segment of the globus pallidus (GPe), a subcortical nucleus centrally located in the indirect pathway of the basal ganglia, plays a pivotal role in processing and broadcasting information received from the striatum and the subthalamic nucleus through its widespread projections across major basal ganglia nuclei. One of the largest neuronal populations of the GPe expresses the Ca2+-binding protein parvalbumin (PV) and projects to multiple nuclei of the basal ganglia and the thalamus and has been shown to be involved in movement disability in Parkinson’s disease (PD). However, most studies to date considered GPe PV neurons as a homogeneous population. We found that the GPe PV neurons can be further subdivided into two non-overlapping populations based on their projections to either the substantia nigra pars reticulata (SNr) or the parafascicular thalamus (PF) and their intrinsic electrophysiological properties. We further investigated the circuit-specific roles of these subpopulations in locomotion and reversal learning as well as their contributions to the impairments of motor and cognitive flexibility in a PD mouse model. Our findings establish the behavioral significance of two distinct GPe PV neuronal populations embedded in discrete neural pathways and their differential contributions to specific subdomains of Parkinsonian-like behaviors.

BackgroundDeep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting.MethodsWe collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases.ResultsTics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi.ConclusionThe results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was th

The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of midbrain dopaminergic neurons localized in the substantia nigra pars compacta (SNc). This degeneration causes cellular and synaptic dysfunctions in the BG network, which are responsible for the appearance of the motor symptoms of Parkinson's disease. Dopamine (DA) modulation and the consequences of its loss on the striatal microcircuit have been extensively studied, and because of the discrete nature of DA innervation of other BG nuclei, its action outside the striatum has been considered negligible. However, there is a growing body of evidence supporting functional extrastriatal DA modulation of both cellular excitability and synaptic transmission. In this review, the functional relevance of DA modulation outside the striatum in both normal and pathological conditions will be discussed.

Striatal medium spiny neurons (MSNs) play a crucial role in various motor and cognitive functions. They are separated into those belonging to the direct pathway (dMSNs) and the indirect pathway (iMSNs) of the basal ganglia, depending on whether they express D1 or D2 type dopamine receptors, respectively. In this thesis I investigated the input processing of both MSN types, the characteristics of dMSN outputs, and the effect that aberrant iMSN activity has on the subthalamic nucleus-globus pallidus externa (STN-GPe) network.In order to verify a previous result from a computational study claiming that dMSNs should receive either more or stronger total input than iMSNs, I performed an analysis of in vivo whole-cell MSN recordings in healthy and dopamine (DA) depleted (6OHDA) anesthetized mice. To test this prediction, I compared subthreshold membrane potential fluctuations and spike-triggered average membrane potentials of the two MSN types. I found that dMSNs in healthy mice exhibited considerably larger fluctuations over a wide frequency range, as well as significantly faster depolarization towards the spiking threshold than iMSNs. However, these effects were not present in recordings from 6OHDA animals. Together, these findings strongly suggest that dMSNs do receive stronger total input than iMSNs in healthy condition.I also examined how different concentrations of dopamine affect neural trial-by-trial (or response) variability in a biophysically detailed compartmental model of a direct-pathway MSN. Some of the sources of trial-by-trial variability include synaptic noise, neural refractory period, and ongoing neural activity. The focus of this study was on the effects of two particular properties of the synaptic input: correlations of synaptic input rates, and the balance between excitatory and inhibitory inputs (E-I balance). The model demonstrates that dopamine is in general a significant diminisher of trial-by-trial variability, but that its efficacy depends, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

Striatal medium spiny neurons (MSNs) play a crucial role in various motor and cognitive functions. They are separated into those belonging to the direct pathway (dMSNs) and the indirect pathway (iMSNs) of the basal ganglia, depending on whether they express D1 or D2 type dopamine receptors, respectively. In this thesis I investigated the input processing of both MSN types, the characteristics of dMSN outputs, and the effect that aberrant iMSN activity has on the subthalamic nucleus-globus pallidus externa (STN-GPe) network.In order to verify a previous result from a computational study claiming that dMSNs should receive either more or stronger total input than iMSNs, I performed an analysis of in vivo whole-cell MSN recordings in healthy and dopamine (DA) depleted (6OHDA) anesthetized mice. To test this prediction, I compared subthreshold membrane potential fluctuations and spike-triggered average membrane potentials of the two MSN types. I found that dMSNs in healthy mice exhibited considerably larger fluctuations over a wide frequency range, as well as significantly faster depolarization towards the spiking threshold than iMSNs. However, these effects were not present in recordings from 6OHDA animals. Together, these findings strongly suggest that dMSNs do receive stronger total input than iMSNs in healthy condition.I also examined how different concentrations of dopamine affect neural trial-by-trial (or response) variability in a biophysically detailed compartmental model of a direct-pathway MSN. Some of the sources of trial-by-trial variability include synaptic noise, neural refractory period, and ongoing neural activity. The focus of this study was on the effects of two particular properties of the synaptic input: correlations of synaptic input rates, and the balance between excitatory and inhibitory inputs (E-I balance). The model demonstrates that dopamine is in general a significant diminisher of trial-by-trial variability, but that its efficacy depends, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

Striatal medium spiny neurons (MSNs) play a crucial role in various motor and cognitive functions. They are separated into those belonging to the direct pathway (dMSNs) and the indirect pathway (iMSNs) of the basal ganglia, depending on whether they express D1 or D2 type dopamine receptors, respectively. In this thesis I investigated the input processing of both MSN types, the characteristics of dMSN outputs, and the effect that aberrant iMSN activity has on the subthalamic nucleus-globus pallidus externa (STN-GPe) network.In order to verify a previous result from a computational study claiming that dMSNs should receive either more or stronger total input than iMSNs, I performed an analysis of in vivo whole-cell MSN recordings in healthy and dopamine (DA) depleted (6OHDA) anesthetized mice. To test this prediction, I compared subthreshold membrane potential fluctuations and spike-triggered average membrane potentials of the two MSN types. I found that dMSNs in healthy mice exhibited considerably larger fluctuations over a wide frequency range, as well as significantly faster depolarization towards the spiking threshold than iMSNs. However, these effects were not present in recordings from 6OHDA animals. Together, these findings strongly suggest that dMSNs do receive stronger total input than iMSNs in healthy condition.I also examined how different concentrations of dopamine affect neural trial-by-trial (or response) variability in a biophysically detailed compartmental model of a direct-pathway MSN. Some of the sources of trial-by-trial variability include synaptic noise, neural refractory period, and ongoing neural activity. The focus of this study was on the effects of two particular properties of the synaptic input: correlations of synaptic input rates, and the balance between excitatory and inhibitory inputs (E-I balance). The model demonstrates that dopamine is in general a significant diminisher of trial-by-trial variability, but that its efficacy depends, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of midbrain dopaminergic neurons localized in the substantia nigra pars compacta (SNc). This degeneration causes cellular and synaptic dysfunctions in the BG network, which are responsible for the appearance of the motor symptoms of Parkinson's disease. Dopamine (DA) modulation and the consequences of its loss on the striatal microcircuit have been extensively studied, and because of the discrete nature of DA innervation of other BG nuclei, its action outside the striatum has been considered negligible. However, there is a growing body of evidence supporting functional extrastriatal DA modulation of both cellular excitability and synaptic transmission. In this review, the functional relevance of DA modulation outside the striatum in both normal and pathological conditions will be discussed., SCOPUS: re.j, info:eu-repo/semantics/published

Bachground: The effect of duration of illness and antipsychotic medication on the volumes of subcortical structures in schizophrenia is inconsistent among previous reports. We implemented a large sample analysis utilizing clinical data from 11 institutions in a previous meta-analysis. Methods: Imaging and clinical data of 778 schizophrenia subjects were taken from a prospective meta-analysis conducted by the COCORO consortium in Japan. The effect of duration of illness and daily dose and type of antipsychotics were assessed using the linear mixed effect model where the volumes of subcortical structures computed by FreeSurfer were used as a dependent variable and age, sex, duration of illness, daily dose of antipsychotics and intracranial volume were used as independent variables, and the type of protocol was incorporated as a random effect for intercept. The statistical significance of fixed-effect of dependent variable was assessed. Results: Daily dose of antipsychotics was positively associated with left globus pallidus volume and negatively associated with right hippocampus. It was also positively associated with laterality index of globus pallidus. Duration of illness was positively associated with bilateral globus pallidus volumes. Type of antipsychotics did not have any effect on the subcortical volumes. Discussion: A large sample size, uniform data collection methodology and robust statistical analysis are strengths of the current study. This result suggests that we need special attention to discuss about relationship between subcortical regional brain volumes and pathophysiology of schizophrenia because regional brain volumes may be affected by antipsychotic medication.

In Parkinson's disease (PD), subthalamic nucleus beta band oscillations are decreased by therapeutic deep-brain stimulation (DBS) and this has been proposed as important to the mechanism of therapy. The globus pallidus is a common alternative target for PD with similar motor benefits as subthalamic DBS, but effects of pallidal stimulation in PD are not well studied, and effects of pallidal DBS on cortical function in PD are unknown. Here, in 20 PD and 14 isolated dystonia human patients of both genders undergoing pallidal DBS lead implantation, we recorded local field potentials from the globus pallidus and in a subset of these, recorded simultaneous sensorimotor cortex ECoG potentials. PD patients had elevated resting pallidal low beta band (13-20 Hz) power compared with dystonia patients, whereas dystonia patients had elevated resting pallidal theta band (4-8 Hz) power compared with PD. We show that this results in disease-specific patterns of interaction between the pallidum and motor cortex: PD patients demonstrated relatively elevated phase coherence with the motor cortex in the beta band and this was reduced by therapeutic pallidal DBS. Dystonia patients had greater theta band phase coherence. Our results support the hypothesis that specific motor phenomenology observed in movement disorders are associated with elevated network oscillations in specific frequency bands, and that DBS in movement disorders acts in general by disrupting elevated synchronization between basal ganglia output and motor cortex.SIGNIFICANCE STATEMENT Perturbations in synchronized oscillatory activity in brain networks are increasingly recognized as important features in movement disorders. The globus pallidus is a commonly used target for deep-brain stimulation (DBS) in Parkinson's disease (PD), however, the effects of pallidal DBS on basal ganglia and cortical oscillations are unknown. Using invasive intraoperative recordings in patients with PD and isolated dystonia, we found disease

This light and electron microscopie immunohistochemical quantitative study aimed at determining the state of the dopamine (DA) and serotonin (5-HT) innervations of the internal (GPi) and external (GPe) segments of the pallidum in cynomolgus monkeys (Macaca fascicularis) rendered parkinsonian by systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to the prominent DA denervation of striatum, the GPi in MPTP monkeys was found to be markedly enriched in DA (TH+) axon varicosities. The posterior sensorimotor region of this major output structure of the basal ganglia was about 8 times more intensely innervated in MPTP monkeys (0.71 ± 0.08 × 106 TH+ axon varicosities/mm3) than in controls (0.09 ± 0.01 × 106). MPTP intoxication also induced a two-fold increase in the density of 5-HT (SERT+) axon varicosities in both GPe and GPi. This augmentation was particularly pronounced anteriorly in the so-called associative and limbic pallidal territories. The total length of the labeled pallidal axons was also significantly increased in MPTP monkeys compared to controls, but the number of DA and 5-HT axon varicosities per axon length unit remained the same in the two groups, indicating that the DA and 5-HT pallidal hyperinnervations seen in MPTP monkeys result from axon sprouting rather than from the appearance of newly formed axon varicosities on non-growing axons. At the ultrastructural level, pallidal TH+ and SERT+ axons were morphologically similar in MPTP and controls, and their synaptic incidence was very low suggesting a volumic mode of transmission. Altogether, our data reveal a significant sprouting of DA and 5-HT pallidal afferents in parkinsonian monkeys, the functional significance of which remains to be determined. We suggest that the marked DA hyperinnervation of the GPi represents a neuroadaptive change designed to normalize pallidal firing patterns associated with the delayed appearance of motor symptoms, whereas the 5-HT hyperinner

This chapter provides an overview of the basal ganglia connectome as revealed by single-axon tracing procedures applied to nonhuman primates. These studies have shown that virtually all basal ganglia components, as well as most brainstem and thalamic nuclei with which they are reciprocally linked, harbor several distinct sets of projection neurons characteristically endowed with a highly collateralized and widely distributed axon. This morphological trait allows a complex and exquisitely precise interaction between the various basal ganglia and their related thalamic and brainstem nuclei. Our findings indicate that the basal ganglia are part of a finely tuned network that extends over several levels of the neuraxis. The anatomical elucidation of this intricate circuitry is essential to understand the complex spatiotemporal sequence of neural events that ensures the flow of cortical information through the basal ganglia, whose alteration leads to major psychomotor disabilities.

In Parkinson's disease (PD), subthalamic nucleus beta band oscillations are decreased by therapeutic deep-brain stimulation (DBS) and this has been proposed as important to the mechanism of therapy. The globus pallidus is a common alternative target for PD with similar motor benefits as subthalamic DBS, but effects of pallidal stimulation in PD are not well studied, and effects of pallidal DBS on cortical function in PD are unknown. Here, in 20 PD and 14 isolated dystonia human patients of both genders undergoing pallidal DBS lead implantation, we recorded local field potentials from the globus pallidus and in a subset of these, recorded simultaneous sensorimotor cortex ECoG potentials. PD patients had elevated resting pallidal low beta band (13-20 Hz) power compared with dystonia patients, whereas dystonia patients had elevated resting pallidal theta band (4-8 Hz) power compared with PD. We show that this results in disease-specific patterns of interaction between the pallidum and motor cortex: PD patients demonstrated relatively elevated phase coherence with the motor cortex in the beta band and this was reduced by therapeutic pallidal DBS. Dystonia patients had greater theta band phase coherence. Our results support the hypothesis that specific motor phenomenology observed in movement disorders are associated with elevated network oscillations in specific frequency bands, and that DBS in movement disorders acts in general by disrupting elevated synchronization between basal ganglia output and motor cortex.SIGNIFICANCE STATEMENT Perturbations in synchronized oscillatory activity in brain networks are increasingly recognized as important features in movement disorders. The globus pallidus is a commonly used target for deep-brain stimulation (DBS) in Parkinson's disease (PD), however, the effects of pallidal DBS on basal ganglia and cortical oscillations are unknown. Using invasive intraoperative recordings in patients with PD and isolated dystonia, we found disease

This chapter provides an overview of the basal ganglia connectome as revealed by single-axon tracing procedures applied to nonhuman primates. These studies have shown that virtually all basal ganglia components, as well as most brainstem and thalamic nuclei with which they are reciprocally linked, harbor several distinct sets of projection neurons characteristically endowed with a highly collateralized and widely distributed axon. This morphological trait allows a complex and exquisitely precise interaction between the various basal ganglia and their related thalamic and brainstem nuclei. Our findings indicate that the basal ganglia are part of a finely tuned network that extends over several levels of the neuraxis. The anatomical elucidation of this intricate circuitry is essential to understand the complex spatiotemporal sequence of neural events that ensures the flow of cortical information through the basal ganglia, whose alteration leads to major psychomotor disabilities.

Background: The effect of duration of illness and antipsychotic medication on the volumes of subcortical structures in schizophrenia is inconsistent among previous reports. We implemented a large sample analysis utilizing clinical data from 11 institutions in a previous meta-analysis. Methods: Imaging and clinical data of 778 schizophrenia subjects were taken from a prospective meta-analysis conducted by the COCORO consortium in Japan. The effect of duration of illness and daily dose and type of antipsychotics were assessed using the linear mixed effect model where the volumes of subcortical structures computed by FreeSurfer were used as a dependent variable and age, sex, duration of illness, daily dose of antipsychotics and intracranial volume were used as independent variables, and the type of protocol was incorporated as a random effect for intercept. The statistical significance of fixed-effect of dependent variable was assessed. Results: Daily dose of antipsychotics was positively associated with left globus pallidus volume and negatively associated with right hippocampus. It was also positively associated with laterality index of globus pallidus. Duration of illness was positively associated with bilateral globus pallidus volumes. Type of antipsychotics did not have any effect on the subcortical volumes. Discussion: A large sample size, uniform data collection methodology and robust statistical analysis are strengths of the current study. This result suggests that we need special attention to discuss about relationship between subcortical regional brain volumes and pathophysiology of schizophrenia because regional brain volumes may be affected by antipsychotic medication.