Activity In Basal Ganglia Research Articles

Neural Networks for Time Perception and Working Memory.

Time is an important concept which determines most human behaviors, however questions remain about how time is perceived and which areas of the brain are responsible for time perception. The aim of this study was to evaluate the relationship between time perception and working memory in healthy adults. Functional magnetic resonance imaging (fMRI) was used during the application of a visual paradigm. In all of the conditions, the participants were presented with a moving black rectangle on a gray screen. The rectangle was obstructed by a black bar for a time period and then reappeared again. During different conditions, participants (n = 15, eight male) responded according to the instructions they were given, including details about time and the working memory or dual task requirements. The results showed activations in right dorsolateral prefrontal and right intraparietal cortical networks, together with the anterior cingulate cortex (ACC), anterior insula and basal ganglia (BG) during time perception. On the other hand, working memory engaged the left prefrontal cortex, ACC, left superior parietal cortex, BG and cerebellum activity. Both time perception and working memory were related to a strong peristriate cortical activity. On the other hand, the interaction of time and memory showed activity in the intraparietal sulcus (IPS) and posterior cingulate cortex (PCC). These results support a distributed neural network based model for time perception and that the intraparietal and posterior cingulate areas might play a role in the interface of memory and timing.

Reduction of manganese intake improves neuropsychological manifestations in rats with minimal hepatic encephalopathy

Brain manganese deposition is led by liver dysfunction and/or portal-systemic shunting in minimal hepatic encephalopathy (MHE). Manganese is toxic and can cause cognitive disorders and extrapyramidal symptoms. Thus, reduction of manganese intake might be considered as a potential treatment strategy for MHE. In this study we aimed to investigate whether low- or no-manganese feed can improve the neuropsychological manifestations in MHE rats. Rats with MHE were established by partially ligating the portal vein and fed a manganese diet (MHE-M, 10mg per kg feed; n=24), a no-manganese diet (MHE-N; n=24) and a half-manganese diet (MHE-H; n=24) for 2, 4, 6 and 8weeks, with six rats in each subgroup. Morris water maze (MWM), open-field test and narrow beam test (NBT) were used to evaluate the cognitive and locomotor situations. Fasted blood ammonia, manganese content and glutamine synthetase (GS) activity in basal ganglia and cortex were measured. A significantly longer MWM escape latency, less locomotor activity, longer NBT latency and total time, higher blood ammonia, higher brain manganese content and GS activity were found in MHE-M rats. However, a significantly shorter MWM escape latency, increased locomotor activity, shorter NBT latency and total time, lower blood ammonia, lower brain manganese content and lower GS activity were found in MHE-N rats after no-manganese feed treatment. Partial improvements were found in MHE rats with half-manganese feed treatment. Reduction of manganese intake can significantly improve the cognitive and locomotor situations in MHE rats by reducing brain manganese content and regulating GS activity.

How people with multiple sclerosis cope with a sustained finger motor task: A behavioural and fMRI study

Motor and non-motor basal ganglia (BG) circuits can help healthy subjects cope with task-induced central fatigue and re-establish motor performance after deterioration.This work aimed to assess whether patients with multiple sclerosis (MS) were able to recover motor performance after deterioration due to a demanding task and whether BG activity played a role in performance recovery in this population.Fourteen patients with MS performed a finger-tapping sequence with their right hand during three fMRI sessions: at baseline, after a demanding finger motor task (5-min sequence repetition) and after a short rest period.We observed deterioration of spatial and temporal accuracy with task repetition, as expected; after rest, temporal but not spatial accuracy recovered. Further, higher subjective fatigue was associated with increased motor performance deterioration and reduced temporal accuracy recovery.The amplitude of the BOLD signal change in the left caudate, putamen, globus pallidus, thalamus and amygdala was high at baseline and significantly reduced after the demanding task. Following rest, activity achieved values similar to the baseline in all these regions except for the amygdala.These findings suggest that patients were in a fatigue-like state since task beginning, as they showed enhanced BOLD signal change in the subcortical structures known to be recruited in healthy subjects only when coping with fatigue to recover motor performance. Abnormalities in motor and non-motor BG functions can contribute to fatigue in MS.

BrainCycles: Experimental Setup for the Combined Measurement of Cortical and Subcortical Activity in Parkinson's Disease Patients during Cycling.

Recently, it has been demonstrated that bicycling ability remains surprisingly preserved in Parkinson's disease (PD) patients who suffer from freezing of gait. Cycling has been also proposed as a therapeutic means of treating PD symptoms, with some preliminary success. The neural mechanisms behind these phenomena are however not yet understood. One of the reasons is that the investigations of neuronal activity during pedaling have been up to now limited to PET and fMRI studies, which restrict the temporal resolution of analysis, and to scalp EEG focused on cortical activation. However, deeper brain structures like the basal ganglia are also associated with control of voluntary motor movements like cycling and are affected by PD. Deep brain stimulation (DBS) electrodes implanted for therapy in PD patients provide rare and unique access to directly record basal ganglia activity with a very high temporal resolution. In this paper we present an experimental setup allowing combined investigation of basal ganglia local field potentials (LFPs) and scalp EEG underlying bicycling in PD patients. The main part of the setup is a bike simulator consisting of a classic Dutch-style bicycle frame mounted on a commercially available ergometer. The pedal resistance is controllable in real-time by custom software and the pedal position is continuously tracked by custom Arduino-based electronics using optical and magnetic sensors. A portable bioamplifier records the pedal position signal, the angle of the knee, and the foot pressure together with EEG, EMG, and basal ganglia LFPs. A handlebar-mounted display provides additional information for patients riding the bike simulator, including the current and target pedaling rate. In order to demonstrate the utility of the setup, example data from pilot recordings are shown. The presented experimental setup provides means to directly record basal ganglia activity not only during cycling but also during other movement tasks in patients who have undergone DBS treatment. Thus, it can facilitate studies comparing bicycling and walking, to elucidate why PD patients often retain the ability to bicycle despite severe freezing of gait. Moreover it can help clarifying the mechanism through which cycling may have therapeutic benefits.

Patients with schizophrenia show aberrant patterns of basal ganglia activation: Evidence from ALE meta-analysis.

The diverse circuits and functional contributions of the basal ganglia, coupled with known differences in dopaminergic function in patients with schizophrenia, suggest they may be an important contributor to the etiology of the hallmark symptoms and cognitive dysfunction experienced by these patients. Using activation-likelihood-estimation meta-analysis of functional imaging research, we investigated differences in activation patterns in the basal ganglia in patients with schizophrenia, relative to healthy controls across task domains. This analysis included 42 functional neuroimaging studies, representing a variety of behavioral domains that have been linked to basal ganglia function in prior work. We provide important new information about the functional activation patterns and functional topography of the basal ganglia for different task domains in healthy controls. Crucially however, we demonstrate that across task domains, patients with schizophrenia show markedly decreased activation in the basal ganglia relative to healthy controls. Our results provide further support for basal ganglia dysfunction in patients with schizophrenia, and the broad dysfunction across task domains may contribute to the symptoms and cognitive deficits associated with schizophrenia.

Impulsivity and aggression mediate regional brain responses in Borderline Personality Disorder: An fMRI study

Fronto-limbic brain networks involved in regulation of impulsivity and aggression are abnormal in Borderline Personality Disorder (BPD). However, it is unclear whether, or to what extent, these personality traits actually modulate brain responses during cognitive processing. Using fMRI, we examined the effects of trait impulsivity, aggression, and depressed mood on regional brain responses in 31 female BPD and 25 control subjects during a Go No-Go task using Ekman faces as targets. First-level contrasts modeled effects of negative emotional context. Second-level regression models used trait impulsivity, aggression and depressed mood as predictor variables of regional brain activations. In BPD, trait impulsivity was positively correlated with activation in the dorsal anterior cingulate cortex, orbital frontal cortex (OFC), basal ganglia (BG), and dorsolateral prefrontal cortex, with no areas of negative correlation. In contrast, aggression was negatively correlated with activation in OFC, hippocampus, and BG, with no areas of positive correlation. Depressed mood had a generally dampening effect on activations. Effects of trait impulsivity on healthy controls differed from effects in BPD, suggesting a disorder-specific response. Negative emotional context and trait impulsivity, but not aggression or depression, diminished task performance across both groups. Negative emotional context may interfere with cognitive functioning in BPD through interaction with the neurobiology of personality traits.

The Effects of Mechanical and Thermal Stimuli on Local Field Potentials and Single Unit Activity in Parkinson’s Disease Patients

Chronic pain is a major, debilitating symptom of Parkinson's disease (PD). Although, deep brain stimulation (DBS) has been shown to improve pain outcomes, the mechanisms underlying this phenomenon are unclear. Microelectrode recording allows us to measure both local field potentials (LFPs) and single neuronal unit activity (SUA). In this study, we examined how single unit and LFP oscillatory activity in the basal ganglia are impacted by mechanical and thermal sensory stimuli and explored their role in pain modulation. We assessed changes in LFPs and SUAs in the subthalamic nucleus (STN), globus pallidus interna (Gpi), and globus pallidus externa (Gpe) following exposure with mechanical or thermal stimuli. Sensory thresholds were determined pre-operatively using quantitative sensory testing. Based on these data, patients were exposed to innocuous and noxious mechanical, pressure, and thermal stimuli at individualized thresholds. In the STN, LFP alpha oscillatory activity and SUA increased in response to innocuous mechanical stimuli; SUA further increased in response to noxious mechanical, noxious pressure, and noxious thermal stimuli (p < 0.05). In the Gpe, LFP low betaactivity and SUA increased with noxious thermal stimuli; SUA also increased in response to innocuous thermal stimuli (p < 0.05). In the Gpi, innocuous thermal stimuli increased LFP gammaactivity; noxious pressure stimuli decreased low betaactivity; SUA increased in response to noxious thermal stimuli (p < 0.05). Our study is the first to demonstrate that mechanical and thermal stimuli alter basal ganglia LFPs and SUAs in PD. While STN SUA increases nearly uniformly to all sensory stimuli, SUA in the pallidal nuclei respond solely to thermal stimuli. Similarly, thermal stimuli yield increases in pallidal LFP activity, but not STN activity. We speculate that DBS may provide analgesia through suppression of stimuli-specific changes in basal ganglia activity, supporting a role for these nuclei in sensory and pain processing circuits.

Altered local spontaneous activity in frontal lobe epilepsy: a resting-state functional magnetic resonance imaging study.

PurposeThe purpose of this study was to investigate the local spatiotemporal consistency of spontaneous brain activity in patients with frontal lobe epilepsy (FLE).MethodEyes closed resting‐state functional magnetic resonance imaging (fMRI) data were collected from 19 FLE patients and 19 age‐ and gender‐matched healthy controls. A novel measure, named FOur‐dimensional (spatiotemporal) Consistency of local neural Activities (FOCA) was used to assess the spatiotemporal consistency of local spontaneous activity (emphasizing both local temporal homogeneity and regional stability of brain activity states). Then, two‐sample t test was performed to detect the FOCA differences between two groups. Partial correlations between the FOCA values and durations of epilepsy were further analyzed.Key FindingsCompared with controls, FLE patients demonstrated increased FOCA in distant brain regions including the frontal and parietal cortices, as well as the basal ganglia. The decreased FOCA was located in the temporal cortex, posterior default model regions, and cerebellum. In addition, the FOCA measure was linked to the duration of epilepsy in basal ganglia.SignificanceOur study suggested that alterations of local spontaneous activity in frontoparietal cortex and basal ganglia was associated with the pathophysiology of FLE; and the abnormality in frontal and default model regions might account for the potential cognitive impairment in FLE. We also presumed that the FOCA measure had potential to provide important insights into understanding epilepsy such as FLE.

Basal ganglia impairments in autism spectrum disorder are related to abnormal signal gating to prefrontal cortex

Research on the biological basis of autism spectrum disorder has yielded a list of brain abnormalities that are arguably as diverse as the set of behavioral symptoms that characterize the disorder. Among these are patterns of abnormal cortical connectivity and abnormal basal ganglia development. In attempts to integrate the existing literature, the current paper tests the hypothesis that impairments in the basal ganglia's function to flexibly select and route task-relevant neural signals to the prefrontal cortex underpins patterns of abnormal synchronization between the prefrontal cortex and other cortical processing centers observed in individuals with autism spectrum disorder (ASD). We tested this hypothesis using a Dynamic Causal Modeling analysis of neuroimaging data collected from 16 individuals with ASD (mean age=25.3 years; 6 female) and 17 age- and IQ-matched neurotypical controls (mean age=25.6, 6 female), who performed a Go/No-Go test of executive functioning. Consistent with the hypothesis tested, a random-effects Bayesian model selection procedure determined that a model of network connectivity in which basal ganglia activation modulated connectivity between the prefrontal cortex and other key cortical processing centers best fit the data of both neurotypicals and individuals with ASD. Follow-up analyses suggested that the largest group differences were observed for modulation of connectivity between prefrontal cortex and the sensory input region in the occipital lobe [t(31)=2.03, p=0.025]. Specifically, basal ganglia activation was associated with a small decrease in synchronization between the occipital region and prefrontal cortical regions in controls; however, in individuals with ASD, basal ganglia activation resulted in increased synchronization between the occipital region and the prefrontal cortex. We propose that this increased synchronization may reflect a failure in basal ganglia signal gating mechanisms, resulting in a non-selective copying of signals to prefrontal cortex. Such a failure to prioritize and filter signals to the prefrontal cortex could result in the pervasive impairments in cognitive flexibility and executive functioning that characterize autism spectrum disorder, and may offer a mechanistic explanation of some of the observed abnormalities in patterns of cortical synchronization in ASD.

EP 103. Gait specific modulation of local field potentials in the STN of patients with Parkinson’s disease

PD patients with implanted DBS electrodes allow for the investigation of basal ganglia activity during gait. Whereas the overall spectral content of local field potentials (LFP) in the BG is known to change with movement, it is still unclear how exactly the BG-LFP change during gait. We investigated the electric local field potentials of the STN of 10 patients with PD during gait. Gait parameters were recorded with inertial sensor units and the gait was subsequently analyzed in parallel to the electrophysiological activity in Matlab. Additionally, we recorded LFPs during rest and control experiments to probe for movement related artifacts. Stimulation was off in all experiments reported here. On a group level, a frequency analysis shows that the high beta frequency band gets significantly downregulated during gait as compared to sitting rest. On an individual level, a linear classifier trained with frequency profiles of small epochs of LFP activity recorded during gait and rest can distinguish between walking and resting episodes with a mean classification accuracy across all patients of 90%. A time–frequency analysis on the group level reveals a distinct modulation pattern. Whereas low frequencies in the theta and alpha range and high frequencies in the gamma range are modulated up and down time-locked to the gait cycle, the beta band gets modulated down during the complete gait cycle.

EP 132. Motivational characteristics of expert performance

Objective Expert performance is characterized by the consistent performance at a superior level in a cognitive, artistic, motor or other domain ( Ericsson and Lehmann, 1996 ). The objective of the current study was to highlight motivational factors that enable the persistent training that is a necessary precondition for expert performance in any domain. Therefore we compared fMRI-activation in experts with those of naive participants during task performance in the field of expertise (finger sequence encoding for pianists, creative writing for writers and portrait drawing for students of fine arts). We hypothesized expert-specific activation of motivational structures in these tasks. Methods We reanalysed fMRI data collected in studies with expert groups of music, creative writing, and drawing ( Erhard et al., 2014 , Pau et al., 2013 ; Neumann et al, in preparation ). Data were acquired using a 3.0 Tesla Siemens MAGNETOM Verio MRI scanner (Erlangen, Germany) with a 32-channel head coil. Echo-Planar-Imaging (EPI) with a repetition time (TR) of 2000 ms for the whole brain volume was measured together with a T1-weighted high-resolution anatomical image. Region of interest analyses comprised the ventral and dorsal striatum, amygdalae and hippocampi, ventromedial and ventrolateral prefrontal cortices, anterior insulae, ventral tegmentum and periaqueductal grey. Results are reported as FWE-corrected values with p Results All texts and portraits produced by the experts were superior as rated by specialists (t > 3.3; p Conclusion Basal ganglia activation of the dominant hemisphere is a common characteristic of the three expert groups investigated across different functional imaging designs. However, the exact localization of increased basal ganglia recruitment differed largely in the three expert groups in comparison to control participants. Whereas drawing experts showed increased activation in the ventral pallidum receiving dopaminergic inputs from the ventral tegmental area, pianists activated motor training associated parts of the putamen, and in expert writers more cognitive aspects seemed to be recruited ( Alexander et al., 1986 ).

EP 141. Physiological effects of subthreshold conditioning TMS anterior of the primary motor cortex

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely used to treat patients suffering from Parkinson’s Disease. Previous studies suggested that DBS effects may be transmitted via cortico-subthalamic projections opening up possibilities to modulate basal ganglia activity using TMS over cortical areas. Also there is evidence suggesting that multifocal DBS of the STN may be more efficient, implying the use of TMS protocols which target more than one cortical motor area. Although TMS over the primary motor cortex (M1) is well characterized, published TMS effects and locations vary for the dorsal premotor cortex (PMd). Our aim was to locate the PMd and investigate effects of dual-site conditioning TMS applied over PMd and M1 for various interstimulus intervals (ISIs). We hypothesized that there may be short latency effects of PMd conditioning (around 6 ms) originating from direct cortico-cortical projections and longer latency effects possibly resulting from subcortical processing. In a first experiment we located the PMd by probing multiple short latency cortico-cortical interactions between cortical areas anterior of M1 and M1 in a paired-pulse TMS experiment. Motor-evoked potentials were recorded from the APB muscle of the right hand. The coils used allowed for stimulation of the same or very near cortical areas. We applied conditioning stimuli at 80% RMT over 8 sites 0–52 mm anterior of M1. These were followed by test pulses applied at 120% RMT over M1 after ISIs of 2–8 ms and changes in M1 excitability was examined to determine a possible PMd location. In a second experiment we tested whether longer latency effects could be observed by applying conditioning stimuli over the estimated PMd location determined in experiment 1 using ISIs between 14 and 38 ms. 18 healthy participants (age 25.3 ± 4.1 y) took part in the first experiment. We found a significant facilitation for conditioning at 36 mm anterior of M1 with an ISI of 6 ms (p = 0.037) Using interpolation we found a cluster of significant data between 30 and 36 mm. 12 subjects participated in the second experiment (age 24.8 ± 3.9 y). Conditioning pulses were applied 32 mm anterior of M1. There was a significant facilitation at an ISIs of 26 ms with 95% RMT (p = 0.005). We found known effects conditioning at 0 mm (over M1) for ISIs of 2, 4 ms (p < 0.001, SICI), 8 ms (p = 0.014, ICF) and 14 to 26 ms (ICF, SICF). We were able to locate a possible effect of PMd conditioning at 30 to 36 mm anterior of M1 consistent with previous studies. Furthermore we were able to show MEP modulation after subthreshold paired-pulse stimulation over this PMd location and M1 for an ISI of 26 ms. Facilitation at this latency may result from modulation of cortico-basal-ganglia-loops consistent with previous findings probing these loops using a combination of TMS and DBS. We plan to use the new stimulation site in a further study to investigate possible therapeutic effects in PD. Supported by Hertie-Stiftung, Cortexplorer (AZ.: P1140048).

Motor sequence learning in the elderly: differential activity patterns as a function of hand modality

Previous research on motor sequence learning (MSL) in the elderly has focused mainly on unilateral tasks, even though bilateral coordination might be impaired in this age group. In this fMRI study, 28 right-handed elderly subjects were recruited. The paradigm consisted of a Novel and a simple Control sequence executed with the right (R), left (L) and both hands (B). Behavioral performance (Accuracy[AC], Inter-tap Interval[ITI]) and associated brain activity were assessed during early learning. Behavioral performance in the Novel task was similar between unilateral conditions whereas in the bimanual condition more errors and slower motor execution were observed. Brain activity increases during learning showed differences between Conditions: R showed increased activity in pre-SMA, basal ganglia and left hippocampus while B showed activity increments mainly in posterior parietal cortex and cerebellum. L did not show any activity modulation during learning. Performance correlates for AC (related to spatial success) and ITI (related to accurate timing) shared a cortico-basal-cerebellar network. However, it was found that the ITI regressor presented additional significant correlations with activity in SMA and basal ganglia in R. The AC regressor showed additional significant correlations with activity in more extended thalamic and cerebellar areas in B. The present findings suggest that, behaviorally, the spatial and temporal components of MSL are impaired in elderly subjects when using both hands. Additionally, differential brain activity patterns were found across hand modalities. The results obtained reveal the existence of a highly specialized network in the dominant hand and identify areas specifically involved in bimanual coordination.

Functional role of striatal A2A, D2, and mGlu5 receptor interactions in regulating striatopallidal GABA neuronal transmission

In this study, the functional role of individual striatal receptors for adenosine (A2AR), dopamine (D2R), and the metabotropic glutamate receptor mGlu5R in regulating rat basal ganglia activity was characterized invivo using dual-probe microdialysis in freely moving rats. In particular, intrastriatal perfusion with the D2R agonist quinpirole (10μM, 60min) decreased ipsilateral pallidal GABA and glutamate levels, whereas intrastriatal CGS21680 (A2AR agonist; 1μM, 60min) was ineffective on either pallidal GABA and glutamate levels or the quinpirole-induced effects. Intrastriatal perfusion with the mGlu5R agonist (RS)-2-chloro-5-hydroxyphenylglycine (600μM, 60min), by itself ineffective on pallidal GABA and glutamate levels, partially counteracted the effects of quinpirole. When combined with CGS21680 (1μM, 60min), (RS)-2-chloro-5-hydroxyphenylglycine (CHPG; 600μM, 60min) fully counteracted the quinpirole (10μM, 60min)-induced reduction in ipsilateral pallidal GABA and glutamate levels. These effects were fully counteracted by local perfusion with the mGlu5R antagonist MPEP (300μM) or the A2AR antagonist ZM 241385 (100 nM). These results suggest that A2ARs and mGlu5Rs interact synergistically in modulating the D2R-mediated control of striatopallidal GABA neurons. Using dual-probe microdialysis, we characterized the functional role of striatal adenosine A2A receptor (A2AR), dopamine D2 receptor (D2R), and metabotropic glutamate receptor 5 (mGluR5) interactions in regulating rat basal ganglia activity. The results suggest the possible usefulness of using an A2AR antagonist and mGluR5 antagonist combination in the treatment of Parkinson's disease to increase the inhibitory D2 signaling on striatopallidal GABA neurons.

Neural substrates and behavioral profiles of romantic jealousy and its temporal dynamics.

Jealousy is not only a way of experiencing love but also a stabilizer of romantic relationships, although morbid romantic jealousy is maladaptive. Being engaged in a formal romantic relationship can tune one’s romantic jealousy towards a specific target. Little is known about how the human brain processes romantic jealousy by now. Here, by combining scenario-based imagination and functional MRI, we investigated the behavioral and neural correlates of romantic jealousy and their development across stages (before vs. after being in a formal relationship). Romantic jealousy scenarios elicited activations primarily in the basal ganglia (BG) across stages, and were significantly higher after the relationship was established in both the behavioral rating and BG activation. The intensity of romantic jealousy was related to the intensity of romantic happiness, which mainly correlated with ventral medial prefrontal cortex activation. The increase in jealousy across stages was associated with the tendency for interpersonal aggression. These results bridge the gap between the theoretical conceptualization of romantic jealousy and its neural correlates and shed light on the dynamic changes in jealousy.

Pallidostriatal Projections Promote β Oscillations in a Dopamine-Depleted Biophysical Network Model.

In the basal ganglia, focused rhythmicity is an important feature of network activity at certain stages of motor processing. In disease, however, the basal ganglia develop amplified rhythmicity. Here, we demonstrate how the cellular architecture and network dynamics of an inhibitory loop in the basal ganglia yield exaggerated synchrony and locking to β oscillations, specifically in the dopamine-depleted state. A key component of this loop is the pallidostriatal pathway, a well-characterized anatomical projection whose function has long remained obscure. We present a synaptic characterization of this pathway in mice and incorporate these data into a computational model that we use to investigate its influence over striatal activity under simulated healthy and dopamine-depleted conditions. Our model predicts that the pallidostriatal pathway influences striatal output preferentially during periods of synchronized activity within GPe. We show that, under dopamine-depleted conditions, this effect becomes a key component of a positive feedback loop between the GPe and striatum that promotes synchronization and rhythmicity. Our results generate novel predictions about the role of the pallidostriatal pathway in shaping basal ganglia activity in health and disease. This work demonstrates that functional connections from the globus pallidus externa (GPe) to striatum are substantially stronger onto fast-spiking interneurons (FSIs) than onto medium spiny neurons. Our circuit model suggests that when GPe spikes are synchronous, this pallidostriatal pathway causes synchronous FSI activity pauses, which allow a transient window of disinhibition for medium spiny neurons. In simulated dopamine-depletion, this GPe-FSI activity is necessary for the emergence of strong synchronization and the amplification and propagation of β oscillations, which are a hallmark of parkinsonian circuit dysfunction. These results suggest that GPe may play a central role in propagating abnormal circuit activity to striatum, which in turn projects to downstream basal ganglia structures. These findings warrant further exploration of GPe as a target for interventions for Parkinson's disease.

PreSMA stimulation changes task-free functional connectivity in the fronto-basal-ganglia that correlates with response inhibition efficiency.

Previous work using transcranial magnetic stimulation (TMS) demonstrated that the right presupplementary motor area (preSMA), a node in the fronto-basal-ganglia network, is critical for response inhibition. However, TMS influences interconnected regions, raising the possibility of a link between the preSMA activity and the functional connectivity within the network. To understand this relationship, we applied single-pulse TMS to the right preSMA during functional magnetic resonance imaging when the subjects were at rest to examine changes in neural activity and functional connectivity within the network in relation to the efficiency of response inhibition evaluated with a stop-signal task. The results showed that preSMA-TMS increased activation in the right inferior-frontal cortex (rIFC) and basal ganglia and modulated their task-free functional connectivity. Both the TMS-induced changes in the basal-ganglia activation and the functional connectivity between rIFC and left striatum, and of the overall network correlated with the efficiency of response inhibition and with the white-matter microstructure along the preSMA-rIFC pathway. These results suggest that the task-free functional and structural connectivity between the rIFCop and basal ganglia are critical to the efficiency of response inhibition. Hum Brain Mapp 37:3236-3249, 2016. © 2016 Wiley Periodicals, Inc.

Targeted brain activation using an MR-compatible wrist torque measurement device and isometric motor tasks during functional magnetic resonance imaging

Dedicated pairs of isometric wrist flexion tasks, with and without visual feedback of the exerted torque, were designed to target activation of the CBL and BG in healthy subjects during functional magnetic resonance imaging (fMRI). Selective activation of the cerebellum (CBL) and basal ganglia (BG), often implicated in movement disorders such as tremor and dystonia, may help identify pathological changes and expedite diagnosis. A prototyped MR-compatible wrist torque measurement device, free of magnetic and conductive materials, allowed safe execution of tasks during fMRI without causing artifacts. A significant increase of activity in CBL and BG was found in healthy volunteers during a constant torque task with visual feedback compared to a constant torque task without visual feedback. This study shows that specific pairs of motor tasks using MR-compatible equipment at the wrist allow for targeted activation of CBL and BG, paving a new way for research into the pathophysiology of movement disorders.

Closed-Loop Modulation of the Pathological Disorders of the Basal Ganglia Network.

A generalized predictive closed-loop control strategy to improve the basal ganglia activity patterns in Parkinson's disease (PD) is explored in this paper. Based on system identification, an input-output model is established to reveal the relationship between external stimulation and neuronal responses. The model contributes to the implementation of the generalized predictive control (GPC) algorithm that generates the optimal stimulation waveform to modulate the activities of neuronal nuclei. By analyzing the roles of two critical control parameters within the GPC law, optimal closed-loop control that has the capability of restoring the normal relay reliability of the thalamus with the least stimulation energy expenditure can be achieved. In comparison with open-loop deep brain stimulation and traditional static control schemes, the generalized predictive closed-loop control strategy can optimize the stimulation waveform without requiring any particular knowledge of the physiological properties of the system. This type of closed-loop control strategy generates an adaptive stimulation waveform with low energy expenditure with the potential to improve the treatments for PD.

How does environmental enrichment reduce repetitive motor behaviors? Neuronal activation and dendritic morphology in the indirect basal ganglia pathway of a mouse model

Repetitive motor behaviors are observed in many neurodevelopmental and neurological disorders (e.g., autism spectrum disorders, Tourette syndrome, fronto-temporal dementia). Despite their clinical importance, the neurobiology underlying these highly stereotyped, apparently functionless behaviors is poorly understood. Identification of mechanisms that mediate the development of repetitive behaviors will aid in the discovery of new therapeutic targets and treatment development. Using a deer mouse model, we have shown that decreased indirect basal ganglia pathway activity is associated with high levels of repetitive behavior. Environmental enrichment (EE) markedly attenuates the development of such aberrant behaviors in mice, although mechanisms driving this effect are unknown. We hypothesized that EE would reduce repetitive motor behaviors by increasing indirect basal ganglia pathway function. We assessed neuronal activation and dendritic spine density in basal ganglia of adult deer mice reared in EE and standard housing. Significant increases in neuronal activation and dendritic spine densities were observed only in the subthalamic nucleus (STN) and globus pallidus (GP), and only for those mice that exhibited an EE-induced decrease in repetitive motor behavior. As the STN and GP lie within the indirect pathway, these data suggest that EE-induced attenuation of repetitive motor behaviors is associated with increased functional activation of the indirect basal ganglia pathway. These results are consistent with our other findings highlighting the importance of the indirect pathway in mediating repetitive motor behaviors.