Basal Ganglia Targets Research Articles

Generalized sleep decoding with basal ganglia signals in multiple movement disorders

Sleep disturbances profoundly affect the quality of life in individuals with neurological disorders. Closed-loop deep brain stimulation (DBS) holds promise for alleviating sleep symptoms, however, this technique necessitates automated sleep stage decoding from intracranial signals. We leveraged overnight data from 121 patients with movement disorders (Parkinson’s disease, Essential Tremor, Dystonia, Essential Tremor, Huntington’s disease, and Tourette’s syndrome) in whom synchronized polysomnograms and basal ganglia local field potentials were recorded, to develop a generalized, multi-class, sleep specific decoder – BGOOSE. This generalized model achieved 85% average accuracy across patients and across disease conditions, even in the presence of recordings from different basal ganglia targets. Furthermore, we also investigated the role of electrocorticography on decoding performances and proposed an optimal decoding map, which was shown to facilitate channel selection for optimal model performances. BGOOSE emerges as a powerful tool for generalized sleep decoding, offering exciting potentials for the precision stimulation delivery of DBS and better management of sleep disturbances in movement disorders.

Protocol for combined N-of-1 trials to assess cerebellar neurostimulation for movement disorders in children and young adults with dyskinetic cerebral palsy.

Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has a major role in the treatment of isolated dystonias, but its efficacy in dyskinetic cerebral palsy (DCP) is lower, due to structural basal ganglia and thalamic damage and lack of improvement of comorbid choreoathetosis and spasticity. The cerebellum is an attractive target for DBS in DCP since it is frequently spared from hypoxic ischemic damage, it has a significant role in dystonia network models, and small studies have shown promise of dentate stimulation in improving CP-related movement and tone disorders. Ten children and young adults with DCP and disabling movement disorders with or without spasticity will undergo bilateral DBS in the dorsal dentate nucleus, with the most distal contact ending in the superior cerebellar peduncle. We will implant Medtronic Percept, a bidirectional neurostimulator that can sense and store brain activity and deliver DBS therapy. The efficacy of cerebellar DBS in improving quality of life and motor outcomes will be tested by a series of N-of-1 clinical trials. Each N-of-1 trial will consist of three blocks, each consisting of one month of effective stimulation and one month of sham stimulation in a random order with weekly motor and quality of life scales as primary and secondary outcomes. In addition, we will characterize abnormal patterns of cerebellar oscillatory activity measured by local field potentials from the intracranial electrodes related to clinical assessments and wearable monitors. Pre- and 12-month postoperative volumetric structural and functional MRI and diffusion tensor imaging will be used to identify candidate imaging markers of baseline disease severity and response to DBS. Our goal is to test a cerebellar neuromodulation therapy that produces meaningful changes in function and well-being for people with CP, obtain a mechanistic understanding of the underlying brain network disorder, and identify physiological and imaging-based predictors of outcomes useful in planning further studies. ClinicalTrials.gov NCT06122675, first registered November 7, 2023.

Publication Rates and Characteristics of Clinical Trials in Deep Brain and Responsive Neurostimulation

Introduction: Prompt dissemination of clinical trial results is essential for ensuring the safety and efficacy of intracranial neurostimulation treatments, including deep brain stimulation (DBS) and responsive neurostimulation (RNS). However, the frequency and completeness of results publication, and reasons for reporting delays, are unknown. Moreover, the patient populations, targeted anatomical locations, and stimulation parameters should be clearly reported for both reproducibility and to identify lacunae in trial design. Here, we examine DBS and RNS trials from 1997 to 2022, chart their characteristics, and examine rates and predictors of results reporting. Methods: Trials were identified using <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>. Associated publications were identified using <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://PubMed.gov" xmlns:xlink="http://www.w3.org/1999/xlink">PubMed.gov</ext-link>. Pearson’s χ² tests were used to assess differences in trial characteristics between published and unpublished trials. Results: Across 449 trials, representing a cumulative cohort of 42,769 patient interventions, there were 37 therapeutic indications and 44 stimulation targets. The most common indication and target were Parkinson’s disease (40.55%) and the subthalamic nucleus (35.88%), respectively. Only 0.89% of trials were in pediatric patients (11.58% were mixed pediatric and adult). Explored targets represented 75% of potential basal ganglia targets but only 29% of potential thalamic targets. Allowing a 1-year grace period after trial completion, 34/169 (20.12%) had results reported on <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>, and 107/169 (63.31%) were published. ∼80% of published trials included details about stimulation parameters used. Published and unpublished trials did not significantly differ by trial characteristics. Conclusion: We highlight key knowledge and performance gaps in DBS and RNS trial research. Over one-third of trials remain unpublished >1 year after completion; pediatric trials are scarce; most of the thalamus remains unexplored; about one-in-five trials fail to report stimulation parameters; and movement disorders comprise the most studied indications.

Successful Treatment with High-Dose Immunoglobulin of a Complicated Patient with Catatonia and Central Nervous System Autoantibodies

Ms. X is a 52-year-old Filipino female with no prior psychiatric or medical history who initially presented to an outside hospital for new onset headache, neck pain, and altered mental status. She was admitted inpatient medicine service and was found to have HIV/AIDs and cryptococcal meningoencephalitis. Ms. X had a good response to appropriate antifungal therapies and was able to discharge home with full resolution of symptoms on high dose fluconozaole. Unfortunately, Ms. X developed transaminitis on high dose fluconazole, the dose was reduced and she presented to our institution with recurrent cryptococcal meningoencephalitis as evidenced by elevated titers of cryptococcal antigen in CSF and MRI studies showing T2 and FLAIR hyperintensities in bilateral basal ganglia, thalamus and medial temporal lobes and evidence of intracranial hypertension. Consequently, Ms. X developed prominent neuropsychiatric symptoms including agitation, cognitive impairment, paranoia, visual hallucinations and symptoms of catatonia. Despite adequate treatment of the cryptococcal infection evidenced by decreasing cryptococcal antigen titers in CSF, and appropriate psychiatric treatment, her neuropsychiatric symptoms persisted and her MRI studies continued to show signs of neuroinflammation in the aforementioned areas. Antibody testing for basal ganglia targets was completed to investigate a possible non-infectious cause of neuroinflammation and neuropsychiatric symptoms. Ms. X was found to have elevated titers of anti-D1, anti-GM1 and anti-tubulin receptor antibodies in her CSF. Due to the severity and treatment resistant nature of her neuropsychiatric symptoms, she was treated with 2 g/kg/day IVIG for 4 days. She showed significant improvement in her neuropsychiatric symptoms after 3 days and full resolution of her neuropsychiatric symptoms 1 week following IVIG. Given remarkable clinical response to IVIG a second round of IVIG was administered 2 weeks later in order to sustain the response. After several months of prolonged hospitalization, Ms X was able to discharge to the care of her family and to date her neuropsychiatric symptoms remain in remission. We propose Ms. X’s persistent, treatment resistant neuropsychiatric symptoms were related to a post-infectious inflammatory encephalopathy that responded robustly to IVIG.

Pediatric Deep Brain Stimulation Using Awake Recording and Stimulation for Target Selection in an Inpatient Neuromodulation Monitoring Unit.

Deep brain stimulation (DBS) for secondary (acquired, combined) dystonia does not reach the high degree of efficacy achieved in primary (genetic, isolated) dystonia. We hypothesize that this may be due to variability in the underlying injury, so that different children may require placement of electrodes in different regions of basal ganglia and thalamus. We describe a new targeting procedure in which temporary depth electrodes are placed at multiple possible targets in basal ganglia and thalamus, and probing for efficacy is performed using test stimulation and recording while children remain for one week in an inpatient Neuromodulation Monitoring Unit (NMU). Nine Children with severe secondary dystonia underwent the NMU targeting procedure. In all cases, 4 electrodes were implanted. We compared the results to 6 children who had previously had 4 electrodes implanted using standard intraoperative microelectrode targeting techniques. Results showed a significant benefit, with 80% of children with NMU targeting achieving greater than 5-point improvement on the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS), compared with 50% of children using intraoperative targeting. NMU targeting improved BFMDRS by an average of 17.1 whereas intraoperative targeting improved by an average of 10.3. These preliminary results support the use of test stimulation and recording in a Neuromodulation Monitoring Unit (NMU) as a new technique with the potential to improve outcomes following DBS in children with secondary (acquired) dystonia. A larger sample size will be needed to confirm these results.

Decoding Movement States in Stepping Cycles Based on Subthalamic LFPs in Parkinsonian Patients.

Gait disturbances are a prominent feature of Parkinson's disease (PD), often refractory to medication or continuous deep brain stimulation (DBS) on basal ganglia targets such as the subthalamic nucleus (STN). Here we sought to identify movement states during stepping cycles, such as left leg stance and right leg stance. To this end we analyzed local field potential (LFP) activity in STN using a combination of the multivariate autoregressive (MAR) model and the Hidden Markov model (HMM). Our results confirm that information is present in the STN related to movement states in stepping cycles, and that it is feasible to decode movement states based on STN LFPs recorded from DBS electrodes. This information can be used to implement temporally flexible stimulation strategies in order to facilitate patterns of neural modulation associated with better gait performance.

Dysregulation of Corticostriatal Connectivity in Huntington's Disease: ARole for Dopamine Modulation.

Aberrant communication between striatum, the main information processing unit of the basal ganglia, and cerebral cortex plays a critical role in the emergence of Huntington’s disease (HD), a fatal monogenetic condition that typically strikes in the prime of life. Although both striatum and cortex undergo substantial cell loss over the course of HD, corticostriatal circuits become dysfunctional long before neurons die. Understanding the dysfunction is key to developing effective strategies for treating a progressively worsening triad of motor, cognitive, and psychiatric symptoms. Cortical output neurons drive striatal activity through the release of glutamate, an excitatory amino acid. Striatal outputs, in turn, release γ-amino butyric acid (GABA) and exert inhibitory control over downstream basal ganglia targets. Ample evidence from transgenic rodent models points to dysregulation of corticostriatal glutamate transmission along with corresponding changes in striatal GABA release as underlying factors in the HD behavioral phenotype. Another contributor is dysregulation of dopamine (DA), a modulator of both glutamate and GABA transmission. In fact, pharmacological manipulation of DA is the only currently available treatment for HD symptoms. Here, we review data from animal models and human patients to evaluate the role of DA in HD, including DA interactions with glutamate and GABA within the context of dysfunctional corticostriatal circuitry.

Distinct Developmental Origins Manifest in the Specialized Encoding of Movement by Adult Neurons of the External Globus Pallidus

SummaryTranscriptional codes initiated during brain development are ultimately realized in adulthood as distinct cell types performing specialized roles in behavior. Focusing on the mouse external globus pallidus (GPe), we demonstrate that the potential contributions of two GABAergic GPe cell types to voluntary action are fated from early life to be distinct. Prototypic GPe neurons derive from the medial ganglionic eminence of the embryonic subpallium and express the transcription factor Nkx2-1. These neurons fire at high rates during alert rest, and encode movements through heterogeneous firing rate changes, with many neurons decreasing their activity. In contrast, arkypallidal GPe neurons originate from lateral/caudal ganglionic eminences, express the transcription factor FoxP2, fire at low rates during rest, and encode movements with robust increases in firing. We conclude that developmental diversity positions prototypic and arkypallidal neurons to fulfil distinct roles in behavior via their disparate regulation of GABA release onto different basal ganglia targets.

In vivo measurement of the frame-based application accuracy of the Neuromate neurosurgical robot.

The application accuracy of the Neuromate neurosurgical robot has been validated in vitro but has not been evaluated in vivo for deep brain stimulation (DBS) electrode implantations. The authors conducted a study to evaluate this application accuracy in routine frame-based DBS procedures, with an independent system of measurement. The Euclidian distance was measured between the point theoretically targeted by the robot and the point actually reached, based on their respective stereotactic coordinates. The coordinates of the theoretical target were given by the robot's dedicated targeting software. The coordinates of the point actually reached were recalculated using the Stereoplan localizer system. This experiment was performed in vitro, with the frame fixed in the robot space without a patient, for 21 points spatially distributed. The in vivo accuracy was then measured in 30 basal ganglia targets in 17 consecutive patients undergoing DBS for movement disorders. The mean in vitro application accuracy was 0.44 ± 0.23 mm. The maximal localization error was 1.0 mm. The mean (± SD) in vivo application accuracy was 0.86 ± 0.32 mm (Δx = 0.37 ± 0.34 mm, Δy = 0.32 ± 0.24 mm, Δz = 0.58 ± 0.31 mm). The maximal error was 1.55 mm. The in vivo application accuracy of the Neuromate neurosurgical robot, measured with a system independent from the robot, in frame-based DBS procedures was better than 1 mm. This accuracy is at least similar to the accuracy of stereotactic frame arms and is compatible with the accuracy required in DBS procedures.

O29: Beyond skeletomotor function of human basal ganglia: oculomotor, visual and affective neurons

Deep brain stimulation (DBS) of targets in basal ganglia is an effective treatment of motor dysfunction in Parkinson’s disease and primary dystonia. However this treatment may be accompanied by unwanted non-motor side effects. To confirm their neurophysiological nature we searched for any neurons in the subthalamic nucleus (STN), substantia nigra pars reticulata (SNr) and globus pallidus (GP) involved in processing of visually presented emotional scenes. Nineteen Parkinson’s disease patients, which underwent implantation of DBS electrodes to STN or GP, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography during a visual emotional task containing a series of photographs varying in emotional valence and arousal. Recordings were analyzed by the WaveClus program which allowed for detection and sorting of individual neurons. Out of 183 neurons that were detected, 130 were found in the STN, 30 in the SNr and 23 in the GP. Twenty percent of the neurons in each of these structures showed eye movement-related activity. In the STN, we observed 35 neurons whose firing rate changed significantly within first 500 ms after presentation of a photograph suggesting their participation in visual or attentional mechanisms. Activity of 14 STN neurons showed significant changes during 500–1500 ms interval in alpha band of the instantaneous firing rate related to the emotional content of presented photographs. Activity of 8 of neurons was related to the arousal while activity of another 6 neurons was changing in relation to the emotional valence. Our results showed that basal ganglia contain relatively high share of oculomotor neurons suggesting their critical role in eye-movement control. In addition, the STN neurons involved in visual processing and in transmission of emotional information provide evidence of separate management of the affective dimensions of valence and arousal. Therefore, it is not surprising that DBS may have various non-motor consequences. Supported by grants: IGA MZ CR NT12282–5/2011; research projects: MSM 0021620849, MSM 6840770012 and PRVOUK-P26/LF1/4.

18. Beyond skeletomotor function of human basal ganglia: Oculomotor, visual and affective neurons

Deep brain stimulation (DBS) of targets in basal ganglia is an effective treatment of motor dysfunction in Parkinson’s disease and primary dystonia. However this treatment may be accompanied by unwanted non-motor side effects. To confirm their neurophysiological nature we searched for any neurons in the subthalamic nucleus (STN), substantia nigra pars reticulata (SNr) and globus pallidus (GP) involved in processing of visually presented emotional scenes. Nineteen Parkinson’s disease patients, which underwent implantation of DBS electrodes to STN or GP, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography during a visual emotional task containing a series of photographs varying in emotional valence and arousal. Recordings were analyzed by the WaveClus program which allowed for detection and sorting of individual neurons. Out of 183 neurons that were detected, 130 were found in the STN, 30 in the SNr and 23 in the GP. Twenty percent of the neurons in each of these structures showed eye movement-related activity. In the STN, we observed 35 neurons whose firing rate changed significantly within first 500 ms after presentation of a photograph suggesting their participation in visual or attentional mechanisms. Activity of 14 STN neurons showed significant changes during 500–1500 ms interval in alpha band of the instantaneous firing rate related to the emotional content of presented photographs. Activity of 8 of neurons was related to the arousal while activity of another 6 neurons was changing in relation to the emotional valence. Our results showed that basal ganglia contain relatively high share of oculomotor neurons suggesting their critical role in eye-movement control. In addition, the STN neurons involved in visual processing and in transmission of emotional information provide evidence of separate management of the affective dimensions of valence and arousal. Therefore, it is not surprising that DBS may have various non-motor consequences. Supported by grants: IGA MZ ČR NT12282–5/2011; research projects: MŠM 0021620849, MŠM 6840770012 and PRVOUK-P26/LF1/4.

Differential Innervation of Direct- and Indirect-Pathway Striatal Projection Neurons

The striatum integrates information from multiple brain regions to shape motor learning. The two major projection cell types in striatum target different downstream basal ganglia targets and have opposing effects on motivated behavior, yet differential innervation of these neuronal subtypes is not well understood. To examine whether input specificity provides a substrate for information segregation in these circuits, we used a monosynaptic rabies virus system to generate brain-wide maps of neurons that form synapses with direct- or indirect-pathway striatal projection neurons. We discovered that sensory cortical and limbic structures preferentially innervated the direct pathway, whereas motor cortex preferentially targeted the indirect pathway. Thalamostriatal input, dopaminergic input, as well as input from specific cortical layers, was similar onto both pathways. We also confirm synaptic innervation of striatal projection neurons by the raphe and pedunculopontine nuclei. Together, these findings provide a framework for guiding future studies of basal ganglia circuit function.

Unilateral deep brain stimulation of the pedunculopontine tegmental nucleus improves oromotor movements in Parkinson’s disease

BackgroundJaw movements are severely affected in Parkinson’s disease. Deep brain stimulation (DBS) of basal ganglia targets is known to ameliorate oromotor control. In this study, we examined the effects of DBS of the pedunculopontine tegmental nucleus (PPTg) on jaw movements in selected parkinsonian patients. MethodsThe effects of low-frequency (25 Hz) stimulation of the PPTg on jaw movements were investigated through electrognathographic analysis in parkinsonian patients who were selected for PPTg stimulation. Changes in jaw velocity and amplitude during voluntary opening and closing movements of the mouth, as well as the maximum frequency of self-paced sequences of opening and closing cycles, were analyzed. ResultsLow-frequency stimulation of the PPTg in the OFF-drugs condition significantly improved the opening and closing velocities, vertical amplitude and rhythm of voluntary movements. In some instances, movement parameters during stimulation were within the range of those recorded in healthy controls. DiscussionThis is the first study investigating the impact of PPTg DBS on oromotor control in parkinsonian patients. The results show that jaw movements may be restored under stimulation and suggest that the pedunculopontine nucleus may play a key role in controlling oromotor activity.

Effect of deep brain stimulation on speech performance in Parkinson's disease.

Deep brain stimulation (DBS) has been reported to be successful in relieving the core motor symptoms of Parkinson's disease (PD) and motor fluctuations in the more advanced stages of the disease. However, data on the effects of DBS on speech performance are inconsistent. While there are some series of patients documenting that speech function was relatively unaffected by DBS of the nucleus subthalamicus (STN), other investigators reported on improvements of distinct parameters of oral control and voice. Though, these ameliorations of single speech modalities were not always accompanied by an improvement of overall speech intelligibility. On the other hand, there are also indications for an induction of dysarthria as an adverse effect of STN-DBS occurring at least in some patients with PD. Since a deterioration of speech function has more often been observed under high stimulation amplitudes, this phenomenon has been ascribed to a spread of current-to-adjacent pathways which might also be the reason for the sporadic observation of an onset of dysarthria under DBS of other basal ganglia targets (e.g., globus pallidus internus/GPi or thalamus/Vim). The aim of this paper is to review and evaluate reports in the literature on the effects of DBS on speech function in PD.

Further Evidence for Celiac Disease-associated Chorea?

<strong>Background:</strong> A number of neurological conditions have been reported to be associated with gluten sensitivity, including ataxia, peripheral neuropathy, epilepsy, and occasionally, chorea. The pathogenic role of anti-gliadin antibodies has been questioned, and pathophysiology remains controversial. <strong>Case Report:</strong> I report chorea in a patient with celiac disease, which responded to a gluten-restricted diet. The response of the movement disorder to change in diet strongly suggests a functional role for anti-gliadin antibodies in the generation of chorea, probably involving basal ganglia targets. <strong>Discussion:</strong> Gluten sensitivity may be a treatable cause of chorea.

The deep brain stimulation of the pedunculopontine tegmental nucleus: towards a new stereotactic neurosurgery

The application of deep brain stimulation (DBS) to the pedunculopontine tegmental nucleus (PPTg) has required profound modifications of classic neurosurgical techniques and of the criteria for evaluation of clinical results. This review analyzes a novel method of targeting the PPTg, based on angio-computerized tomography (angio-CT) scans and the tridimensional reconstruction of nuclei and cerebral vessels, and considers the advantages of applying these methods in comparison to the more traditional approach based on reference points obtained through the evaluation of the bicommessural line. Validation of the results obtained following unilateral PPTg DBS through neurophysiological recordings and objective measurements of functional parameters suggests that the PPTg may be considered as an initial target for the treatment of motor symptoms in selected patients affected by idiopathic Parkinson's disease (PD), which, if required, could be followed by DBS of other target areas. Moreover, on the basis of the observations derived from stimulating the PPTg, the potential utility attributed up to date to intraoperative neurophysiological recordings for identifying neurosurgical targets should be revisited, and the need for changes in the intraoperative management of patients has arisen from the body of evidence accumulated over recent years. The results obtained by different groups following PPTg DBS in parkinsonian patients are not uniform, most likely due to a cautious acceptance of this methodology, the experience progressively acquired, the criteria for patient selection and to subtle differences in target location. Although the role of PPTg in PD and/or in other pathologies remains to be clarified, pursuing the traditional approach on classical basal ganglia targets may limit the perspective of DBS based on multiple implantations.

NEUROBEHAVIORAL AND IMMUNOLOGICAL CONSEQUENCES OF PRENATAL IMMUNE ACTIVATION IN RATS

The striatum integrates information from multiple brain regions to shape motor learning. The two major projection cell types in striatum target different downstream basal ganglia targets and have opposing effects on motivated behavior, yet differential innervation of these neuronal subtypes is not well understood. To examine whether input specificity provides a substrate for information segregation in these circuits, we used a monosynaptic rabies virus system to generate brain-wide maps of neurons that form synapses with direct- or indirect-pathway striatal projection neurons. We discovered that sensory cortical and limbic structures preferentially innervated the direct pathway, whereas motor cortex preferentially targeted the indirect pathway. Thalamostriatal input, dopaminergic input, as well as input from specific cortical layers, was similar onto both pathways. We also confirm synaptic innervation of striatal projection neurons by the raphe and pedunculopontine nuclei. Together, these findings provide a framework for guiding future studies of basal ganglia circuit function.

Identification of the Transcriptional Targets of FOXP2, a Gene Linked to Speech and Language, in Developing Human Brain

Mutations in FOXP2, a member of the forkhead family of transcription factor genes, are the only known cause of developmental speech and language disorders in humans. To date, there are no known targets of human FOXP2 in the nervous system. The identification of FOXP2 targets in the developing human brain, therefore, provides a unique tool with which to explore the development of human language and speech. Here, we define FOXP2 targets in human basal ganglia (BG) and inferior frontal cortex (IFC) by use of chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validate the functional regulation of targets in vitro. ChIP-chip identified 285 FOXP2 targets in fetal human brain; statistically significant overlap of targets in BG and IFC indicates a core set of 34 transcriptional targets of FOXP2. We identified targets specific to IFC or BG that were not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. Many target genes are known to play critical roles in specific aspects of central nervous system patterning or development, such as neurite outgrowth, as well as plasticity. Subsets of the FOXP2 transcriptional targets are either under positive selection in humans or differentially expressed between human and chimpanzee brain. This is the first ChIP-chip study to use human brain tissue, making the FOXP2-target genes identified in these studies important to understanding the pathways regulating speech and language in the developing human brain. These data provide the first insight into the functional network of genes directly regulated by FOXP2 in human brain and by evolutionary comparisons, highlighting genes likely to be involved in the development of human higher-order cognitive processes.

Supplementary Motor Area and Presupplementary Motor Area: Targets of Basal Ganglia and Cerebellar Output

We used retrograde transneuronal transport of neurotropic viruses in Cebus monkeys to examine the organization of basal ganglia and cerebellar projections to two cortical areas on the medial wall of the hemisphere, the supplementary motor area (SMA) and the pre-SMA. We found that both of these cortical areas are the targets of disynaptic projections from the dentate nucleus of the cerebellum and from the internal segment of the globus pallidus (GPi). On average, the number of pallidal neurons that project to the SMA and pre-SMA is approximately three to four times greater than the number of dentate neurons that project to these cortical areas. GPi neurons that project to the pre-SMA are located in a rostral, "associative" territory of the nucleus, whereas GPi neurons that project to the SMA are located in a more caudal and ventral "sensorimotor" territory. Similarly, dentate neurons that project to the pre-SMA are located in a ventral, "nonmotor" domain of the nucleus, whereas dentate neurons that project to the SMA are located in a more dorsal, "motor" domain. The differential origin of subcortical projections to the SMA and pre-SMA suggests that these cortical areas are nodes in distinct neural systems. Although both systems are the target of outputs from the basal ganglia and the cerebellum, these two cortical areas seem to be dominated by basal ganglia input.

Effects of low-frequency stimulation of the subthalamic nucleus on movement in Parkinson's disease

Excessive synchronization of basal ganglia neural activity at low frequencies is considered a hallmark of Parkinson's disease (PD). However, few studies have unambiguously linked this activity to movement impairment through direct stimulation of basal ganglia targets at low frequency. Furthermore, these studies have varied in their methodology and findings, so it remains unclear whether stimulation at any or all frequencies ≤20 Hz impairs movement and if so, whether effects are identical across this broad frequency band. To address these issues, 18 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both subthalamic nuclei were stimulated bilaterally at 5, 10 and 20 Hz after overnight withdrawal of their medication and the effects of the DBS on a finger tapping task were compared to performance without DBS (0 Hz). Tapping rate decreased at 5 and 20 Hz compared to 0 Hz (by 11.8±4.9%, p=0.022 and 7.4±2.6%, p=0.009, respectively) on those sides with relatively preserved baseline task performance. Moreover, the coefficient of variation of tap intervals increased at 5 and 10 Hz compared to 0 Hz (by 70.4±35.8%, p=0.038 and 81.5±48.2%, p=0.043, respectively). These data suggest that the susceptibility of basal ganglia networks to the effects of excessive synchronization may be elevated across a broad low-frequency band in parkinsonian patients, although the nature of the consequent motor impairment may depend on the precise frequencies at which synchronization occurs.