Subthalamic Activity for Motor Execution and Cancelation in Monkeys.

The subthalamic nucleus (STN) receives cortical inputs via the hyperdirect and indirect pathways, projects to the output nuclei of the basal ganglia, and plays a critical role in the control of voluntary movements and movement disorders. STN neurons change their activity during execution of movements, while recent studies emphasize STN activity specific to cancelation of movements. To address the relationship between execution and cancelation functions, we examined STN activity in two Japanese monkeys (Macaca fuscata, both sexes) who performed a goal-directed reaching task with a delay that included Go, Cancel, and NoGo trials. We first examined responses to the stimulation of the forelimb regions in the primary motor cortex and/or supplementary motor area. STN neurons with motor cortical inputs were found in the dorsal somatomotor region of the STN. All these STN neurons showed activity changes in Go trials, suggesting their involvement in execution of movements. Part of them exhibited activity changes in Cancel trials and sustained activity during delay periods, suggesting their involvement in cancelation of planed movements and preparation of movements, respectively. The STN neurons rarely showed activity changes in NoGo trials. Go- and Cancel-related activity was selective to the direction of movements, and the selectivity was higher in Cancel trials than in Go trials. Changes in Go- and Cancel-related activity occurred early enough to initiate and cancel movements, respectively. These results suggest that the dorsal somatomotor region of the STN, which receives motor cortical inputs, is involved in preparation and execution of movements and cancelation of planned movements.

Coupled Activation of the Hyperdirect and Cerebellothalamic Pathways with Zona Incerta Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or ventral intermediate nucleus (VIM) are established targets for the treatment of Parkinson's disease (PD) or essential tremor (ET), respectively. However, DBS of the zona incerta (ZI) can be effective for both disorders. VIM DBS is assumed to achieve its therapeutic effect via activation of the cerebellothalamic (CBT) pathway, whereas the activation of the hyperdirect (HD) pathway likely plays a role in the mechanisms of STN DBS. Interestingly, HD pathway axons also emit collaterals to the ZI and red nucleus (RN) and the CBT pathway courses nearby to the ZI. OBJECTIVE: The aim was to examine the ability of ZI DBS to mutually activate the HD and CBT pathways in a detailed computational model of human DBS. METHODS: We extended a previous model of the human HD pathway to incorporate axon collaterals to the ZI and RN. The anatomical framework of the model system also included representations of the CBT pathway and internal capsule (IC) fibers of passage. We then performed detailed biophysical simulations to quantify DBS activation of the HD, CBT, and IC pathways with electrodes located in either the STN or ZI. RESULTS: STN DBS and ZI DBS both robustly activated the HD pathway. However, STN DBS was limited by IC activation at higher stimulus amplitudes. Alternatively, ZI DBS avoided IC activation while simultaneously activating the HD and CBT pathways. CONCLUSIONS: From both neuroanatomical and biophysical perspectives, ZI DBS represents an advantageous target for coupled activation of the HD and CBT pathways. © 2024 International Parkinson and Movement Disorder Society.

Biophysical and Architectural Mechanisms of Subthalamic Theta under Response Conflict.

The cortico-basal ganglia circuit is needed to suppress prepotent actions and to facilitate controlled behavior. Under conditions of response conflict, the frontal cortex and subthalamic nucleus (STN) exhibit increased spiking and theta band power, which are linked to adaptive regulation of behavioral output. The electrophysiological mechanisms underlying these neural signatures of impulse control remain poorly understood. To address this lacuna, we constructed a novel large-scale, biophysically principled model of the subthalamopallidal (STN-globus pallidus externus) network and examined the mechanisms that modulate theta power and spiking in response to cortical input. Simulations confirmed that theta power does not emerge from intrinsic network dynamics but is robustly elicited in response to cortical input as burst events representing action selection dynamics. Rhythmic burst events of multiple cortical populations, representing a state of conflict where cortical motor plans vacillate in the theta range, led to prolonged STN theta and increased spiking, consistent with empirical literature. Notably, theta band signaling required NMDA, but not AMPA, currents, which were in turn related to a triphasic STN response characterized by spiking, silence, and bursting periods. Finally, theta band resonance was also strongly modulated by architectural connectivity, with maximal theta arising when multiple cortical populations project to individual STN "conflict detector" units because of an NMDA-dependent supralinear response. Our results provide insights into the biophysical principles and architectural constraints that give rise to STN dynamics during response conflict, and how their disruption can lead to impulsivity and compulsivity.SIGNIFICANCE STATEMENT The subthalamic nucleus exhibits theta band power modulation related to cognitive control over motor actions during conditions of response conflict. However, the mechanisms of such dynamics are not understood. Here we developed a novel biophysically detailed and data-constrained large-scale model of the subthalamopallidal network, and examined the impacts of cellular and network architectural properties that give rise to theta dynamics. Our investigations implicate an important role for NMDA receptors and cortico-subthalamic nucleus topographical connectivities in theta power modulation.

Programming of subthalamic nucleus deep brain stimulation with hyperdirect pathway and corticospinal tract-guided parameter suggestions.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for advanced Parkinson's disease. Stimulation of the hyperdirect pathway (HDP) may mediate the beneficial effects, whereas stimulation of the corticospinal tract (CST) mediates capsular side effects. The study's objective was to suggest stimulation parameters based on the activation of the HDP and CST. This retrospective study included 20 Parkinson's disease patients with bilateral STN DBS. Patient-specific whole-brain probabilistic tractography was performed to extract the HDP and CST. Stimulation parameters from monopolar reviews were used to estimate volumes of tissue activated and to determine the streamlines of the pathways inside these volumes. The activated streamlines were related to the clinical observations. Two models were computed, one for the HDP to estimate effect thresholds and one for the CST to estimate capsular side effect thresholds. In a leave-one-subject-out cross-validation, the models were used to suggest stimulation parameters. The models indicated an activation of 50% of the HDP at effect threshold, and 4% of the CST at capsular side effect threshold. The suggestions for best and worst levels were significantly better than random suggestions. Finally, we compared the suggested stimulation thresholds with those from the monopolar reviews. The median suggestion errors for the effect threshold and side effect threshold were 1 and 1.5 mA, respectively. Our stimulation models of the HDP and CST suggested STN DBS settings. Prospective clinical studies are warranted to optimize tract-guided DBS programming. Together with other modalities, these may allow for assisted STN DBS programming.

Elimination of the Cortico-Subthalamic Hyperdirect Pathway Induces Motor Hyperactivity in Mice.

The substantia nigra pars reticulata (SNr) is the output station of the basal ganglia and receives cortical inputs by way of the following three basal ganglia pathways: the cortico-subthalamo (STN)-SNr hyperdirect, the cortico-striato-SNr direct, and the cortico-striato-external pallido-STN-SNr indirect pathways. Compared with the classical direct and indirect pathways via the striatum, the functions of the hyperdirect pathway remain to be fully elucidated. Here we used a photodynamic technique to selectively eliminate the cortico-STN projection in male mice and observed neuronal activity and motor behaviors in awake conditions. After cortico-STN elimination, cortically evoked early excitation in the SNr was diminished, while the cortically evoked inhibition and late excitation, which are delivered through the direct and indirect pathways, respectively, were unchanged. In addition, locomotor activity was significantly increased after bilateral cortico-STN elimination, and apomorphine-induced ipsilateral rotations were observed after unilateral cortico-STN elimination, suggesting that cortical activity was increased. These results are compatible with the notion that the cortico-STN-SNr hyperdirect pathway quickly conveys cortical excitation to the output station of the basal ganglia, resets or suppresses the cortical activity related to ongoing movements, and prepares for the forthcoming movement.SIGNIFICANCE STATEMENT The basal ganglia play a pivotal role in the control of voluntary movements, and their malfunctions lead to movement disorders, such as Parkinson's disease and dystonia. Understanding their functions is important to find better treatments for such diseases. Here we used a photodynamic technique to selectively eliminate the projection from the motor cortex to the subthalamic nucleus, the input station of the basal ganglia, and found greatly reduced early excitatory signals from the cortex to the output station of the basal ganglia and motor hyperactivity. These results suggest that the neuronal signals through the cortico-subthalamic hyperdirect pathway reset or suppress ongoing movements and that blockade of this pathway may be beneficial for Parkinson's disease, which is characterized by oversuppression of movements.

Cortical Control of Subthalamic Neuronal Activity through the Hyperdirect and Indirect Pathways in Monkeys.

The subthalamic nucleus (STN) plays a key role in the control of voluntary movements and basal ganglia disorders, such as Parkinson's disease and hemiballismus. The STN receives glutamatergic inputs directly from the cerebral cortex via the cortico-STN hyperdirect pathway and GABAergic inputs from the external segment of the globus pallidus (GPe) via the cortico-striato-GPe-STN indirect pathway. The STN then drives the internal segment of the globus pallidus, which is the output nucleus of the basal ganglia. Thus, clarifying how STN neuronal activity is controlled by the two inputs is crucial. Cortical stimulation evokes early excitation and late excitation in STN neurons, intervened by a short gap. Here, to examine the origin of each component of this biphasic response, we recorded neuronal activity in the STN, combined with electrical stimulation of the motor cortices and local drug application in two male monkeys (Macaca fuscata) in the awake state. Local application of glutamate receptor antagonists, a mixture of an AMPA/kainate receptor antagonist and an NMDA receptor antagonist, into the vicinity of recorded STN neurons specifically diminished early excitation. Blockade of the striatum (putamen) or GPe with local injection of a GABAA receptor agonist, muscimol, diminished late excitation in the STN. Blockade of striato-GPe transmission with local injection of a GABAA receptor antagonist, gabazine, into the GPe also abolished late excitation. These results indicate that cortically evoked early and late excitation in the STN is mediated by the cortico-STN glutamatergic hyperdirect and the cortico-striato-GPe-STN indirect pathways, respectively.SIGNIFICANCE STATEMENT Here we show that the subthalamic nucleus (STN), an input station of the basal ganglia, receives cortical inputs through the cortico-STN hyperdirect and cortico-striato-external pallido-STN indirect pathways. This knowledge is important for understanding not only the normal functions of the STN, but also the pathophysiology of STN-related disorders and therapy targeting the STN. Lesions or application of high-frequency stimulation in the STN ameliorates parkinsonian symptoms. These procedures could affect all components in the STN, such as afferent inputs through the hyperdirect and indirect pathways, and STN neuronal activity. If we can understand which component is most affected by such procedures, we may be able to identify more effective manipulation targets or methods to treat Parkinson's disease.

Direct Activation of Primary Motor Cortex during Subthalamic But Not Pallidal Deep Brain Stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is an effective treatment for parkinsonian motor signs. Though its therapeutic mechanisms remain unclear, it has been suggested that antidromic activation of the primary motor cortex (M1) plays a significant role in mediating its therapeutic effects. This study tested the hypothesis that antidromic activation of M1 is a prominent feature underlying the therapeutic effect of STN and GPi DBS. Single-unit activity in M1 was recorded using high-density microelectrode arrays in two parkinsonian nonhuman primates each implanted with DBS leads targeting the STN and GPi. Stimulation in each DBS target had similar therapeutic effects, however, antidromic activation of M1 was only observed during STN DBS. Although both animals undergoing STN DBS had similar beneficial effects, the proportion of antidromic-classified cells in each differed, 30 versus 6%. Over 4 h of continuous STN DBS, antidromic activation became less robust, whereas therapeutic benefits were maintained. Although antidromic activation waned over time, synchronization of spontaneous spiking in M1 was significantly reduced throughout the 4 h. Although we cannot discount the potential therapeutic role of antidromic M1 activation at least in the acute phase of STN DBS, the difference in observed antidromic activation between animals, and target sites, raise questions about its hypothesized role as the primary mechanism underlying the therapeutic effect of DBS. These results lend further support that reductions in synchronization at the level of M1 are an important factor in the therapeutic effects of DBS.SIGNIFICANCE STATEMENT Recently there has been great interest and debate regarding the potential role of motor cortical activation in the therapeutic mechanisms of deep brain stimulation (DBS) for Parkinson's disease. In this study we used chronically implanted high density microelectrode arrays in primary motor cortex (M1) to record neuronal population responses in parkinsonian nonhuman primates during subthalamic nucleus (STN) DBS and globus pallidus internus (GPi) DBS. Our results suggest a contribution of antidromic activation of M1 during STN DBS in disrupting synchronization in cortical neuronal populations; however, diminishing antidromic activity over time, and differences in observed antidromic activation between animals and target sites with antidromic activation not observed during GPi DBS, raise questions about its role as the primary mechanism underlying the therapeutic effect of DBS.

An electrophysiological perspective on Parkinson's disease: symptomatic pathogenesis and therapeutic approaches.

Parkinson's disease (PD), or paralysis agitans, is a common neurodegenerative disease characterized by dopaminergic deprivation in the basal ganglia because of neuronal loss in the substantia nigra pars compacta. Clinically, PD apparently involves both hypokinetic (e.g. akinetic rigidity) and hyperkinetic (e.g. tremor/propulsion) symptoms. The symptomatic pathogenesis, however, has remained elusive. The recent success of deep brain stimulation (DBS) therapy applied to the subthalamic nucleus (STN) or the globus pallidus pars internus indicates that there are essential electrophysiological abnormalities in PD. Consistently, dopamine-deprived STN shows excessive burst discharges. This proves to be a central pathophysiological element causally linked to the locomotor deficits in PD, as maneuvers (such as DBS of different polarities) decreasing and increasing STN burst discharges would decrease and increase the locomotor deficits, respectively. STN bursts are not so autonomous but show a "relay" feature, requiring glutamatergic synaptic inputs from the motor cortex (MC) to develop. In PD, there is an increase in overall MC activities and the corticosubthalamic input is enhanced and contributory to excessive burst discharges in STN. The increase in MC activities may be relevant to the enhanced beta power in local field potentials (LFP) as well as the deranged motor programming at the cortical level in PD. Moreover, MC could not only drive erroneous STN bursts, but also be driven by STN discharges at specific LFP frequencies (~ 4 to 6 Hz) to produce coherent tremulous muscle contractions. In essence, PD may be viewed as a disorder with deranged rhythms in the cortico-subcortical re-entrant loops, manifestly including STN, the major component of the oscillating core, and MC, the origin of the final common descending motor pathways. The configurations of the deranged rhythms may play a determinant role in the symptomatic pathogenesis of PD, and provide insight into the mechanism underlying normal motor control. Therapeutic brain stimulation for PD and relevant disorders should be adaptively exercised with in-depth pathophysiological considerations for each individual patient, and aim at a final normalization of cortical discharge patterns for the best ameliorating effect on the locomotor and even non-motor symptoms.

Concurrent Deep Brain Stimulation Reduces the Direct Cortical Stimulation Necessary for Motor Output.

BACKGROUND: Converging literatures suggest that deep brain stimulation (DBS) in Parkinson's disease affects multiple circuit mechanisms. One proposed mechanism is the normalization of primary motor cortex (M1) pathophysiology via effects on the hyperdirect pathway. OBJECTIVES: We hypothesized that DBS would reduce the current intensity necessary to modulate motor-evoked potentials from focally applied direct cortical stimulation (DCS). METHODS: Intraoperative subthalamic DBS, DCS, and preoperative diffusion tensor imaging data were acquired in 8 patients with Parkinson's disease. RESULTS: In 7 of 8 patients, DBS significantly reduced the M1 DCS current intensity required to elicit motor-evoked potentials. This neuromodulation was specific to select DBS bipolar configurations. In addition, the volume of activated tissue models of these configurations were significantly associated with overlap of the hyperdirect pathway. CONCLUSIONS: DBS reduces the current necessary to elicit a motor-evoked potential using DCS. This supports a circuit mechanism of DBS effectiveness, potentially involving the hyperdirect pathway that speculatively may underlie reductions in hypokinetic abnormalities in Parkinson's disease. © 2020 International Parkinson and Movement Disorder Society.

Cortical Potentials Evoked by Subthalamic Stimulation Demonstrate a Short Latency Hyperdirect Pathway in Humans.

A monosynaptic projection from the cortex to the subthalamic nucleus is thought to have an important role in basal ganglia function and in the mechanism of therapeutic subthalamic deep-brain stimulation, but in humans the evidence for its existence is limited. We sought physiological confirmation of the cortico-subthalamic hyperdirect pathway using invasive recording techniques in patients with Parkinson's disease (9 men, 1 woman). We measured sensorimotor cortical evoked potentials using a temporary subdural strip electrode in response to low-frequency deep-brain stimulation in patients undergoing awake subthalamic or pallidal lead implantations. Evoked potentials were grouped into very short latency (<2 ms), short latency (2-10 ms), and long latency (10-100 ms) from the onset of the stimulus pulse. Subthalamic and pallidal stimulation resulted in very short-latency evoked potentials at 1.5 ms in the primary motor cortex accompanied by EMG-evoked potentials consistent with corticospinal tract activation. Subthalamic, but not pallidal stimulation, resulted in three short-latency evoked potentials at 2.8, 5.8, and 7.7 ms in a widespread cortical distribution, consistent with antidromic activation of the hyperdirect pathway. Long-latency potentials were evoked by both targets, with subthalamic responses lagging pallidal responses by 10-20 ms, consistent with orthodromic activation of the thalamocortical pathway. The amplitude of the first short-latency evoked potential was predictive of the chronic therapeutic stimulation contact.SIGNIFICANCE STATEMENT This is the first physiological demonstration of the corticosubthalamic hyperdirect pathway and its topography at high spatial resolution in humans. We studied cortical potentials evoked by deep-brain stimulation in patients with Parkinson's disease undergoing awake lead implantation surgery. Subthalamic stimulation resulted in multiple short-latency responses consistent with activation of hyperdirect pathway, whereas no such response was present during pallidal stimulation. We contrast these findings with very short latency, direct corticospinal tract activations, and long-latency responses evoked through polysynaptic orthodromic projections. These findings underscore the importance of incorporating the hyperdirect pathway into models of human basal ganglia function.

Identifying the neural correlates of doorway freezing in Parkinson's disease.

Freezing of gait (FOG) in Parkinson's disease (PD) is frequently triggered upon passing through narrow spaces such as doorways. However, despite being common the neural mechanisms underlying this phenomenon are poorly understood. In our study, 19 patients who routinely experience FOG performed a previously validated virtual reality (VR) gait paradigm where they used foot-pedals to navigate a series of doorways. Patients underwent testing randomised between both their "ON" and "OFF" medication states. Task performance in conjunction with blood oxygenation level dependent (BOLD) signal changes between "ON" and "OFF" states were compared within each patient. Specifically, as they passed through a doorway in the VR environment patients demonstrated significantly longer "footstep" latencies in the OFF state compared to the ON state. As seen clinically in FOG this locomotive delay was primarily triggered by narrow doorways rather than wide doorways. Functional magnetic resonance imaging revealed that footstep prolongation on passing through doorways was associated with selective hypoactivation in the presupplementary motor area (pSMA) bilaterally. Task-based functional connectivity analyses revealed that increased latency in response to doorways was inversely correlated with the degree of functional connectivity between the pSMA and the subthalamic nucleus (STN) across both hemispheres. Furthermore, increased frequency of prolonged footstep latency was associated with increased connectivity between the bilateral STN. These findings suggest that the effect of environmental cues on triggering FOG reflects a degree of impaired processing within the pSMA and disrupted signalling between the pSMA and STN, thus implicating the "hyperdirect" pathway in the generation of this phenomenon.

A human prefrontal-subthalamic circuit for cognitive control.

The subthalamic nucleus is a key site controlling motor function in humans. Deep brain stimulation of the subthalamic nucleus can improve movements in patients with Parkinson's disease; however, for unclear reasons, it can also have cognitive effects. Here, we show that the human subthalamic nucleus is monosynaptically connected with cognitive brain areas such as the prefrontal cortex. Single neurons and field potentials in the subthalamic nucleus are modulated during cognitive processing and are coherent with 4-Hz oscillations in medial prefrontal cortex. These data predict that low-frequency deep brain stimulation may alleviate cognitive deficits in Parkinson's disease patients. In line with this idea, we found that novel 4-Hz deep brain stimulation of the subthalamic nucleus improved cognitive performance. These data support a role for the human hyperdirect pathway in cognitive control, which could have relevance for brain-stimulation therapies aimed at cognitive symptoms of human brain disease.awx300media15660002226001.

Model-based deconstruction of cortical evoked potentials generated by subthalamic nucleus deep brain stimulation.

Parkinson's disease is associated with altered neural activity in the motor cortex. Chronic high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing parkinsonian motor symptoms and modulates cortical activity. However, the anatomical pathways responsible for STN DBS-mediated cortical modulation remain unclear. Cortical evoked potentials (cEP) generated by STN DBS reflect the response of cortex to subcortical stimulation, and the goal of this study was to determine the neural origin of STN DBS-generated cEP using a two-step approach. First, we recorded cEP over ipsilateral primary motor cortex during different frequencies of STN DBS in awake healthy and unilateral 6-OHDA-lesioned parkinsonian rats. Second, we used a detailed, biophysically based model of the thalamocortical network to deconstruct the neural origin of the recorded cEP. The in vivo cEP included short (R1)-, intermediate (R2)-, and long-latency (R3) responses. Model-based cortical responses to simulated STN DBS matched remarkably well the in vivo responses. The short-latency response was generated by antidromic activation of layer 5 pyramidal neurons, whereas recurrent activation of layer 5 pyramidal neurons via excitatory axon collaterals reproduced the intermediate-latency response. The long-latency response was generated by polysynaptic activation of layer 2/3 pyramidal neurons via the cortico-thalamic-cortical pathway. Antidromic activation of the hyperdirect pathway and subsequent intracortical and cortico-thalamo-cortical synaptic interactions were sufficient to generate cortical potential evoked by STN DBS, and orthodromic activation through basal ganglia-thalamus-cortex pathways was not required. These results demonstrate the utility of cEP to determine the neural elements activated by STN DBS that might modulate cortical activity and contribute to the suppression of parkinsonian symptoms. NEW & NOTEWORTHY Subthalamic nucleus (STN) deep brain stimulation (DBS) is increasingly used to treat Parkinson's disease (PD). Cortical potentials evoked by STN DBS in patients with PD exhibit consistent short-latency (1-3 ms), intermediate-latency (5-15 ms), and long-latency (18-25 ms) responses. The short-latency response occurs as a result of antidromic activation of the hyperdirect pathway comprising corticosubthalamic axons. However, the neural origins of intermediate- and long-latency responses remain elusive, and the dominant view is that these are produced through the orthodromic pathway (basal ganglia-thalamus-cortex). By combining in vivo electrophysiology with computational modeling, we demonstrate that antidromic activation of the cortico-thalamic-cortical pathway is sufficient to generate the intermediate- and long-latency cortical responses to STN DBS.

Altered functional connectivity of the subthalamic nucleus during self-initiated movement in Parkinson's disease.

BACKGROUND AND PURPOSE: Patients with Parkinson's disease (PD) have difficulty performing self-initiated movements. The neural mechanism of this deficiency remains unclear. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the functional connectivity of the subthalamic nucleus (STN) during self-initiated movement in patients with PD. MATERIALS AND METHODS: fMRI were acquired from patients with PD and age- and sex-matched healthy control subjects during a self-initiated right hand tapping task. We selected the bilateral sensorimotor subregions of the STN as regions of interest for our connectivity analysis. RESULTS AND CONCLUSIONS: We found that the STN contralateral to voluntary hand movement exhibited enhanced connectivity with the midbrain, thalamus, putamen, and so on in patients with PD compared to control subjects. In contrast, the STN ipsilateral to the hand movement exhibited enhanced connectivity with the midbrain and insula in PD patients compared to control subjects. Connectivity between the STN contralateral to the hand movement and the primary motor cortex and supplementary motor area was positively correlated with the severity of bradykinesia. Our findings suggest that STN-related connectivity in the hyperdirect and indirect basal ganglia pathways is strengthened during self-initiated movement in patients with PD. These disrupted network connections may contribute to bradykinesia.

Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease.

Noninvasive brain stimulation studies have shown abnormal motor cortical plasticity in Parkinson's disease (PD). These studies used peripheral nerve stimulation paired with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) at specific intervals to induce plasticity. Induction of cortical plasticity through stimulation of the basal ganglia (BG)-M1 connections has not been studied. In the present study, we used a novel technique of plasticity induction by repeated pairing of deep-brain stimulation (DBS) of the BG with M1 stimulation using TMS. We hypothesize that repeated pairing of subthalamic nucleus (STN)-DBS and M1-TMS at specific time intervals will lead to plasticity in the M1. Ten PD human patients with STN-DBS were studied in the on-medication state with DBS set to 3 Hz. The interstimulus intervals (ISIs) between STN-DBS and TMS that produced cortical facilitation were determined individually for each patient. Three plasticity induction conditions with repeated pairings (180 times) at specific ISIs (∼ 3 and ∼ 23 ms) that produced cortical facilitation and a control ISI of 167 ms were tested in random order. Repeated pairing of STN-DBS and M1-TMS at short (∼ 3 ms) and medium (∼ 23 ms) latencies increased M1 excitability that lasted for at least 45 min, whereas the control condition (fixed ISI of 167 ms) had no effect. There were no specific changes in motor thresholds, intracortical circuits, or recruitment curves. Our results indicate that paired-associative cortical plasticity can be induced by repeated STN and M1 stimulation at specific intervals. These results show that STN-DBS can modulate cortical plasticity. SIGNIFICANCE STATEMENT: We introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1-TMS) at specific times can induce cortical plasticity in patients with Parkinson's disease (PD). We found that repeated pairing of STN-DBS with TMS at short (∼ 3 ms) and medium (∼ 23 ms) intervals increased cortical excitability that lasted for up to 45 min, whereas the control condition (fixed latency of 167 ms) had no effects on cortical excitability. This is the first demonstration of associative plasticity in the STN-M1 circuits in PD patients using this novel technique. The potential therapeutic effects of combining DBS and noninvasive cortical stimulation should be investigated further.

Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson's disease.

OBJECTIVES: Firstly, to identify subthalamic region stimulation clusters that predict maximum improvement in rigidity, bradykinesia and tremor, or emergence of side-effects; and secondly, to map-out the cortical fingerprint, mediated by the hyperdirect pathways which predict maximum efficacy. METHODS: High angular resolution diffusion imaging in twenty patients with advanced Parkinson's disease was acquired prior to bilateral subthalamic nucleus deep brain stimulation. All contacts were screened one-year from surgery for efficacy and side-effects at different amplitudes. Voxel-based statistical analysis of volumes of tissue activated models was used to identify significant treatment clusters. Probabilistic tractography was employed to identify cortical connectivity patterns associated with treatment efficacy. RESULTS: All patients responded well to treatment (46% mean improvement off medication UPDRS-III [p < 0.0001]) without significant adverse events. Cluster corresponding to maximum improvement in tremor was in the posterior, superior and lateral portion of the nucleus. Clusters corresponding to improvement in bradykinesia and rigidity were nearer the superior border in a further medial and posterior location. The rigidity cluster extended beyond the superior border to the area of the zona incerta and Forel-H2 field. When the clusters where averaged, the coordinates of the area with maximum overall efficacy was X = -10(-9.5), Y = -13(-1) and Z = -7(-3) in MNI(AC-PC) space. Cortical connectivity to primary motor area was predictive of higher improvement in tremor; whilst that to supplementary motor area was predictive of improvement in bradykinesia and rigidity; and connectivity to prefrontal cortex was predictive of improvement in rigidity. INTERPRETATION: These findings support the presence of overlapping stimulation sites within the subthalamic nucleus and its superior border, with different cortical connectivity patterns, associated with maximum improvement in tremor, rigidity and bradykinesia.

The promotion-like effect of the M1-STN hyperdirect pathway induced by ccPAS enhanced balance performances: From the perspective of brain connectivity.

AIMS: The present study aimed to explore the effect of cortico-cortical paired-associative stimulation (ccPAS) in modulating hyperdirect pathway and its influence on balance performance. METHODS: Forty healthy participants were randomly allocated to the active ccPAS group (n = 20) or the sham ccPAS group (n = 20). The primary motor cortex and subthalamic nucleus were stimulated sequentially with ccPAS. Unlike the active ccPAS group, one wing of coil was tilted to form a 90° angle with scalp of stimulation locations for the sham ccPAS group. Magnetic resonance imaging, functional reach test (FRT), timed up and go (TUG) test, and limit of stability (LOS) test were performed, and correlation between them was also analyzed. RESULTS: Three participants in the sham ccPAS group were excluded because of poor quality of NIfTI images. The active group had strengthened hyperdirect pathway, increased functional connectivity (FC) between orbital part of frontal cortex and bilateral precuneus, and decreased FC among basal ganglia (all p < 0.05). Regional network properties of triangular and orbital parts of IFG, middle cingulate cortex, and hippocampus increased. The active group performed better in FRT and LOS (all p < 0.05). FRT positively correlated with FC of the hyperdirect pathway (r = 0.439, p = 0.007) and FCs between orbital part of frontal cortex and bilateral precuneus (all p < 0.05). CONCLUSION: The ccPAS enhanced balance performance by promotion-like plasticity mechanisms through the hyperdirect pathway.

Evolving characterization of the human hyperdirect pathway.

The hyperdirect pathway (HDP) represents the main glutamatergic input to the subthalamic nucleus (STN), through which the motor and prefrontal cerebral cortex can modulate basal ganglia activity. Further, direct activation of the motor HDP is thought to be an important component of therapeutic deep brain stimulation (DBS), mediating the disruption of pathological oscillations. Alternatively, unintended recruitment of the prefrontal HDP may partly explain some cognitive side effects of DBS therapy. Previous work describing the HDP has focused on non-human primate (NHP) histological pathway tracings, diffusion-weighted MRI analysis of human white matter, and electrophysiology studies involving paired cortical recordings with DBS. However, none of these approaches alone yields a complete understanding of the complexities of the HDP. As such, we propose that generative modeling methods hold promise to bridge anatomy and physiology results, from both NHPs and humans, into a more detailed representation of the human HDP. Nonetheless, numerous features of the HDP remain to be experimentally described before model-based methods can simulate corticosubthalamic activity with a high degree of scientific detail. Therefore, the goals of this review are to examine the experimental evidence for HDP projections from across the primate neocortex and discuss new data which are required to improve the utility of anatomical and biophysical models of the human corticosubthalamic system.

Influence of charges deposited on membranes of human hyperdirect pathway axons on depolarization during subthalamic deep brain stimulation.

Objective.The motor hyperdirect pathway (HDP) is a key target in the treatment of Parkinson's disease with deep brain stimulation (DBS). Biophysical models of HDP DBS have been used to explore the mechanisms of stimulation. Built upon finite element method volume conductor solutions, such models are limited by a resolution mismatch, where the volume conductor is modeled at the macro scale, while the neural elements are at the micro scale. New techniques are needed to better integrate volume conductor models with neuron models.Approach.We simulated subthalamic DBS of the human HDP using finely meshed axon models to calculate surface charge deposition on insulting membranes of nonmyelinated axons. We converted the corresponding double layer extracellular problem to a single layer problem and applied the well-conditioned charge-based boundary element fast multipole method (BEM-FMM) with unconstrained numerical spatial resolution. Commonly used simplified estimations of membrane depolarization were compared with more realistic solutions.Main result.Neither centerline potential nor estimates of axon recruitment were impacted by the estimation method used except at axon bifurcations and hemispherical terminations. Local estimates of axon polarization were often much higher at bifurcations and terminations than at any other place along the axon and terminal arbor. Local average estimates of terminal electric field are higher by 10%-20%.Significance. Biophysical models of action potential initiation in the HDP suggest that axon terminations are often the lowest threshold elements for activation. The results of this study reinforce that hypothesis and suggest that this phenomenon is even more pronounced than previously realized.

Front and center: Maturational dysregulation of frontal lobe functional neuroanatomic connections in attention deficit hyperactivity disorder.

Frontal lobe function may not universally explain all forms of attention deficit hyperactivity disorder (ADHD) but the frontal lobe hypothesis described supports an internally consistent model for integrating the numerous behaviors associated with ADHD. The paper examines the developmental trajectories of frontal and prefrontal lobe development, framing ADHD as maturational dysregulation concluding that the cognitive, motor, and behavioral abilities of the presumptive majority of ADHD children may not primarily be disordered or dysfunctional but reflect maturational dysregulation that is inconsistent with the psychomotor and cognitive expectations for the child's chronological and mental age. ADHD children demonstrate decreased activation of the right and middle prefrontal cortex. Prefrontal and frontal lobe regions have an exuberant network of shared pathways with the diencephalic region, also having a regulatory function in arousal as well as with the ascending reticular formation which has a capacity for response suppression to task-irrelevant stimuli. Prefrontal lesions oftentimes are associated with the regulatory breakdown of goal-directed activity and impulsivity. In conclusion, a presumptive majority of childhood ADHD may result from maturational dysregulation of the frontal lobes with effects on the direct, indirect and/or, hyperdirect pathways.