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The ability to switch between rules associating stimuli and responses depend on a circuit including the dorsomedial prefrontal cortex (dmPFC) and the subthalamic nucleus (STN). However, the precise neural implementations of switching remain unclear. To address this issue, we recorded local field potentials from the STN and from the dmPFC of neuropsychiatric patients during behavioral switching. Drift-diffusion modeling revealed that switching is associated with a shift in the starting point of evidence accumulation. Theta activity increases in dmPFC and STN during successful switch trials, while temporally delayed and excessive levels of theta lead to premature switch errors. This seemingly opposing impact of increased theta in successful and unsuccessful switching is explained by a negative correlation between theta activity and the starting point. Together, these results shed a new light on the neural mechanisms underlying the rapid reconfiguration of stimulus-response associations, revealing a Goldilocks' effect of theta activity on switching behavior., (© 2024. The Author(s).)

Background: The subthalamic nucleus (STN) is an effective neurosurgical target to improve motor symptoms in Parkinson's Disease (PD) patients. MR-guided Focused Ultrasound (MRgFUS) subthalamotomy is being explored as a therapeutic alternative to Deep Brain Stimulation (DBS) of the STN. The hyperdirect pathway provides a direct connection between the cortex and the STN and is likely to play a key role in the therapeutic effects of MRgFUS intervention in PD patients., Objective: This study aims to investigate the topography and somatotopy of hyperdirect pathway projections from the primary motor cortex (M1)., Methods: We used advanced multi-fiber tractography and high-resolution diffusion MRI data acquired on five subjects of the Human Connectome Project (HCP) to reconstruct hyperdirect pathway projections from M1. Two neuroanatomy experts reviewed the anatomical accuracy of the tracts. We extracted the fascicles arising from the trunk, arm, hand, face and tongue area from the reconstructed pathways. We assessed the variability among subjects based on the fractional anisotropy (FA) and mean diffusivity (MD) of the fibers. We evaluated the spatial arrangement of the different fascicles using the Dice Similarity Coefficient (DSC) of spatial overlap and the centroids of the bundles., Results: We successfully reconstructed hyperdirect pathway projections from M1 in all five subjects. The tracts were in agreement with the expected anatomy. We identified hyperdirect pathway fascicles projecting from the trunk, arm, hand, face and tongue area in all subjects. Tract-derived measurements showed low variability among subjects, and similar distributions of FA and MD values among the fascicles projecting from different M1 areas. We found an anterolateral somatotopic arrangement of the fascicles in the corona radiata, and an average overlap of 0.63 in the internal capsule and 0.65 in the zona incerta., Conclusion: Multi-fiber tractography combined with high-resolution diffusion MRI data enables the identification of the somatotopic organization of the hyperdirect pathway. Our preliminary results suggest that the subdivisions of the hyperdirect pathway projecting from the trunk, arm, hand, face, and tongue motor area are intermixed at the level of the zona incerta and posterior limb of the internal capsule, with a predominantly overlapping topographical organization in both regions. Subject-specific knowledge of the hyperdirect pathway somatotopy could help optimize target definition in MRgFUS intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past collaboration with one of the authors GC., (Copyright © 2022 Pujol, Cabeen, Yelnik, François, Fernandez Vidal, Karachi, Bardinet, Cosgrove and Kikinis.)

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder featuring repetitive intrusive thoughts and behaviors associated with a significant handicap. Of patients, 20% are refractory to medication and cognitive behavioral therapy. Refractory OCD is associated with suicidal behavior and significant degradation of social and professional functioning, with high health costs. Deep brain stimulation (DBS) has been proposed as a reversible and controllable method to treat refractory patients, with meta-analyses showing 60% response rate following DBS, whatever the target: anterior limb of the internal capsule (ALIC), ventral capsule/ventral striatum (VC/VS), nucleus accumbens (NAcc), anteromedial subthalamic nucleus (amSTN), or inferior thalamic peduncle (ITP). But how do we choose the "best" target? Functional neuroimaging studies have shown that ALIC-DBS requires the modulation of the fiber tract within the ventral ALIC via the ventral striatum, bordering the bed nucleus of the stria terminalis and connecting the medial prefrontal cortex with the thalamus to be successful. VC/VS effective sites of stimulation were found within the VC and primarily connected to the medial orbitofrontal cortex (OFC) dorsomedial thalamus, amygdala, and the habenula. NAcc-DBS has been found to reduce OCD symptoms by decreasing excessive fronto-striatal connectivity between NAcc and the lateral and medial prefrontal cortex. The amSTN effective stimulation sites are located at the inferior medial border of the STN, primarily connected to lateral OFC, dorsal anterior cingulate, and dorsolateral prefrontal cortex. Finally, ITP-DBS recruits a bidirectional fiber pathway between the OFC and the thalamus. Thus, these functional connectivity studies show that the various DBS targets lie within the same diseased neural network. They share similar efficacy profiles on OCD symptoms as estimated on the Y-BOCS, the amSTN being the target supported by the strongest evidence in the literature. VC/VS-DBS, amSTN-DBS, and ALIC-DBS were also found to improve mood, behavioral adaptability and potentially both, respectively. Because OCD is such a heterogeneous disease with many different symptom dimensions, the ultimate aim should be to find the most appropriate DBS target for a given refractory patient. This quest will benefit from further investigation and understanding of the individual functional connectivity of OCD patients., (Copyright © 2019 Senova, Clair, Palfi, Yelnik, Domenech and Mallet.)

Purpose: This study evaluates the correlation between injuries to deep gray matter nuclei, as quantitated by lesions in these nuclei on MR T2 Fast Spin Echo (T2 FSE) images, with 6-month neurological outcome after severe traumatic brain injury (TBI)., Materials and Methods: Ninety-five patients (80 males, mean age = 36.7y) with severe TBI were prospectively enrolled. All patients underwent a MR scan within the 45 days after the trauma that included a T2 FSE acquisition. A 3D deformable atlas of the deep gray matter was registered to this sequence; deep gray matter lesions (DGML) were evaluated using a semi-quantitative classification scheme. The 6-month outcome was dichotomized into unfavorable (death, vegetative or minimally conscious state) or favorable (minimal or no neurologic deficit) outcome., Results: Sixty-six percent of the patients (63/95) had both satisfactory registration of the 3D atlas on T2 FSE and available clinical follow-up. Patients without DGML had an 89% chance (P = 0.0016) of favorable outcome while those with bilateral DGML had an 80% risk of unfavorable outcome (P = 0.00008). Multivariate analysis based on DGML accurately classified patients with unfavorable neurological outcome in 90.5% of the cases., Conclusion: Lesions in deep gray matter nuclei may predict long-term outcome after severe TBI with high sensitivity and specificity.

The basal ganglia is part of a complex system of neuronal circuits that play a key role in the integration and execution of motor, cognitive and emotional function in the human brain. Parkinson's disease is a progressive neurological disorder of the motor circuit characterized by tremor, rigidity, and slowness of movement. Deep brain stimulation (DBS) of the subthalamic nucleus and the globus pallidus pars interna provides an efficient treatment to reduce symptoms and levodopa-induced side effects in Parkinson's disease patients. While the underlying mechanism of action of DBS is still unknown, the potential modulation of white matter tracts connecting the surgical targets has become an active area of research. With the introduction of advanced diffusion MRI acquisition sequences and sophisticated post-processing techniques, the architecture of the human brain white matter can be explored in vivo . The goal of this study is to investigate the white matter connectivity between the subthalamic nucleus and the globus pallidus. Two multi-fiber tractography methods were used to reconstruct pallido-subthalamic, subthalamo-pallidal and pyramidal fibers in five healthy subjects datasets of the Human Connectome Project. The anatomical accuracy of the tracts was assessed by four judges with expertise in neuroanatomy, functional neurosurgery, and diffusion MRI. The variability among subjects was evaluated based on the fractional anisotropy and mean diffusivity of the tracts. Both multi-fiber approaches enabled the detection of complex fiber architecture in the basal ganglia. The qualitative evaluation by experts showed that the identified tracts were in agreement with the expected anatomy. Tract-derived measurements demonstrated relatively low variability among subjects. False-negative tracts demonstrated the current limitations of both methods for clinical decision-making. Multi-fiber tractography methods combined with state-of-the-art diffusion MRI data have the potential to help identify white matter tracts connecting DBS targets in functional neurosurgery intervention.

It is solidly established that top-down (goal-driven) and bottom-up (stimulus-driven) attention mechanisms depend on distributed cortical networks, including prefrontal and frontoparietal regions. On the other hand, it is less clear whether the BG also contribute to one or the other of these mechanisms, or to both. The current study was principally undertaken to clarify this issue. Parkinson disease (PD), a neurodegenerative disorder primarily affecting the BG, has proven to be an effective model for investigating the contribution of the BG to different brain functions; therefore, we set out to investigate deficits of top-down and bottom-up attention in a selected cohort of PD patients. With this objective in mind, we compared the performance on three computerized tasks of two groups of 12 parkinsonian patients (assessed without any treatment), one otherwise pharmacologically treated and the other also surgically treated, with that of a group of controls. The main behavioral tool for our study was an attentional capture task, which enabled us to tap the competition between top-down and bottom-up mechanisms of visual attention. This task was suitably combined with a choice RT and a simple RT task to isolate any specific deficit of attention from deficits in motor response selection and initiation. In the two groups of patients, we found an equivalent increase of attentional capture but also comparable delays in target selection in the absence of any salient distractor (reflecting impaired top-down mechanisms) and movement initiation compared with controls. In contrast, motor response selection processes appeared to be prolonged only in the operated patients. Our results confirm that the BG are involved in both motor and cognitive domains. Specifically, damage to the BG, as it occurs in PD, leads to a distinct deficit of top-down control of visual attention, and this can account, albeit indirectly, for the enhancement of attentional capture, reflecting weakened ability of top-down mechanisms to antagonize bottom-up control.

Bilateral damage to the basal ganglia causes auto-activation deficit, a neuropsychological syndrome characterized by striking apathy, with a loss of self-driven behaviour that is partially reversible with external stimulation. Some patients with auto-activation deficit also experience a mental emptiness, which is defined as an absence of any self-reported thoughts. We asked whether this deficit in spontaneous activation of mental processing may be reversed during REM sleep, when dreaming activity is potentially elicited by bottom-up brainstem stimulation on the cortex. Sleep and video monitoring over two nights and cognitive tests were performed on 13 patients with auto-activation deficit secondary to bilateral striato-pallidal lesions and 13 healthy subjects. Dream mentations were collected from home diaries and after forced awakenings in non-REM and REM sleep. The home diaries were blindly analysed for length, complexity and bizarreness. A mental blank during wakefulness was complete in six patients and partial in one patient. Four (31%) patients with auto-activation deficit (versus 92% of control subjects) reported mentations when awakened from REM sleep, even when they demonstrated a mental blank during the daytime (n = 2). However, the patients' dream reports were infrequent, short, devoid of any bizarre or emotional elements and tended to be less complex than the dream mentations of control subjects. The sleep duration, continuity and stages were similar between the groups, except for a striking absence of sleep spindles in 6 of 13 patients with auto-activation deficit, despite an intact thalamus. The presence of spontaneous dreams in REM sleep in the absence of thoughts during wakefulness in patients with auto-activation deficit supports the idea that simple dream imagery is generated by brainstem stimulation and is sent to the sensory cortex. However, the lack of complexity in these dream mentations suggests that the full dreaming process (scenario, emotions, etc.) require these sensations to be interpreted by higher-order cortical areas. The absence of sleep spindles in localized lesions in the basal ganglia highlights the role of the pallidum and striatum in spindling activity during non-REM sleep.

Huntington disease (HD) is associated with early and severe damage to the basal ganglia and particularly the striatum. We investigated cortico-striatal connectivity modifications occurring in HD patients using a novel approach which focuses on the projection of the connectivity profile of the basal ganglia onto the cortex. This approach consists in computing, for each subcortical structure, surface connectivity measures representing its strength of connections to the cortex and comparing these measures across groups. In this study, we focused on Huntington disease as an application of this new approach. First, surface cortico-striatal connectivity measures of a group of healthy subjects were averaged in order to infer the "normal" connectivity profile of the striatum to the cortex. Second, a statistical analysis was performed from the surface connectivity measures of healthy subjects and HD patients in order to detect the cortical gyri presenting altered cortico-striatal connectivity in HD. Lastly, percentage differences of connectivity between healthy subjects and patients were inferred, for each nucleus of the striatum, from the connectivity measures of the cortical gyri presenting a significant connectivity difference between the two groups. These percentage differences characterize the axonal disruptions between the striatum and the cortex occurring in HD. We found selective region-specific degeneration of cortical connections predominating for associative and primary sensorimotor connections and with relative preservation of limbic connections. Our method can be used to infer novel connectivity-based markers of HD pathological process.

Doubt, and its behavioural correlate, checking, is a normal phenomenon of human cognition that is dramatically exacerbated in obsessive-compulsive disorder. We recently showed that deep brain stimulation in the associative-limbic area of the subthalamic nucleus, a central core of the basal ganglia, improved obsessive-compulsive disorder. To understand the physiological bases of symptoms in such patients, we recorded the activity of individual neurons in the therapeutic target during surgery while subjects performed a cognitive task that gave them the possibility of unrestricted repetitive checking after they had made a choice. We postulated that the activity of neurons in this region could be influenced by doubt and checking behaviour. Among the 63/87 task-related neurons recorded in 10 patients, 60% responded to various combinations of instructions, delay, movement or feedback, thus highlighting their role in the integration of different types of information. In addition, task-related activity directed towards decision-making increased during trials with checking in comparison with those without checking. These results suggest that the associative-limbic subthalamic nucleus plays a role in doubt-related repetitive thoughts. Overall, our results not only provide new insight into the role of the subthalamic nucleus in human cognition but also support the fact that subthalamic nucleus modulation by deep brain stimulation reduced compulsive behaviour in patients with obsessive-compulsive disorder.

In humans, the control of voluntary movement, in which the corticobasal ganglia (BG) circuitry participates, is mainly lateralized. However, several studies have suggested that both the contralateral and ipsilateral BG systems are implicated during unilateral movement. Bilateral improvement of motor signs in patients with Parkinson's disease (PD) has been reported with unilateral lesion or high-frequency stimulation (HFS) of the internal part of the globus pallidus or the subthalamic nucleus (STN-HFS). To decipher the mechanisms of production of ipsilateral movements induced by the modulation of unilateral BG circuitry activity, we recorded left STN neuronal activity during right STN-HFS in PD patients operated for bilateral deep brain stimulation. Left STN single cells were recorded in the operating room during right STN-HFS while patients experienced, or did not experience, right stimulation-induced dyskinesias. Most of the left-side STN neurons (64%) associated with the presence of right dyskinesias were inhibited, with a significant decrease in burst and intraburst frequencies. In contrast, left STN neurons not associated with right dyskinesias were mainly activated (48%), with a predominant increase 4-5 ms after the stimulation pulse and a decrease in oscillatory activity. This suggests that unilateral neuronal STN modulation is associated with changes in the activity of the contralateral STN. The fact that one side of the BG system can influence the functioning of the other could explain the occurrence of bilateral dyskinesias and motor improvement observed in PD patients during unilateral STN-HFS, as a result of a bilateral disruption of the pathological activity in the corticosubcortical circuitry.

Functional and connectivity changes in corticostriatal systems have been reported in the brains of patients with obsessive-compulsive disorder (OCD); however, the relationship between basal ganglia activity and OCD severity has never been adequately established. We recently showed that deep brain stimulation of the subthalamic nucleus (STN), a central basal ganglia nucleus, improves OCD. Here, single-unit subthalamic neuronal activity was analysed in 12 OCD patients, in relation to the severity of obsessions and compulsions and response to STN stimulation, and compared with that obtained in 12 patients with Parkinson's disease (PD). STN neurons in OCD patients had lower discharge frequency than those in PD patients, with a similar proportion of burst-type activity (69 vs 67%). Oscillatory activity was present in 46 and 68% of neurons in OCD and PD patients, respectively, predominantly in the low-frequency band (1-8 Hz). In OCD patients, the bursty and oscillatory subthalamic neuronal activity was mainly located in the associative-limbic part. Both OCD severity and clinical improvement following STN stimulation were related to the STN neuronal activity. In patients with the most severe OCD, STN neurons exhibited bursts with shorter duration and interburst interval, but higher intraburst frequency, and more oscillations in the low-frequency bands. In patients with best clinical outcome with STN stimulation, STN neurons displayed higher mean discharge, burst and intraburst frequencies, and lower interburst interval. These findings are consistent with the hypothesis of a dysfunction in the associative-limbic subdivision of the basal ganglia circuitry in OCD's pathophysiology.

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model.

Deep brain stimulation (DBS) is a new neurosurgical method principally used for the treatment of Parkinson disease (PD). Many new applications of DBS are under development, including the treatment of intractable psychiatric diseases. Brain imaging is used for the selection of patients for DBS, to localize the target nucleus, to detect complications, and to evaluate the final electrode contact position. In patients with implanted DBS systems, there is a risk of electrode heating when MR imaging is performed. This contraindicates MR imaging unless specific precautions are taken. Involvement of neuroradiologists in DBS procedures is essential to optimize presurgical evaluation, targeting, and postoperative anatomic results. The precision of the neuroradiologic correlation with anatomic data and clinical outcomes in DBS promises to yield significant basic science and clinical advances in the future.

Two parkinsonian patients who experienced transient hypomanic states when the subthalamic nucleus (STN) was stimulated during postoperative adjustment of the electrical parameters for antiparkinsonian therapy agreed to have the mood disorder reproduced, in conjunction with motor, cognitive, and behavioral evaluations and concomitant functional neuroimaging. During the experiment, STN stimulation again induced a hypomanic state concomitant with activation of cortical and thalamic regions known to process limbic and associative information. This observation suggests that the STN plays a role in the control of a complex behavior that includes emotional as well as cognitive and motor components. The localization of the four contacts of the quadripolar electrode was determined precisely with an interactive brain atlas. The results showed that (i) the hypomanic state was caused only by stimulation through one contact localized in the anteromedial STN; (ii) both this contact and the contact immediately dorsal to it improved the parkinsonian motor state; (iii) the most dorsal and ventral contacts, located at the boundaries of the STN, neither induced the behavioral disorder nor improved motor performance. Detailed analysis of these data led us to consider a model in which the three functional modalities, emotional, cognitive, and motor, are not processed in a segregated manner but can be subtly combined in the small volume of the STN. This nucleus would thus serve as a nexus that integrates the motor, cognitive, and emotional components of behavior and might consequently be an effective target for the treatment of behavioral disorders that combine emotional, cognitive, and motor impairment.

In this study, we examined how the motor, premotor and associative basal ganglia territories process movement parameters such as the complexity and the frequency of movement. Twelve right-handed volunteers were studied using EPI BOLD contrast (3 T) while performing audio-paced finger tapping tasks designed to differentiate basal ganglia territories. Tasks varied movement complexity (repetitive index tapping, simple sequence of finger movements and complex sequence of 10 moves) and frequency (from 0.5 to 3 Hz). Activation maps were coregistered onto a 3-D brain atlas derived from post-mortem brains. Three main patterns of activation were observed. In the posterior putamen and the sensorimotor cortex, signal increased with movement frequency but not with movement complexity. In premotor areas, the anterior putamen and the ventral posterolateral thalamus, signal increased regularly with increasing movement frequency and complexity. In rostral frontal areas, the caudate nucleus, the subthalamic nucleus and the ventral anterior/ventrolateral thalamus, signal increased mainly during the complex task and the high frequency task (3 Hz). These data show the different roles of motor, premotor and associative basal ganglia circuits in the processing of motor-related operations and suggest that activation can be precisely located within the entire circuitry of the basal ganglia.

Background and Purpose: Although the subthalamic nucleus is the most frequently used target for surgical treatment of Parkinson's disease, the criteria on which it can be identified on T2-weighted images have never been clearly defined. This study was conducted to characterize the precise anatomic distribution of T2-weighted hyposignal in the subthalamic region and to correlate this hyposignal with iron content in the subthalamic nucleus., Methods: The T2-weighted MR imaging acquisitions of 15 patients with Parkinson's disease were fused with a digitized version of the Schaltenbrand and Wahren anatomic atlas. The MR signal intensity within the anatomic limits of the subthalamic nucleus was evaluated. An anatomic specimen obtained at autopsy was used to evaluate iron content., Results: In all patients, the subthalamic nucleus was hypointense on both sides in the anterior half of the nucleus. At more posterior levels of the nucleus, hypointensity was less frequently observed (20-80%). Hypointensity was never observed at the most posterior pole. Iron was present in the anteromedial part of the nucleus but absent at the most posterior levels., Conclusion: The hypointense signal intensity located lateral to the red nucleus and dorsolateral to the substantia nigra correlates with the presence of iron and corresponds anatomically to the subthalamic nucleus. It can therefore be used as a landmark for electrode implantation in patients with Parkinson's disease. It should, however, be emphasized that although hypointensity was always present in the anterior half of the subthalamic nucleus, the posterior part of the nucleus was not visible in most cases., (Copyright American Society of Neuroradiology)