Integration of valence and conflict processing through cellular-field interactions in human subgenual cingulate during emotional face processing in treatment-resistant depression.

The subgenual anterior cingulate cortex (sgACC) has been identified as a key brain area involved in various cognitive and emotional processes. While the sgACC has been implicated in both emotional valuation and emotional conflict monitoring, it is still unclear how this area integrates multiple functions. We characterized both single neuron and local field oscillatory activity in 14 patients undergoing sgACC deep brain stimulation for treatment-resistant depression. During recording, patients were presented with a modified Stroop task containing emotional face images that varied in valence and congruence. We further analyzed spike-field interactions to understand how network dynamics influence single neuron activity in this area. Most single neurons responded to both valence and congruence, revealing that sgACC neuronal activity can encode multiple processes within the same task, indicative of multifunctionality. During peak neuronal response, we observed increased spectral power in low frequency oscillations, including theta-band synchronization (4-8 Hz), as well as desynchronization in beta-band frequencies (13-30 Hz). Theta activity was modulated by current trial congruency with greater increases in spectral power following non-congruent stimuli, while beta desynchronizations occurred regardless of emotional valence. Spike-field interactions revealed that local sgACC spiking was phase-locked most prominently to the beta band, whereas phase-locking to the theta band occurred in fewer neurons overall but was modulated more strongly for neurons that were responsive to task. Our findings provide the first direct evidence of spike-field interactions relating to emotional cognitive processing in the human sgACC. Furthermore, we directly related theta oscillatory dynamics in human sgACC to current trial congruency, demonstrating it as an important regulator during conflict detection. Our data endorse the sgACC as an integrative hub for cognitive emotional processing through modulation of beta and theta network activity.

Functional brain network features specify DBS outcome for patients with treatment resistant depression.

Deep brain stimulation (DBS) has shown therapeutic benefits for treatment resistant depression (TRD). Stimulation of the subcallosal cingulate gyrus (SCG) aims to alter dysregulation between subcortical and cortex. However, the 50% response rates for SCG-DBS indicates that selection of appropriate patients is challenging. Since stimulation influences large-scale network function, we hypothesized that network features can be used as biomarkers to inform outcome. In this pilot project, we used resting-state EEG recorded longitudinally from 10 TRD patients with SCG-DBS (11 at baseline). EEGs were recorded before DBS-surgery, 1-3 months, and 6 months post surgery. We used graph theoretical analysis to calculate clustering coefficient, global efficiency, eigenvector centrality, energy, and entropy of source-localized EEG networks to determine their topological/dynamical features. Patients were classified as responders based on achieving a 50% or greater reduction in Hamilton Depression (HAM-D) scores from baseline to 12 months post surgery. In the delta band, false discovery rate analysis revealed that global brain network features (segregation, integration, synchronization, and complexity) were significantly lower and centrality of subgenual anterior cingulate cortex (ACC) was higher in responders than in non-responders. Accordingly, longitudinal analysis showed SCG-DBS increased global network features and decreased centrality of subgenual ACC. Similarly, a clustering method separated two groups by network features and significant correlations were identified longitudinally between network changes and depression symptoms. Despite recent speculation that certain subtypes of TRD are more likely to respond to DBS, in the SCG it seems that underlying brain network features are associated with ability to respond to DBS. SCG-DBS increased segregation, integration, and synchronizability of brain networks, suggesting that information processing became faster and more efficient, in those patients in whom it was lower at baseline. Centrality results suggest these changes may occur via altered connectivity in specific brain regions especially ACC. We highlight potential mechanisms of therapeutic effect for SCG-DBS.

Limb Preference Changes after Focused-Ultrasound Thalamotomy for Tremor.

BACKGROUND: Magnetic resonance-guided focused-ultrasound (MRgFUS) thalamotomy is an effective treatment for essential and other tremors. It targets the ventrointermedius (Vim) nucleus, which is the thalamic relay in a proprioceptive pathway, and contains kinesthetic cells. Although MRgFUS thalamotomy reduces some risks associated with more invasive surgeries, it still has side effects, such as balance and gait disturbances; these may be caused by the lesion impacting proprioception. OBJECTIVES: Our aim was to quantitatively measure the effects of MRgFUS on proprioception and limb use in essential tremor patients. We hypothesized that this thalamotomy alters proprioception, because the sensorimotor Vim thalamus is lesioned. METHODS: Proprioception was measured using the Kinarm exoskeleton robot in 18 patients. Data were collected pre-operatively, and then 1 day, 3 months, and 1 year after surgery. Patients completed four tasks, assessing motor coordination and postural control, goal-directed movement and bimanual planning, position sense, and kinesthesia. RESULTS: Immediately after surgery there were changes in posture speed (indicating tremor improvement), and in bimanual hand use, with the untreated limb being preferred. However, these measures returned to pre-operative baseline over time. There were no changes in parameters related to proprioception. None of these measures correlated with lesion size or lesion-overlap with the dentato-rubro-thalamic tract. CONCLUSIONS: This is the first quantitative assessment of proprioception and limb preference following MRgFUS thalamotomy. Our results suggest that focused-ultrasound lesioning of the Vim thalamus does not degrade proprioception but alters limb preference. This change may indicate a required "relearning" in the treated limb, because the effect is transient. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High-resolution virtual brain modeling personalizes deep brain stimulation for treatment-resistant depression: Spatiotemporal response characteristics following stimulation of neural fiber pathways.

Over the past 15 years, deep brain stimulation (DBS) has been actively investigated as a groundbreaking therapy for patients with treatment-resistant depression (TRD); nevertheless, outcomes have varied from patient to patient, with an average response rate of ∼50%. The engagement of specific fiber tracts at the stimulation site has been hypothesized to be an important factor in determining outcomes, however, the resulting individual network effects at the whole-brain scale remain largely unknown. Here we provide a computational framework that can explore each individual's brain response characteristics elicited by selective stimulation of fiber tracts. We use a novel personalized in-silico approach, the Virtual Big Brain, which makes use of high-resolution virtual brain models at a mm-scale and explicitly reconstructs more than 100,000 fiber tracts for each individual. Each fiber tract is active and can be selectively stimulated. Simulation results demonstrate distinct stimulus-induced event-related potentials as a function of stimulation location, parametrized by the contact positions of the electrodes implanted in each patient, even though validation against empirical patient data reveals some limitations (i.e., the need for individual parameter adjustment, and differential accuracy across stimulation locations). This study provides evidence for the capacity of personalized high-resolution virtual brain models to investigate individual network effects in DBS for patients with TRD and opens up novel avenues in the personalized optimization of brain stimulation.

Personality changes with subcallosal cingulate deep brain stimulation in patients with treatment-resistant depression.

BACKGROUND: Deep brain stimulation (DBS) is a promising investigational approach for treatment-resistant depression. However, reports suggesting changes in personality with DBS for movement disorders have raised clinical and ethical concerns. We prospectively examined changes in personality dimensions and antidepressant response to subcallosal cingulate (SCC)-DBS for treatment-resistant depression. METHODS: Twenty-two patients with treatment-resistant depression underwent SCC-DBS. We used the NEO Five-Factor Inventory for personality assessment at baseline and every 3 months until 15 months post-DBS. We assessed depression severity monthly using the Hamilton Depression Rating Scale. RESULTS: We found a significant decrease in neuroticism (p = 0.002) and an increase in extraversion (p = 0.001) over time, showing a change toward normative data. Improvement on the Hamilton Depression Rating Scale was correlated with decreases in neuroticism at 6 months (p = 0.001) and 12 months (p < 0.001), and with an increase in extraversion at 12 months (p = 0.01). Changes on the Hamilton Depression Rating Scale over time had a significant covariate effect on neuroticism (p < 0.001) and extraversion (p = 0.001). Baseline openness and agreeableness predicted response to DBS at 6 (p = 0.006) and 12 months (p = 0.004), respectively. LIMITATIONS: Limitations included a small sample size, a lack of sham control and the use of subjective personality evaluation. CONCLUSION: We observed positive personality changes following SCC-DBS, with reduced neuroticism and increased extraversion related to clinical improvement in depression, suggesting a state effect. As well, pretreatment levels of openness and agreeableness may have predicted subsequent response to DBS. The NEO Five-Factor Inventory assessment may have a role in clinical decision-making and prognostic evaluation in patients with treatment-resistant depression who undergo SCC-DBS.

Case studies in neuroscience: deep brain stimulation changes upper limb cortical motor maps in dystonia.

Deep brain stimulation of the globus pallidus pars interna (GPi-DBS) is an effective treatment for primary dystonia; however, its therapeutic mechanism is poorly understood. Because improvement is gradual, GPi-DBS treatment likely involves short- and long-term mechanisms. Abnormal plasticity resulting in somatotopic reorganization is involved in the development of dystonia and has been proposed as a possible mechanism for this gradual improvement, yet it has not been directly investigated. We hypothesized that GPi-DBS will lead to progressive changes in the cortical representations (motor maps) of upper limb muscles. Neuronavigated robotic transcranial magnetic stimulation was used to map the cortical representation of five upper limb muscles in six healthy controls and a 45-yr-old female cervical dystonia patient before (Pre) and at four time points (Post5 to Post314), 5 to 314 days after GPi-DBS. Motor map area and volume decreased in all muscles following GPi-DBS, while changes in overlap and center of gravity distance between muscles were variable. Despite these motor map changes, only dystonic tremor improved after a year of DBS; neck position worsened slightly. These preliminary findings suggest that GPi-DBS may reduce the cortical representation and excitability of upper limb muscles in dystonia and that these changes can occur without clinical improvement.NEW & NOTEWORTHY Neuronavigated robotic transcranial magnetic stimulation was used to investigate changes in upper limb muscle representation in a cervical dystonia patient before and at four time points up to 314 days after globus pallidus pars interna deep brain stimulation (GPi-DBS). GPi-DBS altered excitability and motor cortical representation of upper limb muscles; however, these changes were not associated with clinical improvement.

Long-Lasting Electrophysiological After-Effects of High-Frequency Stimulation in the Globus Pallidus: Human and Rodent Slice Studies.

Deep-brain stimulation (DBS) of the globus pallidus pars interna (GPi) is a highly effective therapy for movement disorders, yet its mechanism of action remains controversial. Inhibition of local neurons because of release of GABA from afferents to the GPi is a proposed mechanism in patients. Yet, high-frequency stimulation (HFS) produces prolonged membrane depolarization mediated by cholinergic neurotransmission in endopeduncular nucleus (EP, GPi equivalent in rodent) neurons. We applied HFS while recording neuronal firing from an adjacent electrode during microelectrode mapping of GPi in awake patients (both male and female) with Parkinson disease (PD) and dystonia. Aside from after-suppression and no change in neuronal firing, high-frequency microstimulation induced after-facilitation in 38% (26/69) of GPi neurons. In neurons displaying after-facilitation, 10 s HFS led to an immediate decrease of bursting in PD, but not dystonia patients. Moreover, the changes of bursting patterns in neurons with after-suppression or no change after HFS, were similar in both patient groups. To explore the mechanisms responsible, we applied HFS in EP brain slices from rats of either sex. As in humans, HFS in EP induced two subtypes of after-excitation: excitation or excitation with late inhibition. Pharmacological experiments determined that the excitation subtype, induced by lower charge density, was dependent on glutamatergic transmission. HFS with higher charge density induced excitation with late inhibition, which involved cholinergic modulation. Therefore HFS with different charge density may affect the local neurons through multiple synaptic mechanisms. The cholinergic system plays a role in mediating the after-facilitatory effects in GPi neurons, and because of their modulatory nature, may provide a basis for both the immediate and delayed effects of GPi-DBS. We propose a new model to explain the mechanisms of DBS in GPi.SIGNIFICANCE STATEMENT Deep-brain stimulation (DBS) in the globus pallidus pars interna (GPi) improves Parkinson disease (PD) and dystonia, yet its mechanisms in GPi remain controversial. Inhibition has been previously described and thought to indicate activation of GABAergic synaptic terminals, which dominate in GPi. Here we report that 10 s high-frequency microstimulation induced after-facilitation of neural firing in a substantial proportion of GPi neurons in humans. The neurons with after-facilitation, also immediately reduced their bursting activities after high-frequency stimulation in PD, but not dystonia patients. Based on these data and further animal experiments, a mechanistic hypothesis involving glutamatergic, GABAergic, and cholinergic synaptic transmission is proposed to explain both short- and longer-term therapeutic effects of DBS in GPi.

Both 50 and 30 Hz continuous theta burst transcranial magnetic stimulation depresses the cerebellum.

The cerebellum is implicated in the pathophysiology of numerous movement disorders, which makes it an attractive target for noninvasive neurostimulation. Continuous theta burst stimulation (cTBS) can induce long lasting plastic changes in human brain; however, the efficacy of different simulation protocols has not been investigated at the cerebellum. Here, we compare a traditional 50-Hz and a modified 30-Hz cTBS protocols at modulating cerebellar activity in healthy subjects. Seventeen healthy adults participated in two testing sessions where they received either 50-Hz (cTBS50) or 30-Hz (cTBS30) cerebellar cTBS. Cerebellar brain inhibition (CBI), a measure of cerebello-thalamocortical pathway strength, and motor evoked potentials (MEP) were measured in the dominant first dorsal interosseous muscle before and after (up to ~ 40 min) cerebellar cTBS. Both cTBS protocols induced cerebellar depression, indicated by significant reductions in CBI (P < 0.001). No differences were found between protocols (cTBS50 and cTBS30) at any time point (P = 0.983). MEP amplitudes were not significantly different following either cTBS protocol (P = 0.130). The findings show cerebellar excitability to be equally depressed by 50-Hz and 30-Hz cTBS in heathy adults and support future work to explore the efficacy of different cerebellar cTBS protocols in movement disorder patients where cerebellar depression could provide therapeutic benefits.

Clinical Perspectives on Psychiatric Neurosurgery.

INTRODUCTION: Surgical interventions such as stereotactic radiosurgery and magnetic resonance-guided focused ultrasound, and neuromodulatory interventions such as deep brain stimulation (DBS) and vagal nerve stimulation, are under investigation to remediate psychiatric conditions resistant to conventional therapies involving drugs and psychological supports. OBJECTIVE: Given the complicated history of psychiatric neurosurgery and its renaissance today, we sought to examine current perceptions and predictions about the field among practicing functional neurosurgeons. METHODS: We designed a 51-question online survey comprising Likert-type, multiple-choice, and rank-order questions and distributed it to members of the American Society for Stereotactic and Functional Neurosurgery (ASSFN). Descriptive and inferential statistical analyses were performed on the data. RESULTS: We received 38 completed surveys. Half (n = 19) of responders reported devoting at least a portion of their clinical practice to psychiatric neurosurgery, utilizing DBS and treating obsessive compulsive disorder (OCD) most frequently overall. Respondents indicated that psychiatric neurosurgery is more medically effective (OR 0, p = 0.03242, two-sided Fisher's exact test) and has clearer clinical indications for the treatment of OCD than for the treatment of depression (OR 0.09775, p = 0.005137, two-sided Fisher's exact test). Seventy-one percent of all respondents (n = 27) supported the clinical utility of ablative surgery in modern neuropsychiatric practice, 87% (n = 33) agreed that ablative procedures constitute a valid treatment alternative to DBS for some patients, and 61% (n = 23) agreed that ablative surgery may be an acceptable treatment option for patients who are unlikely to comply with postoperative care. CONCLUSIONS: This up-to-date account of practices, perceptions, and predictions about psychiatric neurosurgery contributes to the knowledge about evolving attitudes over time and informs priorities for education and further surgical innovation on the psychiatric neurosurgery landscape.