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Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by exposure to dopamine-receptor blockers. Data on TD burden in Israel are scarce. This analysis assesses the clinical and economic burden of TD in Israeli patients.This retrospective analysis used a national health plan database (Maccabi Healthcare Services), representing 25% of the Israeli population. The study included adults alive at index date with an International Classification of Diseases, Ninth Revision, Clinical Modification TD diagnosis before 2018 and more than or equal to 1-year enrollment before diagnosis. Tardive dyskinesia patients were matched to non-TD patients (1:3) by underlying psychiatric condition, birth year, and sex. Treatment patterns and 2018 annual health care resource utilization and costs were assessed.Of 454 TD patients alive between 2013 and 2018, 333 alive on January 1, 2018, were matched to 999 non-TD patients. At baseline, TD patients had lower socioeconomic status and higher proportion of chronic kidney disease and antipsychotic medication use; all analyses were adjusted accordingly. Tardive dyskinesia patients had significantly more visits to general physicians, neurologists, psychiatrists, physiotherapists, and emergency departments versus non-TD patients (all P0.05). Tardive dyskinesia patients also had significantly longer hospital stays than non-TD patients ( P = 0.003). Total healthcare and medication costs per patient were significantly higher in the TD versus non-TD population (US $11,079 vs US $7145, P = 0.018).Israeli TD patients have higher clinical and economic burden than non-TD patients. Understanding real-world health care resource utilization and costs allows clinicians and decision makers to quantify TD burden and prioritize resources for TD patients' treatment.

We propose extrapolating Conviction Narrative Theory (CNT) to clinical psychology and psychiatry. We demonstrate how CNT principles may benefit assessment, therapy, and possibly even modify public health views of neuropsychiatric disorders. Our commentary focuses on hoarding disorder as a model, elaborates on discrepancies in the scientific literature and suggests how the CNT may resolve them.

Background Psychogenic nonepileptic seizures (PNES) represent one of the most sizable treatment challenges in neuropsychiatry. Although the underlying mechanism is far from being understood, several interventions have been suggested. However, patients with comorbid psychiatric diagnoses and epilepsy are excluded from most intervention studies. Objective To To present a within-group posttreatment vs pretreatment study representing the retrospective clinical results of an integrative psychotherapy model. Methods: We present the clinical results of 22 patients with PNES diagnosed in an epilepsy center and treated in our neuropsychiatry clinic using an integrative rehabilitative psychotherapy. Therapy included presenting the diagnosis, psychoeducation, seizure reduction behavioral techniques, and coping with past and present stressors. Insomuch as integrative biopsychosocial psychotherapy is based on an individualized treatment protocol for each patient, treatment was individualized and case specific. Results By the end of treatment, 36% of patients had become seizure free and a further 54% achieved a major seizure reduction (reduction of more than 70%). Seventy-two percent of patients kept at least 70% seizure reduction at follow-up. Global Assessment of Functioning scores improved from a mean of 43.09 to a mean of 72.81 at the end of treatment and 69.72 at follow-up. In addition, we present 3 case descriptions that emphasize the individualized nature of psychotherapeutic decisions. Conclusions Our results support the feasibility and effectiveness of biopsychosocial based integrative psychotherapy for PNES and set principles for future treatment and prospective clinical trials in the field of individualized psychotherapy.

Βeta oscillatory activity (human: 13–35 Hz; primate: 8–24 Hz) is pervasive within the cortex and basal ganglia. Studies in Parkinson’s disease patients and animal models suggest that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine tone remains unclear. We recorded neural activity in the cortex and basal ganglia of healthy non-human primates while acutely and chronically up- and down-modulating dopamine levels. We assessed changes in beta oscillations in patients with Parkinson’s following acute and chronic changes in dopamine tone. Here we show beta oscillation frequency is strongly coupled with dopamine tone in both monkeys and humans. Power, coherence between single-units and local field potentials (LFP), spike-LFP phase-locking, and phase-amplitude coupling are not systematically regulated by dopamine levels. These results demonstrate that beta frequency is a key property of pathological oscillations in cortical and basal ganglia networks., Dopamine tone modulation generates changes in beta oscillation physiology. Here the authors show beta frequency, and not power, coherence, phase-locking, or PAC is monotonically linked to dopamine tone and is likely the key property of pathological oscillations in cortical and basal ganglia networks.

Psychogenic nonepileptic seizures (PNES) are of the most elusive phenomena in epileptology. Patients with PNES present episodes resembling epileptic seizures in their semiology yet lacking the underlying epileptic brain activity. These episodes are assumed to be related to psychological distress from past trauma, yet the underlying mechanism of this manifestation is still unknown. Using resting-state functional magnetic resonance imaging (fMRI), we investigated functional connectivity changes within and between large-scale brain networks in 9 patients with PNES, compared with a group of 13 age- and gender-matched healthy controls. Functional magnetic resonance imaging analyses identified functional connectivity disturbances between the medial temporal lobe (MTL) and the sensorimotor cortex and between the MTL and ventral attention networks in patients with PNES. Within network connectivity reduction was found within the visual network. Our findings suggest that PNES relate to changes in connectivity in between areas that are involved in memory processing and motor activity and attention control. These results may shed new light on the way by which traumatic memories may relate to PNES.

Beta oscillatory activity (13-30Hz) is pervasive within the cortico-basal ganglia (CBG) network. Studies in Parkinson’s disease (PD) patients and animal models suggested that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine-tone remains unclear. We recorded neural activity in the CBG network of non-human-primates (NHP) while acutely up- and down-modulating dopamine levels. Further, we assessed changes in beta oscillations of PD patients following acute and chronic changes in dopamine-tone. Beta oscillation frequency was strongly coupled with dopamine-tone in both NHPs and human patients. In contrast, power, coherence between single-units and LFP, and spike-LFP phase-locking were not systematically regulated by dopamine levels. These results demonstrate via causal manipulations that frequency, rather than other properties, is the key property of pathological oscillations in the CBG networks. These insights can lead to improvements in understanding of CBG physiology, PD progression tracking and patient care.

Background The hours immediately following a traumatic event may present a window of opportunity to interrupt the consolidation of memories of the traumatic event, and this may prevent PTSD development. This theory has been validated in a series of analogue studies, showing that a visuo-spatial task reduces intrusive memories, however clinical studies are scarce. Objective This pilot RCT examined the use of a semi-immersive Virtual Reality visuospatial task, as an intervention to interrupt memory consolidation, in the Emergency Department (ED) in the immediate hours following a traumatic event. We hypothesised that participants who had received the intervention would present with lower levels of PTSD symptoms than the control group who received no intervention. Method Seventy-seven adult survivors of traumatic events, meeting study criteria, were recruited in the ED of a Level III Trauma Centre. Survivors arrived at the ED less than one hour, on average, after the trauma. After signing informed consent, participants were randomized to the SnowWorld intervention or control group. Both groups completed self-report questionnaires, and the intervention group used SnowWorld for up to 10 minutes. Results No significant differences between the intervention and control groups were found regarding PTSD symptom levels two weeks and six months following the traumatic event. Conclusions These results add to the growing literature examining the use of a concurrent task to reduce intrusions following a traumatic event. In contrast to previous clinical studies, this study did not show significant group differences; however, it replicates an analogue study that used a specifically developed app. Further studies are needed to elucidate possible reasons for these conflicting results.

Tremor is a core feature of Parkinson’s disease and the most easily recognized Parkinsonian sign. Nonetheless, its pathophysiology remains poorly understood. Here, we show that multispectral spiking activity in the posterior-dorso-lateral oscillatory (motor) region of the subthalamic nucleus distinguishes resting tremor from the other Parkinsonian motor signs and strongly correlates with its severity. We evaluated microelectrode-spiking activity from the subthalamic dorsolateral oscillatory region of 70 Parkinson’s disease patients who underwent deep brain stimulation surgery (114 subthalamic nuclei, 166 electrode trajectories). We then investigated the relationship between patients’ clinical Unified Parkinson’s Disease Rating Scale score and their peak theta (4–7 Hz) and beta (13–30 Hz) powers. We found a positive correlation between resting tremor and theta activity (r = 0.41, P, We found Parkinson’s disease resting tremor to be strongly correlated with subthalamic theta–beta activity scale. Furthermore, theta–beta coactivity was found to be negatively correlated with this symptom. Thus, our results show that resting tremor worsens as subthalamic theta activity increases and beta decreases., Graphical Abstract Graphical Abstract

Background A wide variety of conversion factors for a levodopa-equivalent-dose (LED) have been proposed for each Parkinson's disease (PD) medication. The currently-used set of conversion factors is based on studies that relied on subjective experience or theoretical assumptions. This set was never validated in patients receiving polytherapy. Objectives To use real-life data to identify an optimal set of conversion factors independent of prior assumptions regarding clinical efficacy of different medications. Methods Retrospective analysis of data from 206 cognitively-preserved patients with advanced PD receiving polytherapy before deep brain stimulation (DBS) surgery. A nonlinear automated problem solver was used to find a set of conversion factors that, when applied, minimized the coefficient of variation of LEDs in a relatively homogenous cohort of patients. Results Independent and model-free evaluation of a wide range of possible sets of conversion factors to LED suggested a set of normalized conversion factors for immediate release levodopa (1.00), controlled release levodopa (0.88), and amantadine (1.23). A minimal clinical benefit of entacapone was observed for patients with motor fluctuations. Our analysis could not detect conversion factors for dopamine agonists and MAO-B inhibitors, possibly because their clinical contribution when added to levodopa is limited. Conclusions Independent from previous studies and prior assumptions we show that the currently-used LED conversion factors for immediate release levodopa, controlled release levodopa and amantadine are largely correct and that dopamine agonists, MAO-B inhibitors and entacapone, given in addition to levodopa, have little additional clinical value for PD patients with motor fluctuations.

Objective Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) in patients with Parkinson's disease and dystonia improves motor symptoms and quality of life. Traditionally, pallidal borders have been demarcated by electrophysiological microelectrode recordings (MERs) during DBS surgery. However, detection of pallidal borders can be challenging due to the variability of the firing characteristics of neurons encountered along the trajectory. MER can also be time-consuming and therefore costly. Here we show the feasibility of real-time machine learning classification of striato-pallidal borders to assist neurosurgeons during DBS surgery. Approach An electrophysiological dataset from 116 trajectories of 42 patients consisting of 11 774 MER segments of background spiking activity in five classes of disease was used to train the classification algorithm. The five classes included awake Parkinson's disease patients, as well as awake and lightly anesthetized genetic and non-genetic dystonia patients. A machine learning algorithm was designed to provide prediction of the striato-pallidal borders, based on hidden Markov models (HMMs) and the L1-distance measure in normalized root mean square (NRMS) and power spectra of the MER. We tested its performance prospectively against the judgment of three electrophysiologists in the operating rooms of three hospitals using newly collected data. Main results The awake and the light anesthesia dystonia classes could be merged. Using MER NRMS and spectra, the machine learning algorithm was on par with the performance of the three electrophysiologists across the striatum-GPe, GPe-GPi, and GPi-exit transitions for all disease classes. Significance Machine learning algorithms enable real-time GPi navigation systems to potentially shorten the duration of electrophysiological mapping of pallidal borders, while ensuring correct pallidal border detection.

Older adults have poor recognition of isolated facial expressions, yet outside the lab, such faces are typically perceived with contextual expressive bodies. In fact, recent work suggests that real-life facial expressions may be ambiguous while contextual information such as body language may be more diagnostic for decoding emotions. We examined the recognition of emotion from incongruent face-body composites and found that compared to young adults, older adults gave the body far more weight when recognizing emotion. These results are consistent with a social-expertise view and suggest that in real-life, older adults may employ an advantageous holistic approach to emotion perception. (PsycINFO Database Record

Obsessive-compulsive disorder (OCD) is a common and serious psychiatric disorder. Although subthalamic nucleus deep brain stimulation (DBS) has been studied as a treatment for OCD patients the underlying mechanism of this treatment and the optimal method of stimulation are unknown. To study the neural basis of subthalamic nucleus DBS in OCD patients we used a novel, implantable DBS system with long-term local field potential sensing capability. We focus our analysis on two patients with OCD who experienced severe treatment-resistant symptoms and were implanted with subthalamic nucleus DBS systems. We studied them for a year at rest and during provocation of OCD symptoms (46 recording sessions) and compared them to four Parkinson’s disease (PD) patients implanted with subthalamic nucleus DBS systems (69 recording sessions). We show that the dorsal (motor) area of the subthalamic nucleus in OCD patients displays a beta (25–35 Hz) oscillatory activity similar to PD patients whereas the ventral (limbic-cognitive) area of the subthalamic nucleus displays distinct theta (6.5–8 Hz) oscillatory activity only in OCD patients. The subthalamic nucleus theta oscillatory activity decreases with provocation of OCD symptoms and is inversely correlated with symptoms severity over time. We conclude that beta oscillations at the dorsal subthalamic nucleus in OCD patients challenge their pathophysiologic association with movement disorders. Furthermore, theta oscillations at the ventral subthalamic nucleus in OCD patients suggest a new physiological target for OCD therapy as well as a promising input signal for future emotional-cognitive closed-loop DBS.

Objective Adaptive deep-brain stimulation (aDBS) based on subthalamic nucleus (STN) electrophysiology has recently been proposed to improve clinical outcomes of DBS for Parkinson's disease (PD) patients. Many current models for aDBS are based on one or two electrophysiological features of STN activity, such as beta or gamma activity. Although these models have shown interesting results, we hypothesized that an aDBS model that includes many STN activity parameters will yield better clinical results. The objective of this study was to investigate the most appropriate STN neurophysiological biomarkers, detectable over long periods of time, that can predict OFF and ON levodopa states in PD patients. Approach Long-term local field potentials (LFPs) were recorded from eight STNs (four PD patients) during 92 recording sessions (44 OFF and 48 ON levodopa states), over a period of 3-12 months. Electrophysiological analysis included the power of frequency bands, band power ratio and burst features. A total of 140 engineered features was extracted for 20,040 epochs (each epoch lasting 5 seconds). Based on these engineered features, machine-learning models classified LFPs as OFF vs ON levodopa states. Main results Beta and gamma band activity alone poorly predicts OFF vs ON levodopa states, with an accuracy of 0.66 and 0.64, respectively. Group machine-learning analysis slightly improved prediction rates, but personalized machine-learning analysis, based on individualized engineered electrophysiological features, were markedly better, predicting OFF vs ON levodopa states with an accuracy of 0.8 for support vector machine learning models. Significance We showed that individual patients have unique sets of STN neurophysiological biomarkers that can be detected over long periods of time. Machine-learning models revealed that personally classified engineered features most accurately predict OFF vs ON levodopa states. Future development of aDBS for PD patients might include personalized machine-learning algorithms. Clinical trials: This study was supervised and authorized by the Ethics Committees of the IRB of the Hadassah Medical Center (no.0403-13-HMO) and the Israel Ministry of Health (no.HT6752), and it received clinical trials registration (no. NCT01962194).

This study is the first to show spontaneous gamma oscillations under NMDA antagonist in nonhuman primates. These oscillations appear in synchrony in the cortex and the basal ganglia. Phase analysis refutes the confounding effects of volume conduction and supports the funneling and amplifying architecture of the cortico-basal ganglia loops. These results suggest an abnormal network phenomenon with a unique spectral signature that could account for pathological mental and neurological states.

Subthalamic nucleus field potentials have attracted growing research and clinical interest over the last few decades. However, it is unclear whether subthalamic field potentials represent locally generated neuronal subthreshold activity or volume conductance of the organized neuronal activity generated in the cortex. This study aimed at understanding of the physiological origin of subthalamic field potentials and determining the most accurate method for recording them. We compared different methods of recordings in the human subthalamic nucleus: spikes (300–9,000 Hz) and field potentials (3–100 Hz) recorded by monopolar micro- and macroelectrodes, as well as by differential-bipolar macroelectrodes. The recordings were done outside and inside the subthalamic nucleus during electrophysiological navigation for deep brain stimulation procedures (150 electrode trajectories) in 41 Parkinson’s disease patients. We modeled the signal and estimated the contribution of nearby/independent vs. remote/common activity in each recording configuration and area. Monopolar micro- and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity. However, bipolar macroelectrode recordings inside the subthalamic nucleus can detect locally generated potentials. These results are confirmed by high correspondence between the model predictions and actual correlation of neuronal activity recorded by electrode pairs. Differential bipolar macroelectrode subthalamic field potentials can overcome volume conductance effects and reflect locally generated neuronal activity. Bipolar macroelectrode local field potential recordings might be used as a biological marker of normal and pathological brain functions for future electrophysiological studies and navigation systems as well as for closed-loop deep brain stimulation paradigms. NEW & NOTEWORTHY Our results integrate a new method for human subthalamic recordings with a development of an advanced mathematical model. We found that while monopolar microelectrode and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity, bipolar macroelectrode recordings inside the subthalamic nucleus (STN) detect locally generated potentials that are significantly different than those recorded outside the STN. Differential bipolar subthalamic field potentials can be used in navigation and closed-loop deep brain stimulation paradigms.

BACKGROUND Microelectrode recordings along preplanned trajectories are often used for accurate definition of the subthalamic nucleus (STN) borders during deep brain stimulation (DBS) surgery for Parkinson's disease. Usually, the demarcation of the STN borders is performed manually by a neurophysiologist. The exact detection of the borders is difficult, especially detecting the transition between the STN and the substantia nigra pars reticulata. Consequently, demarcation may be inaccurate, leading to suboptimal location of the DBS lead and inadequate clinical outcomes. METHODS We present machine-learning classification procedures that use microelectrode recording power spectra and allow for real-time, high-accuracy discrimination between the STN and substantia nigra pars reticulata. RESULTS A support vector machine procedure was tested on microelectrode recordings from 58 trajectories that included both STN and substantia nigra pars reticulata that achieved a 97.6% consistency with human expert classification (evaluated by 10-fold cross-validation). We used the same data set as a training set to find the optimal parameters for a hidden Markov model using both microelectrode recording features and trajectory history to enable real-time classification of the ventral STN border (STN exit). Seventy-three additional trajectories were used to test the reliability of the learned statistical model in identifying the exit from the STN. The hidden Markov model procedure identified the STN exit with an error of 0.04 ± 0.18 mm and detection reliability (error

The subthalamic nucleus (STN), a preferred target for treating movement disorders, has a crucial role in inhibition and execution of movement. To better understand the mechanism of movement regulation in the STN of Parkinson's disease patients, we compared the same movement with different context, facilitation vs. inhibition context. We recorded subthalamic multiunit activity intra-operatively while parkinsonian patients (off medications, n = 43 patients, 173 recording sites) performed increasingly complex oddball paradigms with frequent and deviant tones: first, passive listening to tone series with no movement (‘None-Go’ task, n = 7, 28 recording sites); second, pressing a button after every tone (‘All-Go’ task, n = 7, 26 recording sites); and third, pressing a button only for frequent tones, thus adding inhibition of movement following deviant tones (‘Go-NoGo’ task, n = 29, 119 recording sites). The STN responded mainly to movement-involving tasks. In the limbic-associative STN, evoked response to the deviant tone (inhibitory cue) was not significantly different between the Go-NoGo and the All-Go task. However, the evoked response to the frequent tone (go cue) in the Go-NoGo task was significantly reduced. The reduction was mainly prominent in the negative component of the evoked response amplitude aligned to the press. Successful movement inhibition was correlated with higher baseline activity. We suggest that the STN in Parkinson's disease patients adapts to movement inhibition context by selectively decreasing the amplitude of neuronal activity. Thus, the STN enables movement inhibition not by increasing responses to the inhibitory cue but by reducing responses to the release cue. The negative component of the evoked response probably facilitates movement and a higher baseline activity enables successful inhibition of movement. These discharge modulations were found in the ventromedial, non-motor domain of the STN and therefore suggest a significant role of the limbic- associative STN domains in movement planning and in global movement regulation.

Treatment-resistant obsessive-compulsive disorder (OCD) is considered a severe psychiatric disorder that causes severe functional decline. In the past, these patients were treated by selective ablation of neuronal pathways related to the pathophysiology of OCD. Deep brain stimulation is an effective and safe treatment alternative that enables reversible changes in neural circuits and reduces OCD symptoms. In this paper we present the outcome of a treatment-resistant OCD patient who underwent deep brain stimulation procedure for the first time in Israel. The patient has achieved a significant decline in OCD symptoms as well as improvement in personal and social functioning. The discussion focuses on methods to implement deep brain stimulation for OCD patients in Israel.

Background Therapeutic outcomes of STN-DBS for movement and psychiatric disorders depend on electrode location within the STN. Electrophysiological and functional mapping of the STN has progressed considerably in the past years, identifying beta-band oscillatory activity in the dorsal STN as a motor biomarker. It also has been suggested that STN theta-alpha oscillations, involved in impulse control and action inhibition, have a ventral source. However, STN local field potential mapping of motor, associative, and limbic areas is often limited by poor spatial resolution. Objectives Providing a high-resolution electrophysiological map of the motor, associative and limbic anatomical sub-areas of the subthalamic nucleus. Methods We have analyzed high-spatial-resolution STN microelectrode electrophysiology recordings of PD patients (n = 303) that underwent DBS surgery. The patients' STN intraoperative recordings of spiking activity (933 electrode trajectories) were combined with their imaging data (n = 83 patients, 151 trajectories). Results We found a high theta-alpha (7-10 Hz) oscillatory area, located near the STN ventromedial border in 29% of the PD patients. Theta-alpha activity in this area has higher power and lower central frequency in comparison to theta-alpha activity in more dorsal subthalamic areas. When projected on the DISTAL functional atlas, the theta-alpha oscillatory area overlaps with the STN limbic subarea. Conclusions We suggest that theta-alpha oscillations can serve as an electrophysiological marker for the ventral subthalamic nucleus limbic subarea. Therefore, theta-alpha oscillations can guide optimal electrode placement in neuropsychiatric STN-DBS procedures and provide a reliable biomarker input for future closed-loop DBS device. © 2019 International Parkinson and Movement Disorder Society.

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS. ispartof: Molecular Psychiatry vol:26 issue:4 pages:1-14 ispartof: location:England status: Published online

Optimal outcomes of deep brain stimulation (DBS) surgery are often an elusive goal. Constant “one-program” stimulation does not reflect the reality of changing clinical symptoms. Closed-loop technology might provide a solution. Closed-loop design will likely integrate multi-sourced sensing data, computed using information from a population database and individual hierarchical paradigms to continuously titrate parameters of stimulation. Proof of principle already exists for the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model and in human Parkinson’s disease (PD) patients. Many elements of such a feedback system have already been developed.

To better understand the mechanism of movement facilitation and inhibition in the subthalamic nucleus (STN), we recorded subthalamic multiunit activity intra-operatively while parkinsonian patients (n=43 patients, 173 sites) performed increasingly complex oddball paradigms: auditory (‘None-Go’, n=7, 28), simple movement (‘All-Go’, n=7, 26) and movement inhibition (‘Go-NoGo’, n=29, 119) tasks. To enable physiological sampling of the different subthalamic nucleus domains in both hemispheres, each patient performed one of the oddball paradigms several times.The human STN responded mainly to movement-involving tasks: movement execution at the motor STN and movement planning at the limbic-associative STN. In the limbic-associative STN, responses to the inhibitory cue (deviant tone) in the movement inhibition task were not significantly different from the simple movement task. However, responses to the go cue (frequent tone) were significantly reduced. The reduction was mainly in the negative component of the evoked response amplitude. Successful movement inhibition was correlated with higher baseline activity before the inhibitory cue.We suggest that the STN adapts to movement inhibition context by selectively decreasing the amplitude of neuronal activity. Thus, the STN enables movement inhibition not by increasing responses to the inhibitory cue but by reducing responses to the release cue. The negative component of the evoked response probably facilitates movement and a higher baseline activity enables successful inhibition of movement. These discharge modulations were found in the ventromedial, non-motor domain of the STN and therefore suggest a significant role of the associative-limbic domains in movement planning and in global movement regulation.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a proven and effective therapy for the management of the motor symptoms of Parkinson's disease (PD). While accurate positioning of the stimulating electrode is critical for success of this therapy, precise identification of the STN based on imaging can be challenging. We developed a method to accurately visualize the STN on a standard clinical magnetic resonance imaging (MRI). The method incorporates a database of 7-Tesla (T) MRIs of PD patients together with machine-learning methods (hereafter 7 T-ML). OBJECTIVE: To validate the clinical application accuracy of the 7 T-ML method by comparing it with identification of the STN based on intraoperative microelectrode recordings. METHODS: Sixteen PD patients who underwent microelectrode-recordings guided STN DBS were included in this study (30 implanted leads and electrode trajectories). The length of the STN along the electrode trajectory and the position of its contacts to dorsal, inside, or ventral to the STN were compared using microelectrode-recordings and the 7 T-ML method computed based on the patient's clinical 3T MRI. RESULTS: All 30 electrode trajectories that intersected the STN based on microelectrode-recordings, also intersected it when visualized with the 7 T-ML method. STN trajectory average length was 6.2 ± 0.7 mm based on microelectrode recordings and 5.8 ± 0.9 mm for the 7 T-ML method. We observed a 93% agreement regarding contact location between the microelectrode-recordings and the 7 T-ML method. CONCLUSION: The 7 T-ML method is highly consistent with microelectrode-recordings data. This method provides a reliable and accurate patient-specific prediction for targeting the STN.

Subcallosal Brodmann's Area 25 (Cg25) Deep Brain Stimulation (DBS) is a new promising therapy for treatment resistant major depressive disorder (TR-MDD). While different DBS stimulating parameters may have an impact on the efficacy and safety of the therapy, there is no data to support a protocol for optimal stimulation parameters for depression. Here we present a prospective multi-center double-blind randomized crossed-over 13-month study that evaluated the effects of High (130 Hz) vs Low (20 Hz) frequency Cg25 stimulation for nine patients with TR-MDD. Four out of nine patients achieved response criteria (≥40% reduction of symptom score) compared to mean baseline values at the end of the study. The mean percent change of MADRS score showed a similar improvement in the high and low frequency stimulation groups after 6 months of stimulation (−15.4 ± 21.1 and −14.7 ± 21.1 respectively). The mean effect at the end of the second period (6 months after cross-over) was higher than the first period (first 6 months of stimulation) in all patients (−23.4 ± 19.9 (n = 6 periods) and −13.0 ± 22 (n = 9 periods) respectively). At the end of the second period, the mean percent change of the MADRS scores improved more in the high than low frequency groups (−31.3 ± 19.3 (n = 4 patients) and −7.7 ± 10.9 (n = 2 patients) respectively). Given the small numbers, detailed statistical analysis is challenging. Nonetheless the results of this study suggest that long term high frequency stimulation might confer the best results. Larger scale, randomized double blind trials are needed in order to evaluate the most effective stimulation parameters.

Objective The clinical outcome of patients with Parkinson disease (PD) who undergo subthalamic nucleus (STN) deep brain stimulation (DBS) is, in part, determined by the length of the electrode trajectory through the motor STN domain, the dorsolateral oscillatory region (DLOR). Trajectory length has been found to correlate with the stimulation-related improvement in patients' motor function (estimated by part III of the United Parkinson's Disease Rating Scale [UPDRS]). Therefore, it seems that ideally trajectories should have maximal DLOR length. Methods We retrospectively studied the influence of various anatomic aspects of the brains of patients with PD and the geometry of trajectories planned on the length of the DLOR and STN recorded during DBS surgery. We examined 212 trajectories and 424 microelectrode recording tracks in 115 patients operated on in our center between 2010 and 2015. Results We found a strong correlation between the length of the recorded DLOR and STN. Trajectories that were more lateral and/or posterior in orientation had a longer STN and DLOR pass, although the DLOR/STN fraction length remained constant. The STN target was more lateral when the third ventricle was wider, and the latter correlated with older age and male gender. Conclusions Trajectory angles correlate with the recorded STN and DLOR lengths, and should be altered toward a more posterolateral angle in older patients and atrophied brains to compensate for the changes in STN location and geometry. These fine adjustments should yield a longer motor domain pass, thereby improving the patient's predicted outcome.

Classical rate models of basal ganglia circuitry associate discharge rate of the globus pallidus external and internal segments (GPe, GPi respectively) solely with dopaminergic state and predict an inverse ratio between the discharge rates of the two pallidal segments. By contrast, the effects of other rate modulators such as general anesthesia (GA) on this ratio have been ignored. To respond to this need, we recorded the neuronal activity in the GPe and GPi in awake and anesthetized human patients with dystonia (57 and 53 trajectories respectively) and in awake patients with Parkinson's disease (PD, 16 trajectories) undergoing deep brain stimulation procedures. This triad enabled us to dissociate pallidal discharge ratio from general discharge modulation. An automatic offline spike detection and isolation quality system was used to select 1560 highly-isolated units for analysis. The mean discharge rate in the GPi of awake PD patients was dramatically higher than in awake dystonia patients although the firing rate in the GPe was similar. Firing rates in dystonic patients under anesthesia were lower in both nuclei. Surprisingly, in all three groups, GPe firing rates were correlated with firing rates in the ipsilateral GPi. Thus, the firing rate ratio of ipsilateral GPi/GPe pairs was similar in awake and anesthetized patients with dystonia and significantly higher in PD. We suggest that pallidal activity is modulated by at least two independent processes: dopaminergic state which changes the GPi/GPe firing rate ratio, and anesthesia which modulates firing rates in both pallidal nuclei without changing the ratio between their firing rates. This article is protected by copyright. All rights reserved.

Microelectrode recordings along preplanned trajectories are often used for accurate definition of the subthalamic nucleus (STN) borders during deep brain stimulation (DBS) surgery for Parkinson's disease. Usually, the demarcation of the STN borders is performed manually by a neurophysiologist. The exact detection of the borders is difficult, especially detecting the transition between the STN and the substantia nigra pars reticulata. Consequently, demarcation may be inaccurate, leading to suboptimal location of the DBS lead and inadequate clinical outcomes.We present machine-learning classification procedures that use microelectrode recording power spectra and allow for real-time, high-accuracy discrimination between the STN and substantia nigra pars reticulata.A support vector machine procedure was tested on microelectrode recordings from 58 trajectories that included both STN and substantia nigra pars reticulata that achieved a 97.6% consistency with human expert classification (evaluated by 10-fold cross-validation). We used the same data set as a training set to find the optimal parameters for a hidden Markov model using both microelectrode recording features and trajectory history to enable real-time classification of the ventral STN border (STN exit). Seventy-three additional trajectories were used to test the reliability of the learned statistical model in identifying the exit from the STN. The hidden Markov model procedure identified the STN exit with an error of 0.04 ± 0.18 mm and detection reliability (error 1 mm) of 94%.The results indicate that robust, accurate, and automatic real-time electrophysiological detection of the ventral STN border is feasible. © 2016 International Parkinson and Movement Disorder Society.

A high percentage of patients with Parkinson's disease suffer from depression in addition to their motor disabilities. However, the etiology of this depression and its relation to Parkinson's disease are unknown. Within the framework of the monoamine deficiency hypothesis of depression, we propose that the dopaminergic and serotonergic systems are coupled by the lateral habenula, and argue that altered basal ganglia activity leads to lateral habenula hyperactivity, which in turn down-regulates the serotonergic system, resulting in depressive symptoms in patients with Parkinson's disease. We tested this hypothesis using the unilateral 6-hydroxydopamine hemiparkinsonian rat model of Parkinson's disease. Behavior was assessed using the novelty suppressed feeding and forced swim tests, and the effective connectivity of the serotonergic system was estimated by manganese-enhanced magnetic resonance imaging of the raphe nuclei. The results show depression-like behaviors and reduced raphe connectivity with the lateral habenula, dentate gyrus of the hippocampus, thalamus and hypothalamus in the 6-hydroxydopamine rat groups. More importantly, partial restoration of the raphe connectivity and partial normalization of behavior were achieved by dopamine replacement therapy (apomorphine, 10 mg/kg, s.c. daily). Furthermore, nearly complete behavioral normalization was reached after a bilateral electric lesion of the lateral habenula. These findings provide a plausible link between Parkinson's disease and depression and open up avenues for new therapeutic interventions in depression and possibly in Parkinson's disease.

Although triiodothyronine (T3) is widely used clinically, preclinical support for its antidepressant-like effects is limited, and the mechanisms are unknown. We evaluated 1) the antidepressant-like effects of T3 in the novelty suppressed feeding test (NSFT), tail suspension test (TST), and forced swim test (FST), 2) the role of presynaptic 5-HT 1A receptors in the antidepressant-like mechanism of T3 by the hypothermic response to the 5-HT 1A receptor agonist, 8-hydroxy- N,N -dipropyl-2-aminotetralin (8-OH-DPAT), 3) the thyroid hormone receptor type mediating the antidepressant-like effects by concurrent administration of the specific thyroid hormone α receptor (TRα) antagonist, dronedarone, and 4) the presence of these effects in both genders. Male and female BALB/c mice were administered 1) T3 (20, 50, 200, or 500 μg/kg per day) or vehicle or 2) T3 (50 μg/kg per day), dronedarone (100 μM/day), or the combination intraperitoneally for 21 days and then underwent a behavioral test battery. The NSFT showed a shortened latency to feed in males at the two lower T3 doses. The TST and FST showed decreased immobility in male mice at T3 doses >20 μg/kg per day and in females at all T3 doses. Concurrent dronedarone prevented T3 effects in males on the NSFT and in the TST and FST in both genders. Attenuation of 8-OH-DPAT-induced hypothermia was observed in males only and may be reduced by concurrent dronedarone. These findings support an antidepressant-like effect of T3. Attenuation of 8-OH-DPAT-induced hypothermia in males only suggests the need to evaluate a possible gender disparity in the role of presynaptic 5-HT 1A receptors in T3 antidepressant mechanisms. Blockade by dronedarone of the antidepressant-like effects of T3 suggests that these effects are TRα receptor-mediated.

The thyroid hormone triiodothyronine (T3) may accelerate and augment the action of antidepressants. Antidepressants up-regulate neurogenesis in adult rodent hippocampus. We studied the effect of T3 and T3+fluoxetine in enhancement of hippocampal neurogenesis beyond that induced by fluoxetine alone and the correlation with antidepressant behaviour in the novelty suppressed feeding test (NSFT). Rats were administered fluoxetine (5 mg/kg.d), T3 (50 µg/kg.d), fluoxetine (5 mg/kg.d)+T3 (50 µg/kg.d) or saline, for 21 d. Neurogenesis was studied by doublecortin (DCX) immunohistochemistry in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). In the NSFT, latency to feeding in animals deprived of food was measured. Fluoxetine and fluoxetine+T3 increased the number of doublecortin-positive (DCX+) cells in the SGZ compared to saline ( p =0.00005, p =0.008, respectively). There was a trend towards an increased number of DCX+ cells by T3 compared to saline ( p =0.06). Combined treatment with fluoxetine+T3 further increased the number of DCX+ cells compared to T3 or fluoxetine alone ( p =0.001, p =0.014, respectively). There was no effect of any of the treatments on number of DCX+ cells in the SVZ. In the NSFT, all treatments (T3, fluoxetine+T3 and fluoxetine) reduced latency to feeding compared to saline ( p =0.0004, p =0.00001, p =0.00009, respectively). Fluoxetine+T3 further reduced latency to feeding compared to T3 alone ( p =0.05). The results suggest that enhancement of antidepressant action by T3 may be related to its effect of increasing hippocampal neurogenesis and that the antidepressant effect of these treatments is specific to the hippocampus and does not represent a general effect on cell proliferation.

Until recently, a review of nonpharmacological, somatic treatments of psychiatric disorders would have included only electroconvulsive therapy (ECT). This situation is now changing very substantially Although ECT remains the only modality in widespread clinical use, several new techniques are under investigation. Their principal indication in the psychiatric context is the treatment of major depression, but other applications are also being studied. All the novel treatments involve brain stimulation, which is achieved by different technological methods. The treatment closest to the threshold of clinical acceptability is transcranial magnetic stimulation (TMS). Although TMS is safe and relatively easy to administer, its efficacy has still to be definitively established. Other modalities, at various stages of research development, include magnetic seizure therapy (MST), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). We briefly review the development and technical aspects of these treatments, their potential role in the treatment of major depression, adverse effects, and putative mechanism of action. As the only one of these treatment modalities that is in widespread clinical use, more extended consideration is given to ECT. Although more than half a century has elapsed since ECT was first introduced, it remains the most effective treatment for major depression, with efficacy in patients refractory to antidepressant drugs and an acceptable safety profile. Although they hold considerable promise, the novel brain stimulation techniques reviewed here will be need to be further developed before they achieve clinical acceptability.