Unmet Needs of Women Living with Parkinson's Disease: Gaps and Controversies.

Personalized medicine considering sex, gender, and cultural context has become the vanguard of delivery of care. However, women's issues in Parkinson disease (PD), especially from a psychosocial standpoint, have been an overlooked field. The key research areas include women-inclusive drug and device studies and genetic and hormonal considerations. Moreover, women with PD need to be educated and empowered on how to communicate their symptoms and needs, get engaged in research, get organized as a community, and support one another. Women with PD need tools to help track and convey their unique motor and nonmotor symptoms and psychological and social support needs. The management of PD needs to be customized to include the unique stages of women's lives, including menstrual cycles, pregnancy, perimenopause, menopause, and postmenopause. Specific guidelines for the use of hormonal treatments and customized dopamine replacement dosing need to be developed. Women need guidance on culturally sensitive wellness and self-care strategies that are customized for them. Basic core competencies in knowledge for all clinicians treating women with PD need to be established, including how to accurately diagnose, proactively identify, and treat the symptoms of PD in women and to ensure timely referral for specialty care, advanced therapies, and research studies. Caregivers and families need guidance on holistically supporting women with PD. The voices of women living with PD must be amplified to catalyze real change in this neglected field. This paper provides an overview of the current knowledge, gaps, and possible strategies to deal with the unmet needs of women living with PD with a focus on the clinical and psychosocial aspects. © 2022 International Parkinson and Movement Disorder Society.

Deep brain stimulation: is it time to change gears by closing the loop?

Objective.Adaptive deep brain stimulation (aDBS) is a form of invasive stimulation that was conceived to overcome the technical limitations of traditional DBS, which delivers continuous stimulation of the target structure without considering patients' symptoms or status in real-time. Instead, aDBS delivers on-demand, contingency-based stimulation. So far, aDBS has been tested in several neurological conditions, and will be soon extensively studied to translate it into clinical practice. However, an exhaustive description of technical aspects is still missing.Approach.in this topical review, we summarize the knowledge about the current (and future) aDBS approach and control algorithms to deliver the stimulation, as reference for a deeper undestending of aDBS model.Main results.We discuss the conceptual and functional model of aDBS, which is based on the sensing module (that assesses the feedback variable), the control module (which interpretes the variable and elaborates the new stimulation parameters), and the stimulation module (that controls the delivery of stimulation), considering both the historical perspective and the state-of-the-art of available biomarkers.Significance.aDBS modulates neuronal circuits based on clinically relevant biofeedback signals in real-time. First developed in the mid-2000s, many groups have worked on improving closed-loop DBS technology. The field is now at a point in conducting large-scale randomized clinical trials to translate aDBS into clinical practice. As we move towards implanting brain-computer interfaces in patients, it will be important to understand the technical aspects of aDBS.

Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry.

Importance: Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome. Objective: To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome. Design, Setting, and Participants: The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide. Exposures: Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%]). Main Outcomes and Measures: Scores on the Yale Global Tic Severity Scale and adverse events. Results: The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P < .001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P < .001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P < .001). The overall adverse event rate was 35.4% (56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). Conclusions and Relevance: Deep brain stimulation was associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.

New targets for deep brain stimulation treatment of Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) has been shown to be an effective treatment for patients with Parkinson's disease. Strong clinical evidence supports the improvement of motor and non-motor complications and quality of life, with some data suggesting that GPi DBS might be less effective than STN DBS. However, neither STN nor GPi stimulation provides a satisfactory control of non-dopaminergic symptoms, such as gait and balance impairment and cognitive decline, which are frequent and disabling symptoms in advanced Parkinson's disease patients. Therefore, several efforts have been made to discover alternative and new targets to overcome these current DBS limitations. Among these new targets, the stimulation of the pedunculopontine nucleus has initially appeared encouraging. However, findings from different double-blind trials have mitigated the enthusiasm. A multi-target strategy aimed at improving symptoms with different pathogenetic mechanisms might be a promising approach in the next years.

Neuromodulation: a more comprehensive concept beyond deep brain stimulation.

As currently understood, neuromodulation comprises not only electrical and magnetic stimulation but also chemical and genetic manipulations. The fact that adverse events induced by some of these treatments are largely reversible has sparked great interest in the development of new applications and targets for neuromodulatory treatments. As the number of indications and studies increases, so does research in associated fields. This chapter provides a brief introduction and discusses the overall contents of this volume of the International Review of Neurobiology.

Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson's disease.

Epidural motor cortex stimulation has been reported to be effective in treating some movement disorders. Nevertheless, clinical results have been variable and no double-blinded evaluations have been reported. The aim of this study was to investigate efficacy and safety of unilateral subdural motor cortex stimulation in patients with essential tremor and Parkinson's disease. Six patients with essential tremor and five parkinsonian patients were selected. Craniotomy was performed under local anaesthesia with conscious sedation. A four contact electrode (Resume II model 3587, Medtronic, Inc) was positioned on the motor cortex, after identification of the area with direct monopolar cortical stimulation. Soon after surgery, a variety of different settings of stimulation were assessed using standard rating scales to select the optimal stimulation parameters. The effects of chronic stimulation were evaluated in both groups of patients after 3 months (double-blinded fashion) and 1 year (open fashion). In essential tremor, contralateral hand tremor scores significantly improved (P = 0.04) with stimulation during the double-blinded study, whereas in Parkinson's disease, there were no changes in the OFF medication/on stimulation motor scores compared with off stimulation. At 1 year, tremor was improved by stimulation in two out of three patients with essential tremor available at follow-up, whereas no improvement was observed in the five parkinsonian patients. One parkinsonian patient had a cortical venous infarct. Three other patients had self-limiting seizures with aggressive trials of stimulation in the period of dosage selection. These findings suggest that unilateral subdural motor cortex stimulation may be useful for contralateral hand tremor in selected patients with essential tremor but was not effective in improving parkinsonian signs in our series.

Gamma knife thalamotomy for disabling tremor: a blinded evaluation.

BACKGROUND: Gamma knife thalamotomy (GKT) has been used as a therapeutic option for patients with disabling tremor refractory to medications. Impressive improvement of tremor has been reported in the neurosurgical literature, but the reliability of such data has been questioned. OBJECTIVE: To prospectively evaluate clinical outcomes after GKT for disabling tremor with blinded assessments. DESIGN: Prospective study with blinded independent neurologic evaluations. SETTING: University hospital. PATIENTS: Consecutive patients who underwent unilateral GKT for essential tremor and Parkinson disease tremor at our center. These patients were unwilling or deemed unsuitable candidates for deep brain stimulation or other surgical procedures. INTERVENTIONS: Unilateral GKT and regular follow-up evaluations for up to 30 months, with blinded video evaluations by a movement disorders neurologist. MAIN OUTCOME MEASURES: Clinical outcomes, as measured by the Fahn-Tolosa-Marin Tremor Rating Scale and activities of daily living scores, and incidence of adverse events. RESULTS: From September 1, 2006, to November 30, 2008, 18 patients underwent unilateral GKT for essential tremor and Parkinson disease tremor at our center. Videos for 14 patients (11 with essential tremor, 3 with Parkinson disease tremor) with at least 6 months' postoperative follow-up were available for analysis (mean [SD] follow-up duration, 19.2 [7.3] months; range, 7-30 months). The Fahn-Tolosa-Marin Tremor Rating Scale activities of daily living scores improved significantly after GKT (P = .03; median and mean change scores, 2.5 and 2.7 points, respectively [range of scale was 0-27]), but there was no significant improvement in other Fahn-Tolosa-Marin Tremor Rating Scale items (P = .53 for resting tremor, P = .24 for postural tremor, P = .62 for action tremor, P = .40 for drawing, P > .99 for pouring water, P = .89 for head tremor). Handwriting and Unified Parkinson's Disease Rating Scale activities of daily living scores tended to improve (P = .07 and .11, respectively). Three patients developed delayed neurologic adverse events. CONCLUSIONS: Overall, we found that GKT provided only modest antitremor efficacy. Of the 2 patients with essential tremor who experienced marked improvement in tremor, 1 subsequently experienced a serious adverse event. Further prospective studies with careful neurologic evaluation of outcomes are necessary before GKT can be recommended for disabling tremor on a routine clinical basis.

Pathological gambling in Parkinson's disease improves on chronic subthalamic nucleus stimulation.

Pathological gambling (PG) related to dopaminergic treatment in Parkinson's disease (PD) is part of a spectrum of behavioral disorders called the dopamine dysregulation syndrome (DDS). We describe a series of PD patients with preoperative active PG due to dopaminergic treatment from a total of 598 patients who have undergone surgery for subthalamic nucleus stimulation for disabling motor fluctuations. The patients had systematic open assessment of behavioral symptoms and standardized assessments of motor symptoms, mood, and apathy. Seven patients (6 men, 1 woman; age, 54 +/- 9 years; levodopa equivalent dose, 1,390 +/- 350 mg/day) had preoperative PG over a mean of 7 years, intolerant to reduction in medication. Six had nonmotor fluctuations and four had other behavioral symptoms consistent with a diagnosis of the DDS. After surgery, motor symptoms improved, allowing for 74% reduction of dopaminergic treatment, below the dosage of gambling onset. In all patients, PG resolved postoperatively after 18 months on average (range, 0-48), although transient worsening occurred in two. Improvement paralleled the time course and degree of reduction in dopaminergic treatment. Nonmotor fluctuations, off period dysphoria, and other symptoms of the DDS improved. Two patients developed persistent apathy. In conclusion, PG and other symptoms of the DDS-associated dopaminergic treatment improved in our patients following surgery. Dopaminergic dysregulation commonly attributed to pulsatile overstimulation of the limbic dopaminergic system may be subject to desensitization on chronic subthalamic stimulation, which has a relative motor selectivity and allows for decrease in dopaminergic treatment.

Basic algorithms for the programming of deep brain stimulation in Parkinson's disease.

The clinical success of deep brain stimulation (DBS) for treating Parkinson's disease (PD) critically depends on the quality of postoperative neurological management. Movement disorder specialists becoming involved with this therapy need to acquire new skills to adapt optimally stimulation parameters and medication after implantation of a DBS system. At first glance, the infinite number of theoretically possible parameter combinations seems to make programming a complex and time-consuming art. This article outlines a stepwise and standardized approach, reducing the possible parameter settings in DBS to a few relevant combinations. The basic programming algorithms for thalamic, subthalamic, and pallidal stimulation in PD are explained and summarized in flowcharts.

Psychiatric symptoms following surgery for Parkinson's disease with an emphasis on subthalamic stimulation.

Bilateral subthalamic stimulation is a very effective neurosurgical treatment for advanced Parkinson's disease. Despite the range and frequency of psychiatric symptoms occurring in the postoperative state, most of these symptoms are transient and manageable. In clinical practice, preoperative psychiatric vulnerability, as with that of preoperative cognitive status, takes on an important role. Psychiatric assessment and active preoperative and postoperative intervention can potentially modify psychiatric outcomes. These psychiatric and psychological issues will take on greater importance, particularly with the rapid expansion of the number of neurosurgical sites and the need for adequate assessment and optimal management of patients. The paucity of the literature underscores the need for well-designed studies on psychiatric issues investigating both pathophysiology and clinical outcomes.

Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.

Response to levodopa in parkinsonian patients with bilateral subthalamic nucleus stimulation.

The response to levodopa changes over time in Parkinson's disease, probably due to alterations in the dopaminergic system, progression of the disease and pulsatile oral intake of the drug. Bilateral high-frequency stimulation of the subthalamic nucleus (STN) allows a large reduction or the complete cessation of levodopa intake in patients with advanced Parkinson's disease. We studied variation in the motor short-duration response (SDR) during a levodopa challenge in bilaterally STN-stimulated patients. Twenty-eight consecutive patients with a mean duration of Parkinson's disease of 16.6 +/- 6.0 years at the time of surgery were enrolled. Fourteen patients were evaluated both before STN stimulation and 3 months after surgery (group 1) whereas the other 14 patients were assessed before implantation and after a mean of 3 years of STN stimulation (group 2). After drug withdrawal for one night, the hand-tapping test (TT) was carried out every 15 min, together with evaluation of dyskinesias using a modified Goetz scale. The Unified Parkinson's Disease Rating Scale (UPDRS) motor score was assessed every 30 min. In operated patients, STN stimulation was stopped 15 min before starting the clinical evaluations. A suprathreshold oral levodopa dose was given after one motor evaluation and two TTs. The clinical evaluation was carried out until the TT score returned to the baseline. In group 1, six patients continued without levodopa after surgery and the other eight received a daily mean dose of 337 mg; in group 2, seven patients continued without levodopa and the other seven received a daily mean dose of 386 mg. The main change in the levodopa SDR was a significant reduction in levodopa-induced dyskinesias in both groups. In those patients of group 1 who did not receive levodopa after surgery, the motor UPDRS magnitude decreased and the 'on' UPDRS motor score worsened. In group 2, the results were similar, but in the patients who continued to receive levodopa after surgery the TT magnitude increased. On the whole, chronic bilateral STN stimulation tended to decrease the magnitude of the levodopa SDR without changing the duration and latency of the response. These results suggest that continuous STN stimulation induces long-term plastic changes of the dopaminergic system, with slow and partial desensitization. In addition, the persistence of levodopa intake after surgery might hinder this beneficial process.

Treatment results: Parkinson's disease.

Deep brain stimulation (DBS) is a neurosurgical treatment of Parkinson's disease that is applied to three targets: the ventral intermediate nucleus of the thalamus (Vim), the globus pallidus internas (GPi) and the subthalamic nucleus (STN). Vim DBS mainly improves contralateral tremor and, therefore, is being supplanted by DBS of the two other targets, even in patients with tremor dominant disease. STN and GPi DBS improve off-motor phases and dyskinesias. There is little comparative data between these procedures. The magnitude of the motor improvement seems more constant with STN than GPi DBS. STN DBS allows a decrease in antiparkinsonian drug doses and consumes moderate current. These advantages of STN over GPi DBS are offset by the need for more intensive postoperative management. The DBS procedure has the unique advantage of reversibility and adjustability over time. Patients with young-onset Parkinson's disease suffering from levodopa-induced motor complications but still responding well to levodopa and who exhibit no behavioral, mood, or cognitive impairment benefit the most from STN DBS. Adverse effects more specific of the DBS procedure are infection, cutaneous erosion, and lead breaking or disconnection. Intracranial electrode implantation can induce a hematoma or contusion. Most authors agree that the benefit to risk ratio of DBS is favorable.

Intraoperative micro- and macrostimulation of the subthalamic nucleus in Parkinson's disease.

Studying the clinical effects induced by electrical stimulation of the subthalamic nucleus (STN) area in a parkinsonian patient under local anesthesia is a mandatory step to determine the precise location of the final chronic electrode. Using multiple microelectrodes, preferably in a concentric parallel array allows a precise mapping of the STN region. The most reliable features to determine the suitable target are stimulation-induced dyskinesias and rigidity decrease at a low intensity without adverse effects or only at far higher intensities. New skills are needed to assess all stimulation-induced effects and interpret them in anatomo-functional terms.