Mood and behavioural effects of subthalamic stimulation in Parkinson's disease

doi:10.1016/S1474-4422(13)70294-1

The Lancet Neurology

Volume 13, Issue 3, March 2014, Pages 287-305

https://doi.org/10.1016/S1474-4422(13)70294-1 Get rights and content

Summary

Deep-brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for motor complications in Parkinson's disease. 20 years of experience with this procedure have contributed to improved understanding of the role of the STN in motor, cognitive, and emotional control. In Parkinson's disease, the pathological STN neuronal activity leads to motor, cognitive, and emotional inhibition. Deafferentation of the STN by DBS can reverse such behavioural inhibition. The release of this brake allows both motor and non-motor improvement, but can also be associated with excessive motor, cognitive, and emotional behavioural disinhibition. Conversely, the notable reduction in anti-parkinsonian drug dose allowed by motor improvement can unveil mesolimbic hypodopaminergic behaviours such as apathy, anxiety, or depression. Fine-tuning of stimulation parameters with dopaminergic drugs is necessary to prevent or improve pathological behaviours.

Introduction

Subthalamic nucleus deep-brain stimulation (STN-DBS) is a well recognised treatment for motor complications of levodopa therapy in patients with Parkinson's disease. Patient selection, surgical technique, mechanisms of DBS, postoperative management, and motor outcomes have been extensively reviewed.1, 2, 3, 4 However, patients with Parkinson's disease can also have non-motor symptoms related both to the dopaminergic deficit affecting the mesolimbic system (such as fatigue, apathy, anxiety, depression, and pain—the so-called hypodopaminergic syndrome) and to a dopaminergic overdose (impulse control disorders, punding, and dopamine dysregulation syndrome—the so-called hyperdopaminergic syndrome).5, 6

Since its first applications, much work has been published on the neuropsychiatric changes after STN-DBS, raising concerns over its safety. The reports are conflicting, ranging from new onset or worsening of pre-existing behavioural disorders to improvement of neuropsychiatric symptoms after STN-DBS. Therefore, after 20 years of STN-DBS use, improved understanding is needed of the mechanisms behind either worsening or improvement in mood and behavioural effects, which will eventually result in rational management and improved outcomes. Stimulation of the brain target can be switched on and off to study the pathophysiology of diseases, which is especially useful when combined with neuroimaging and neurophysiology studies. In this Review, we focus on the effects of STN-DBS on emotions and non-motor behaviour, summarising clinical observations and showing how the technique has contributed to progress in understanding the pathophysiology of dopamine-dependent behaviours.

Section snippets

STN function

The STN, or corpus Luysii, first described by J B Luys in 1865, is a lens-shaped, obliquely oriented nucleus, located at the diencephalon-mesencephalic junction. The average size of the human STN is 3 × 5 × 12 mm.7, 8, 9 Despite this small size, the STN is thought of as one of the driving forces of the basal ganglia.¹⁰ In 1927, J P Martin described the “syndrome of the body of Luys”, based on clinicopathological observations after a lesion of the STN. This syndrome included not only severe

Acute neuropsychiatric effects of STN-DBS

Concerns have been raised about the neuropsychiatric effects of STN-DBS.⁵² To distinguish between acute and chronic behavioural changes is important; acute changes rely more on a direct effect of stimulation and the lesion-like effect of surgery.⁵³ STN stimulation mimics both the motor and behavioural effects of dopaminergic drugs,⁵⁴ which explains why acute effects resemble the hyperdopaminergic side-effects of dopaminergic drugs. In the acute phase after surgery, the synergistic activity of

Chronic neuropsychiatric effects of STN-DBS

The available randomised clinical trials comparing STN-DBS with either best medical treatment or GPi-DBS (table 3) have mostly focused on motor outcomes of STN-DBS in Parkinson's disease.71, 97, 107, 108, 109, 110, 111, 112 Non-motor symptoms have not been systematically assessed and, when they have been assessed, methodology has been variable, making conclusions difficult to draw.97, 107, 108, 109, 112

Comparison of STN-DBS and GPi-DBS in Parkinson's disease

There are two decades of experience with STN-DBS and GPi-DBS for treatment of motor complications in Parkinson's disease.21, 153, 154, 155 In a consensus meeting,¹³⁴ participants stated in their conclusion that STN-DBS surgery might be complicated by increased depression, apathy, and impulsivity, and worsening of verbal fluency and executive dysfunction, whereas no cognitive-behavioural complications of GPi-DBS were mentioned. These conclusions have somewhat supported the general opinion that

Lessons for improved understanding and management of behavioural issues

STN-DBS has contributed to improved understanding of the pathophysiology and management of neuropsychiatric issues in Parkinson's disease, which represent an important burden for patients and caregivers. To better improve management of these symptoms, prompt diagnosis and careful follow-up are essential. A multidisciplinary approach with systematic assessment of non-motor dopamine-dependent symptoms¹⁶⁵ is essential to screen for changes in motivation and mood, and to manage and prevent

Conclusions and future directions

Data from anatomy, electrophysiology, imaging, and clinical observation have shown that the STN has not only motor but also cognitive, motivational, and emotional functions. Placing of a DBS electrode into the motor STN is unlikely not to have cognitive and emotional effects, in view of the small size of the STN, the functional overlap of its regions, and the diffusion of stimulation. This likelihood raises the question of whether such spread to non-motor territories can be beneficial or not in

Search strategy and selection criteria

We identified references through searches of our own files, and of PubMed using the terms “behaviour and subthalamic stimulation”, “clinical randomized trials”, “DBS”, “mood”, “Parkinson's disease”, “subthalamic”, and “stimulation”, between Jan 1, 1993, and Sept 30, 2013, and through searching the lists of references of selected papers. We selected papers on the basis of their originality and relevance to the purpose of this Review.

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Cited by (232)

Subacute alpha frequency (10Hz) subthalamic stimulation for emotional processing in Parkinson's disease
2023, Brain Stimulation
Psychiatric comorbidities are common in Parkinson's disease (PD) and may change with high-frequency stimulation targeting the subthalamic nucleus. Numerous accounts indicate subthalamic alpha-frequency oscillation is implicated in emotional processing. While intermittent alpha-frequency (10Hz) stimulation induces positive emotional effects, with more ventromedial contacts inducing larger effects, little is known about the subacute effect of ventral 10Hz subthalamic stimulation on emotional processing.
To evaluate the subacute effect of 10Hz stimulation at bilateral ventral subthalamic nucleus on emotional processing in PD patients using an affective task, compared to that of clinical-frequency stimulation and off-stimulation.
Twenty PD patients with bilateral subthalamic deep brain stimulation for more than six months were tested with the affective task under three stimulation conditions (10Hz, 130Hz, and off-stimulation) in a double-blinded randomized design.
While 130Hz stimulation reduced arousal ratings in all patients, 10Hz stimulation increased arousal selectively in patients with higher depression scores. Furthermore, 10Hz stimulation induced a positive shift in valence rating to negative emotional stimuli in patients with lower apathy scores, and 130Hz stimulation led to more positive valence to emotional stimuli in the patients with higher apathy scores. Notably, we found correlational relationships between stimulation site and affective rating: arousal ratings increase with stimulation from anterior to posterior site, and positive valence ratings increase with stimulation from dorsal to ventral site of the ventral subthalamic nucleus.
Our findings highlight the distinctive role of 10Hz stimulation on subjective emotional experience and unveil the spatial organization of the stimulation effect.
Longitudinal neonatal brain development and socio-demographic correlates of infant outcomes following preterm birth
2023, Developmental Cognitive Neuroscience
Preterm birth results in premature exposure of the brain to the extrauterine environment during a critical period of neurodevelopment. Consequently, infants born preterm are at a heightened risk of adverse behavioural outcomes in later life. We characterise longitudinal development of neonatal regional brain volume and functional connectivity in the first weeks following preterm birth, sociodemographic factors, and their respective relationships to psychomotor outcomes and psychopathology in toddlerhood. We study 121 infants born preterm who underwent magnetic resonance imaging shortly after birth, at term-equivalent age, or both. Longitudinal regional brain volume and functional connectivity were modelled as a function of psychopathology and psychomotor outcomes at 18 months. Better psychomotor functioning in toddlerhood was associated with greater relative right cerebellar volume and a more rapid decrease over time of sensorimotor degree centrality in the neonatal period. In contrast, increased 18-month psychopathology was associated with a more rapid decrease in relative regional subcortical volume. Furthermore, while socio-economic deprivation was related to both psychopathology and psychomotor outcomes, cognitively stimulating parenting predicted psychopathology only. Our study highlights the importance of longitudinal imaging to better predict toddler outcomes following preterm birth, as well as disparate environmental influences on separable facets of behavioural development in this population.
Energy Delivered by Subthalamic Deep Brain Stimulation for Parkinson Disease Correlates With Depressive Personality Trait Shift
2023, Neuromodulation
Citation Excerpt :
The release of this brake allows motor improvement. Conversely, the notable reduction in antiparkinsonian drug dose allowed by motor improvement can unveil mesolimbic hypodopaminergic behaviors such as apathy, anxiety, or depression.7 However, in our sample, the changes in LEDD did not correlate with a worsening in depressive symptoms, which means that the change in depressive trait score, measured with the MMPI-2, could be correlated directly with the effects of the current spread produced by the DBS.
Despite the large amount of literature examining the potential influence of subthalamic nucleus deep brain stimulation (STN-DBS) on psychiatric symptoms and cognitive disorders, only a few studies have focused on its effect on personality. We investigated the correlation between total electrical energy delivered (TEED) and the occurrence of depressive traits in patients with Parkinson disease (PD) after one year of DBS.
Our study involved 20 patients with PD (12 women, mean [±SD] age 57.60 ± 7.63 years) who underwent bilateral STN-DBS, whose personality characteristics were assessed using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), according to the core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT-PD) procedure.
We found that despite a marked improvement in motor functions and quality of life after 12 months, patients showed a significant increase in MMPI-2 subscales for depression (D scale and Depression scale) and in other content component scales (low self-esteem, work interference, and negative treatment indicators). Interestingly, only the TEED on the right side was inversely correlated with the changes in scale D (r_s = −0.681, p = 0.007), whereas depressive traits did not correlate with disease duration, levodopa equivalent daily dose (LEDD) reduction, patient’s age, or severity of motor symptoms.
Our preliminary observations indicate that despite the excellent motor outcome and general improvement in quality of life, DBS treatment can result in patients poorly adjusting to their personal, familiar, and socio-professional life. Different influences and multiple factors (such as TEED, intra/postsurgical procedure, coping mechanisms, and outcome expectations) may affect depressive traits. Further advances are expected to improve stimulation methods.
Magnetoencephalography to measure the effect of contact point-specific deep brain stimulation in Parkinson's disease: A proof of concept study
2023, NeuroImage: Clinical
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for disabling fluctuations in motor symptoms in Parkinson’s disease (PD) patients. However, iterative exploration of all individual contact points (four in each STN) by the clinician for optimal clinical effects may take months.
In this proof of concept study we explored whether magnetoencephalography (MEG) has the potential to noninvasively measure the effects of changing the active contact point of STN-DBS on spectral power and functional connectivity in PD patients, with the ultimate aim to aid in the process of selecting the optimal contact point, and perhaps reduce the time to achieve optimal stimulation settings.
The study included 30 PD patients who had undergone bilateral DBS of the STN. MEG was recorded during stimulation of each of the eight contact points separately (four on each side). Each stimulation position was projected on a vector running through the longitudinal axis of the STN, leading to one scalar value indicating a more dorsolateral or ventromedial contact point position. Using linear mixed models, the stimulation positions were correlated with band-specific absolute spectral power and functional connectivity of i) the motor cortex ipsilateral tot the stimulated side, ii) the whole brain.
At group level, more dorsolateral stimulation was associated with lower low-beta absolute band power in the ipsilateral motor cortex (p = .019). More ventromedial stimulation was associated with higher whole-brain absolute delta (p = .001) and theta (p = .005) power, as well as higher whole-brain theta band functional connectivity (p = .040). At the level of the individual patient, switching the active contact point caused significant changes in spectral power, but the results were highly variable.
We demonstrate for the first time that stimulation of the dorsolateral (motor) STN in PD patients is associated with lower low-beta power values in the motor cortex. Furthermore, our group-level data show that the location of the active contact point correlates with whole-brain brain activity and connectivity. As results in individual patients were quite variable, it remains unclear if MEG is useful in the selection of the optimal DBS contact point.
Subthalamic and pallidal stimulation in Parkinson's disease induce distinct brain topological reconstruction
2022, NeuroImage
The subthalamic nucleus (STN) and globus pallidus internus (GPi) are the two most common and effective target brain areas for deep brain stimulation (DBS) treatment of advanced Parkinson's disease. Although DBS has been shown to restore functional neural circuits of this disorder, the changes in topological organization associated with active DBS of each target remain unknown. To investigate this, we acquired resting-state functional magnetic resonance imaging (fMRI) data from 34 medication-free patients with Parkinson's disease that had DBS electrodes implanted in either the subthalamic nucleus or internal globus pallidus (n = 17 each), in both ON and OFF DBS states. Sixteen age-matched healthy individuals were used as a control group. We evaluated the regional information processing capacity and transmission efficiency of brain networks with and without stimulation, and recorded how stimulation restructured the brain network topology of patients with Parkinson's disease. For both targets, the variation of local efficiency in motor brain regions was significantly correlated (p < 0.05) with improvement rate of the Uniform Parkinson's Disease Rating Scale-III scores, with comparable improvements in motor function for the two targets. However, non-motor brain regions showed changes in topological organization during active stimulation that were target-specific. Namely, targeting the STN decreased the information transmission of association, limbic and paralimbic regions, including the inferior frontal gyrus angle, insula, temporal pole, superior occipital gyri, and posterior cingulate, as evidenced by the simultaneous decrease of clustering coefficient and local efficiency. GPi-DBS had a similar effect on the caudate and lenticular nuclei, but enhanced information transmission in the cingulate gyrus. These effects were not present in the DBS-OFF state for GPi-DBS, but persisted for STN-DBS. Our results demonstrate that DBS to the STN and GPi induce distinct brain network topology reconstruction patterns, providing innovative theoretical evidence for deciphering the mechanism through which DBS affects disparate targets in the human brain.
Management of Impulse Control and Related Disorders in Parkinson's Disease: An Expert Consensus
2024, Movement Disorders

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ReviewMood and behavioural effects of subthalamic stimulation in Parkinson's disease

Summary

Introduction

Section snippets

STN function

Acute neuropsychiatric effects of STN-DBS

Chronic neuropsychiatric effects of STN-DBS

Comparison of STN-DBS and GPi-DBS in Parkinson's disease

Lessons for improved understanding and management of behavioural issues

Conclusions and future directions

Search strategy and selection criteria

Lancet Neurol

Lancet Neurol

Handb Clin Neurol

Rev Neurol (Paris)

Rev Neurol (Paris)

Trends Neurosci

Lancet

Neurosci Res

Exp Neurol

Neuroimage

Trends Neurosci

Neuroimage

Clin Neurophysiol

Curr Opin Neurobiol

Trends Neurosci

Handb Clin Neurol

Clin Neurophysiol

J Neurol Sci

Parkinsonism Relat Disord

Parkinsonism Relat Disord

Lancet Neurol

Neuropsychologia

Neuropsychologia

Curr Biol

Lancet Neurol

Lancet Neurol

Neuroimage

Latest view on the mechanism of action of deep brain stimulation

Mov Disord

Subthalamic stimulation in Parkinson's disease: restoring the balance of motivated behaviours

Brain

Recherches sur le système cérébro-spinal, sa structure, ses fonctions et ses maladies

Description d'une nouvelle région de substance grise située à la base de l'encéphale

Encephale

Functional anatomy of the basal ganglia

Mov Disord

Anatomy and physiology of the subthalamic nucleus: a driving force of the basal ganglia

Adv Behav Biol

Hemichorea resulting from a local lesion of the brain (syndrome of the body of Luys)

Brain

Hemiballismus

Clin Neuropharmacol

Mirthful laughter induced by subthalamic nucleus stimulation

Mov Disord

Parallel organization of functionally segregated circuits linking basal ganglia and cortex

Annu Rev Neurosci

Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior

Proc Natl Acad Sci USA

The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for basal ganglia models and deep brain stimulation

J Neurosci

Reversal of experimental parkinsonism by lesions of the subthalamic nucleus

Science

Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys

Eur J Neurosci

The corticostriatal and corticosubthalamic pathways: two entries, one target. So what?

Front Syst Neurosci

Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold

Nat Neurosci

Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism

Science

Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats

Eur J Neurosci

Cortical and subcortical contributions to Stop signal response inhibition: role of the subthalamic nucleus

J Neurosci

Inhibition of ongoing responses in patients with Parkinson's disease

J Neurol Neurosurg Psychiatry

Neuromagnetic evidence of abnormal movement-related beta desynchronization in Parkinson's disease

Cereb Cortex

Aggressive behavior induced by intraoperative stimulation in the triangle of Sano

Review
Mood and behavioural effects of subthalamic stimulation in Parkinson's disease