Modulation of subthalamic alpha activity to emotional stimuli correlates with depressive symptoms in Parkinson's disease1

Background : Deep brain stimulation of the subthalamic nucleus is an effective treatment for patients with advanced Parkinson's disease. However, affective side effects following subthalamic deep brain stimulation have been reported. Here, we aim to elucidate the influence of affective state on emotional processing as indexed by local field potential activity and to identify neurophysiological markers in patients at risk of developing depressive symptoms during subthalamic deep brain stimulation. Methods : Subthalamic local field potentials were directly recorded via electrodes implanted for deep brain stimulation in 12 Parkinson's disease patients while viewing emotionally salient and neutral pictures. Parkinson's disease patients were assessed for depressive symptoms using the Beck depression inventory at the time of operation and 3 months after continuous subthalamic nucleus deep brain stimulation. Results : We found a significant event‐related desynchronization in the local alpha frequency band (8–12 Hz) for emotionally arousing but not neutral pictures. The the event‐related desynchronization (ERD) in the alpha frequency band was reduced for pleasant stimuli in patients with mild to moderate depressive symptoms compared with patients without depression. The alpha‐ERD to unpleasant stimuli showed the opposite pattern. Consistently, the index of event‐related alpha desynchronization (alpha ERD for pleasant stimuli minus alpha ERD for unpleasant stimuli) correlated with the Beck depression inventory at the time of the recordings and at 3 months after continuous deep brain stimulation. The alpha ERD to unpleasant pictures correlated significantly with the Beck depression inventory score at 3 months after chronic deep brain stimulation. Discusion : In conclusion, we found mood‐congruent stimulus processing in the subthalamic nucleus of Parkinson's disease patients. Electrophysiological markers such as event‐related desynchronization of subthalamic alpha activity reflect state‐dependent emotional processing and may potentially be used to predict depressive mood disturbances in Parkinson's disease patients with chronic subthalamic deep brain stimulation at an early stage. © 2011 Movement Disorder Society     

An association between affective lability and executive functioning in bipolar disorder

Studies suggest altered affect regulation manifested by affective lability in manic/mixed and euthymic states in patients with bipolar disorder (BD). Altered affect regulation may arise from disturbances in interactions between the cognitive and the emotional brain networks. However, the relationship between affective lability and executive function has not previously been studied. Our aim was to investigate affective lability, as measured with the Affective Lability Scale (ALS) in patients with BD (N=32) compared to healthy controls (HC) (N=60), and its relationship to executive functioning. We found significantly higher ALS scores in the BD than in the HC group, indicating a higher degree of affective lability in patients with BD. Sub-sample analysis revealed a significant positive relationship between affective lability and semantic set shifting abilities in BD only. These findings suggest that higher levels of affective lability compared with controls are a trait as well as state dependent in BD, and that disturbed affective lability may arise from an aberrant interaction between cognitive and emotional brain networks.     

Affective lability predicts decreased habituation in posttraumatic stress symptom responding during a single laboratory session of imaginal exposure

Affective lability, or the instability of emotional states, is associated with heightened levels of trauma-related emotional responding and posttraumatic stress disorder (PTSD) symptoms. However, the impact of affective lability, specifically on habituation to idiographic trauma cues, has yet to be examined among trauma-exposed individuals. The current study examined differential response trajectories to trauma-related imaginal exposure as a function of affective lability. Specifically, 72 women with a history of sexual victimization participated in a laboratory-based study involving a single session of repeated imaginal exposures to idiographic traumatic event cues. As hypothesized, participants higher in affective lability reported less reduction in trauma-cue elicited posttraumatic stress symptoms across exposure trials. Given these results, it will be important to continue to extend these laboratory findings to better understand how elevated affective lability is related to response to trauma-focused exposure therapy among individuals with PTSD or other trauma-related psychopathology (e.g., borderline personality disorder).     

A self report measure of affective lability

OBJECTIVES—The development and validation of theCenter for Neurologic Study- Lability Scale (CNS-LS), the first selfreport measure of affective lability in patients with amyotrophiclateral sclerosis (ALS).
METHODS—Potential questionnaire items wereidentified through interviews with patients and families and expertreview. Potential items, as well as measures of affect intensity,affective lability in psychopathology, and depression were administeredto 99 patients with ALS for item selection and the examination offactor structure and construct validity. Test-retest reliability wasexamined using an additional sample of 31 patients with ALS, andcriterion related validity was examined by comparing CNS-LS scores withphysicians' diagnoses of affective lability in a sample of 77 patientswith ALS.
RESULTS—A seven item questionnaire emerged,composed of two subscales measuring labile laughter (four items) andlabile tearfulness (three items). The CNS-LS showed a pattern ofassociations with affect intensity, affective lability inpsychopathology, and depression consistent with a scale measuringaffective lability. The CNS-LS also showed good test-retest reliabilityand internal consistency, and successfully predicted physicians'diagnoses of affective lability. An auxiliary subscale measuring labilefrustration, anger, and impatience also emerged.
CONCLUSIONS—The CNS-LS is a short, easilyadministered, and psychometrically sound measure of affective labilityfor use with patients with ALS. It has potential applications as both aclinical screening device and a research tool. The need for futureresearch into the relation of depression as well as labile frustration,anger, and impatience to the syndrome of affective lability inneurological disorders is discussed.

     

Effects of levodopa and subthalamic nucleus stimulation on cognitive and affective functioning in Parkinson's disease.

In Parkinson's disease (PD), levodopa and subthalamic nucleus (STN) stimulation lead to major improvement in motor symptoms. Effects of both treatments on cognition and affective status are less well understood. Motor, cognitive, and affective symptoms may relate to the dysfunctioning of parallel cortico-striatal loops. The aim of this study was to assess cognition, behavior, and mood, with and without both treatments in the same group of PD patients. A group of 22 nondemented PD patients was included in this study. Patients were tested twice before surgery (off and on levodopa) and twice 3 months after surgery (OFF and ON STN stimulation, off levodopa). Cognitive and affective effects of STN stimulation and levodopa had some common, but also different, effects. STN stimulation improved performance on the planning test, associated with the dorsolateral prefrontal cortex. However, the treatments had opposite effects on tests associated with the orbitofrontal cortex; specifically, levodopa impaired while STN stimulation improved performance on the extinction phase of a reversal/extinction task. Acutely, both treatments improved motivation and decreased fatigue and anxiety. On chronic treatment (3 months after surgery), depression improved, whereas apathy worsened 3 months after surgery. To conclude, there were significant but contrasting effects of levodopa and STN stimulation on cognition and affective functions.     

Modeling the relationship between affective lability, impulsivity, and suicidal behavior in patients with borderline personality disorder

This article reviews the concept of affective lability and suggests that new models are needed to characterize the relationship between affective states such as affective lability, impulsivity, and suicidal behavior. The association of affective lability, impulsivity, and suicidal behavior is most relevant to understanding the risk of suicide in individuals with borderline personality disorder. The relationship between affective lability and suicide might be explained as 1) a form of bipolarity, 2) a form of impulse dyscontrol, 3) a quantitative disorder of affect, or 4) an environmental reactivity. Our opinion of the relevant literature suggests that a quantitative disorder of affect accompanied by the inability to control these affects are the essential components leading to the risk of suicidal behavior. Characterizing the dyscontrol and high intensity of affect leads to a reconceptualization of depression in patients with borderline personality disorder and to a re-examination of the causal chain of events leading to suicidal behavior. The implications for clinical practice resulting from the proposed model are discussed.     

Deep brain stimulation of the subthalamic nucleus enhances emotional processing in Parkinson disease

BACKGROUND: High-frequency electrical stimulation of the subthalamic nucleus is a new and highly effective therapy for complications of long-term levodopa therapy and motor symptoms in advanced Parkinson disease (PD). Clinical observations indicate additional influence on emotional behavior. METHODS: Electrical stimulation of deep brain nuclei with pulse rates above 100 Hz provokes a reversible, lesioning-like effect. Here, the effect of deep brain stimulation of the subthalamic nucleus on emotional, cognitive, and motor performance in patients with PD (n = 12) was examined. The results were compared with the effects of a suprathreshold dose of levodopa intended to transiently restore striatal dopamine deficiency. Patients were tested during medication off/stimulation off (STIM OFF), medication off/stimulation on (STIM ON), and during the best motor state after taking levodopa without deep brain stimulation (MED). RESULTS: More positive self-reported mood and an enhanced mood induction effect as well as improvement in emotional memory during STIM ON were observed, while during STIM OFF, patients revealed reduced emotional performance. Comparable effects were revealed by STIM ON and MED. Cognitive performance was not affected by the different conditions and treatments. CONCLUSIONS: Deep brain stimulation of the subthalamic nucleus selectively enhanced affective processing and subjective well-being and seemed to be antidepressive. Levodopa and deep brain stimulation had similar effects on emotion. This finding may provide new clues about the neurobiologic bases of emotion and mood disorders, and it illustrates the important role of the basal ganglia and the dopaminergic system in emotional processing in addition to the well-known motor and cognitive functions.     

Pathological gambling in Parkinson's disease: Subthalamic oscillations during economics decisions

Pathological gambling develops in up to 8% of patients with Parkinson's disease. Although the pathophysiology of gambling remains unclear, several findings argue for a dysfunction in the basal ganglia circuits. To clarify the role of the subthalamic nucleus in pathological gambling, we studied its activity during economics decisions. We analyzed local field potentials recorded from deep brain stimulation electrodes in the subthalamic nucleus while parkinsonian patients with (n = 8) and without (n = 9) pathological gambling engaged in an economics decision‐making task comprising conflictual trials (involving possible risk‐taking) and non conflictual trials. In all parkinsonian patients, subthalamic low frequencies (2–12 Hz) increased during economics decisions. Whereas, in patients without gambling, low‐frequency oscillations exhibited a similar pattern during conflictual and non conflictual stimuli, in those with gambling, low‐frequency activity increased significantly more during conflictual than during non conflictual stimuli. The specific low‐frequency oscillatory pattern recorded in patients with Parkinson's disease who gamble could reflect a subthalamic dysfunction that makes their decisional threshold highly sensitive to risky options. When parkinsonian patients process stimuli related to an economics task, low‐frequency subthalamic activity increases. This task‐related change suggests that the cognitive‐affective system that drives economics decisional processes includes the subthalamic nucleus. The specific subthalamic neuronal activity during conflictual decisions in patients with pathological gambling supports the idea that the subthalamic nucleus is involved in behavioral strategies and in the pathophysiology of gambling. © 2013 International Parkinson and Movement Disorder Society     

Dopamine efflux in the rat striatum evoked by electrical stimulation of the subthalamic nucleus: potential mechanism of action in Parkinson's disease

The precise mechanism whereby continuous high-frequency electrical stimulation of the subthalamic nucleus ameliorates motor symptoms of Parkinson's disease is unknown. We examined the effects of high-frequency stimulation of regions dorsal to and within the subthalamic nucleus on dopamine efflux in the striatum of urethane-anaesthetized rats using constant potential amperometry. Complementary extracellular electrophysiological studies determined the activity of subthalamic nucleus neurons in response to similar electrical stimulation of the subthalamic nucleus. High-frequency stimulation of the subthalamic nucleus increased action potential firing in the subthalamic nucleus only during the initial stimulation period and was followed by a cessation of firing over the remainder of stimulation. Electrical stimulation of the subthalamic nucleus with 15 pulses elicited stimulus-time-locked increases in striatal dopamine efflux with maximal peak effects occurring at 50 Hz frequency and 300 microA intensity. Extended subthalamic nucleus stimulation (1000 pulses at 50 Hz; 300 microA) elicited a similar peak increase in striatal dopamine efflux that was followed by a relatively lower steady-state elevation in extracellular dopamine over the course of stimulation. In contrast, extended stimulation immediately adjacent and dorsal to the subthalamic nucleus resulted in an 11-fold greater increase in dopamine efflux that remained elevated over the course of the stimulation. Immunohistochemical staining for tyrosine hydroxylase revealed catecholaminergic fibers running immediately dorsal to and through the subthalamic nucleus. Taken together, these results suggest that enhanced dopamine release within the basal ganglia may be an important mechanism whereby high-frequency stimulation of the subthalamic nucleus improves motor symptoms of Parkinson's disease.     

Deep brain stimulation of the subthalamic nucleus improves sense of well-being in Parkinson's disease

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of Parkinson's disease. Although a range of psychiatric and behavioral problems have been documented following deep brain stimulation, the short-term effects of subthalamic nucleus stimulation on patients' mood have only been investigated in a few studies. Our aim was to compare self-reported mood in Parkinson's patients with deep brain stimulation of the subthalamic nucleus ON versus OFF. Twenty-three Parkinson's patients with bilateral deep brain stimulation of the subthalamic nucleus and 11 unoperated Parkinson's patients completed a mood visual analogue scale twice. Operated patients were tested with deep brain stimulation of the subthalamic nucleus both ON and OFF. All were assessed on medication. The operated Parkinson's group reported feeling significantly better coordinated, stronger, and more contented with deep brain stimulation ON compared to OFF. Fourteen of the 16 mood scales changed in a positive direction when deep brain stimulation of the subthalamic nucleus was ON. When changes in motor scores were taken into account, the operated patients still reported feeling better-coordinated, but also less gregarious with stimulation ON. Unoperated Parkinson's patients showed no differences on any of these measures between their 2 ratings. Short-term changes in deep brain stimulation of the subthalamic nucleus have a small and mostly positive effect on mood, which may be partly related to improvements in motor symptoms. The implications for day-to-day management of patients with deep brain stimulation of the subthalamic nucleus are discussed.     

Pathological crying induced by deep brain stimulation

Pathological crying (PLC)—an affective gesture without any or an adequate emotion—occurs with various diseases. A recent theory suggests that PLC is caused by a disruption of higher order cortical association areas from the cerebellum which computes profiles of psychomotor responses. We report a patient with Parkinson's disease who developed PLC during stimulation of the subthalamic nucleus (STN) predominantly of the right hemisphere. Positron emission tomography imaging showed thalamo‐ponto‐cerebellar activation during such stimulation. These findings indicate that the STN and possibly also ponto‐cerebellar pathways are involved in psychomotor control and in the modulation of PLC. © 2007 Movement Disorder Society     

Characterizing affective instability in borderline personality disorder

OBJECTIVE: This study sought to understand affective instability among patients with borderline personality disorder by examining the degree of instability in six affective domains. The authors also examined the subjective intensity with which moods are experienced and the association between instability and intensity of affect. METHOD: In a group of 152 patients with personality disorders, subjective affective intensity and six dimensions of affective instability were measured. The mean scores for lability and intensity for each affective domain for patients with borderline personality disorder were compared with those of patients with other personality disorders through analyses that controlled for other axis I affective disorders, age, and sex. RESULTS: Greater lability in terms of anger and anxiety and oscillation between depression and anxiety, but not in terms of oscillation between depression and elation, was associated with borderline personality disorder. Contrary to expectation, the experience of an increase in subjective affective intensity was not more prominent in patients with borderline personality disorder than in those with other personality disorders. CONCLUSIONS: By applying a finer-grained perspective on affective instability than those of previous personality disorder studies, this study points to patterns of affective experience characteristic of patients with borderline personality disorder.     

Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat

High frequency stimulation (130 Hz) of the subthalamic nucleus has dramatic beneficial motor effects in severe parkinsonian patients. However, the mechanisms underlying these clinical results remain obscure. The objective of the present work was to study the neurochemical changes induced in rats by high frequency stimulation of the subthalamic nucleus by using intracerebral microdialysis within its target structures. Our results show that high frequency stimulation of the subthalamic nucleus induces a significant increase of extracellular glutamate levels in the ipsilateral globus pallidus and substantia nigra while GABA was augmented only in the substantia nigra. These data suggest that functional effects induced by high frequency stimulation of the subthalamic nucleus might imply distal mechanisms involving the synaptic relationships with the subthalamic efferences. They question the current view that the direct inhibition of the subthalamic neurons is induced by high frequency stimulation.     

Associations between retrospective versus ecological momentary assessment measures of emotion and eating disorder symptoms in anorexia nervosa

This study examined the unique associations between eating disorder symptoms and two emotion-related constructs (affective lability and anxiousness) assessed via distinct methodologies in anorexia nervosa (AN). Women (N = 116) with full or subthreshold AN completed baseline emotion and eating disorder assessments, followed by two weeks of ecological momentary assessment (EMA). Hierarchical regressions were used to examine unique contributions of baseline and EMA measures of affective lability and anxiousness in accounting for variance in baseline eating disorder symptoms and EMA dietary restriction, controlling for age, body mass index, depression, and AN diagnostic subtype. Only EMA affective lability was uniquely associated with baseline eating disorder symptoms and EMA dietary restriction. Anxiousness was uniquely associated with baseline eating disorder symptoms regardless of assessment method; neither of the anxiousness measures was uniquely associated with EMA dietary restriction. Affective lability and anxiousness account for variance in global eating disorder symptomatology; AN treatments targeting these emotion-related constructs may prove useful.     

Deep brain stimulation of the subthalamic nucleus improves sense of well‐being in parkinson's disease

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of Parkinson's disease. Although a range of psychiatric and behavioral problems have been documented following deep brain stimulation, the short‐term effects of subthalamic nucleus stimulation on patients' mood have only been investigated in a few studies. Our aim was to compare self‐reported mood in Parkinson's patients with deep brain stimulation of the subthalamic nucleus ON versus OFF. Twenty‐three Parkinson's patients with bilateral deep brain stimulation of the subthalamic nucleus and 11 unoperated Parkinson's patients completed a mood visual analogue scale twice. Operated patients were tested with deep brain stimulation of the subthalamic nucleus both ON and OFF. All were assessed on medication. The operated Parkinson's group reported feeling significantly better coordinated, stronger, and more contented with deep brain stimulation ON compared to OFF. Fourteen of the 16 mood scales changed in a positive direction when deep brain stimulation of the subthalamic nucleus was ON. When changes in motor scores were taken into account, the operated patients still reported feeling better‐coordinated, but also less gregarious with stimulation ON. Unoperated Parkinson's patients showed no differences on any of these measures between their 2 ratings. Short‐term changes in deep brain stimulation of the subthalamic nucleus have a small and mostly positive effect on mood, which may be partly related to improvements in motor symptoms. The implications for day‐to‐day management of patients with deep brain stimulation of the subthalamic nucleus are discussed. © 2012 Movement Disorder Society     

Effects of bilateral subthalamic nucleus stimulation on parkinsonian gait.

Gait analysis was carried out to assess the effects of L-dopa and bilateral subthalamic nucleus stimulation on gait velocity, cadence, stride length, and gait kinematics in nine patients with PD. Substantial effects of bilateral subthalamic nucleus stimulation on gait, with an increase in gait velocity and stride length comparable to that of a suprathreshold L-dopa dose, were found. Interestingly, stride length was more improved by L-dopa and cadence more by subthalamic nucleus stimulation. In two patients with freezing during the "on" period, subthalamic nucleus stimulation failed to reduce this symptom effectively.     

Sensory timing cues improve akinesia of grasping movements in Parkinson's disease: a comparison to the effects of subthalamic nucleus stimulation.

Five parkinsonian subjects with chronic bilateral stimulation of the subthalamic nucleus and five sex- and age-matched healthy controls grasped, lifted, and held an instrumented object. The grip-lift task was either performed at self-determined speed or in response to an auditory cuing signal. Parkinsonian subjects performed the task with subthalamic nucleus stimulation switched ON and OFF. In Parkinson's disease, stimulation of the subthalamic nucleus and the presentation of auditory timing cues improved akinesia of both the grasp and lift components of the task. The finding that auditory timing cues improve akinesia in the absence of subthalamic nucleus stimulation suggests that the basal ganglia are less involved in the control of movements made in response to environmental cues. However, subthalamic nucleus stimulation caused parkinsonian subjects to apply excessive grip forces, regardless of whether the movement was made under self-determined or externally guided speed conditions. This implies that subthalamic nucleus stimulation produces a generalized upregulation in the gain of all components of a movement without the subtlety of focused control that is required to normalize performance.     

Failure of long-term pallidal stimulation corrected by subthalamic stimulation in PD

Bilateral high-frequency continuous stimulation of the internal globus pallidus or subthalamic nucleus constitutes a new therapeutic approach for the treatment of patients with severe PD. The authors report two patients in whom stimulation of the globus pallidus failed to give long-term relief and was successfully replaced by bilateral subthalamic stimulation. The results emphasize the reversibility of deep brain stimulation therapy and suggest that the subthalamic target is preferable to the pallidal target.     

Bilateral stimulation of nucleus subthalamicus in advanced Parkinson's disease: no effects on, and of, autonomic dysfunction.

It is not known whether bilateral stimulation of the subthalamic nucleus, performed to improve skeletal motor control in advanced Parkinson's disease, also affects central autonomic regulation of cardiovascular motor function. Furthermore, reduced treatment with dopaminergic and other drugs after bilateral stimulation of the subthalamic nucleus could affect cardiovascular autonomic reflexes and/or other factors controlling blood pressure level. The primary aim of this study was to investigate putative effects of bilateral stimulation of the subthalamic nucleus on the autonomic nervous system, using respiratory heart rate variability and blood pressure responses to tilt as indices. Baseline autonomic tests were performed in 19 patients with Parkinson's disease and 10 matched healthy subjects. Patients were divided in two groups and re-investigated after 1 year of optimized pharmacological treatment (n = 8) or 1 year of bilateral subthalamic nucleus stimulation (n = 11). Both skeletal motor dysfunction and dopaminergic drug treatment were significantly reduced after 1 year of bilateral subthalamic nucleus stimulation. However, heart rate variability as well as blood pressure during tilt was reduced compared to baseline to a similar extent in both patient groups. The number of individual patients showing pathological autonomic test results at 1-year follow-up increased only in the subthalamic nucleus stimulation group. Despite reduced pharmacological treatment and reduced motor disability, bilateral subthalamic nucleus stimulation does not improve cardiovascular autonomic reflex function or protect against development of cardiovascular autonomic failure in Parkinson's disease. Preoperative cardiovascular autonomic reflex dysfunction, conversely, does not exclude an excellent stimulation effect.