Tract-based analysis of target engagement by subcallosal cingulate deep brain stimulation for treatment resistant depression

BackgroundDeep brain stimulation (DBS) of subcallosal cingulate cortex (SCC) is a promising investigational therapy for treatment-resistant depression (TRD). However, outcomes vary, likely due to suboptimal DBS placement. Ideal placement is proposed to stimulate 4 SCC white matter bundles; however, no quantitative data have linked activation of these target tracts to response.ObjectiveHere we used the volume of tissue activated (VTA) and probabilistic diffusion tensor imaging (DTI) to quantify tract activation relating to response.MethodsDTI was performed in 19 TRD patients who received SCC-DBS. We defined clinical response as >48% reduction from baseline in the Hamilton Depression Rating Scale. Bilateral VTAs were generated based on subject-specific stimulation parameters. Patient-specific tract maps emanating from the VTAs were calculated using whole-brain probabilistic DTI. The four target tracts were isolated using tract-specific quantification and examined for overlap with DBS activated tissue.ResultsMedial frontal and temporal projections were stimulated in all responders at 6 and 12 months. Individual tract-based generalized linear mixed model analysis revealed a significant tract-by-response interaction at both 6 (F(1,135) = 3.828, p = 0.001) and 12 (F(1,135) = 5.688, p < 0.001) months, with post hoc tests revealing a response-related increase in cingulum activation at 6 months (t(135) = 2.418, p = 0.017) and decrease in forceps minor activation at 12 months (t(135) = -2.802, p = 0.006).ConclusionsA wider profile of white matter tracts, particularly to the medial frontal, was associated with DBS response. Cingulum bundle stimulation may promote early response and excess stimulation of the forceps minor might be detrimental. Our work supports prospective patient-specific targeting to inform personalized DBS.     

Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats

Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is currently being investigated as a treatment for major depression. Despite the encouraging findings of the initial clinical series, several questions remain unanswered, including the most effective stimulation parameters (i.e., current intensity and frequency) and whether unilateral stimulation is also beneficial. We have recently found that some of the effects of SCG DBS could be modeled by stimulating the ventromedial prefrontal cortex (vmPFC) of rats undergoing the forced swim test (FST). Here we investigate whether changes in a number of DBS parameters, including electrode placement, influence outcome in this paradigm. Overall, we found that the antidepressant-like effects of DBS varied as a function of stimulation settings and target. The strongest response was observed with a current intensity of 200 μA, followed by 100 μA, and 300 μA. In contrast, 400 μA produced no effect. Using 200 μA, a frequency of 130 Hz was more effective than 20 Hz. An intriguing finding was that left unilateral stimulation was as effective as bilateral DBS. When different targets within the vmPFC were considered, a significant antidepressant-like response was observed after PL DBS, whereas IL stimulation was associated with a non-significant reduction in immobility scores. In summary, vmPFC DBS at high frequency and moderate intensity led to a maximal response in the FST.     

Non-invasive brain stimulation and the autonomic nervous system

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive methods of brain stimulation (NIBS) that can induce significant effects on cortical and subcortical neural networks. Both methods are relatively safe if appropriate guidelines are followed, and both can exert neuromodulatory effects that may be applied to the investigation of the autonomic nervous system (ANS). In addition, ANS measures can shed important light onto the neurobiologic mechanisms of NIBS. Here we present a systematic review on studies testing NIBS and ANS simultaneously. We structure our findings into four broad (not mutually exclusive) categories: (i) studies in which ANS function was modified by NIBS versus those in which it was not; (ii) studies in which NIBS was used to understand ANS function, (iii) studies in which ANS was used to understand NIBS mechanisms and (iv) NIBS/ANS studies conducted in healthy subjects versus those in patients with neuropsychiatric diseases. Forty-four articles were identified and no conclusive evidence of the effects of NIBS on ANS was observed, mainly because of the heterogeneity of included studies. Based on a comprehensive summary of this literature we propose how NIBS might be further developed to enhance our understanding of the cortical mechanisms of autonomic regulation and perhaps to modulate autonomic activity for therapeutic purposes.     

Expectation enhances autonomic responses to stimulation of the human subthalamic limbic region

Recent studies show that the placebo component of a treatment can be investigated by administering therapies either overtly or covertly, without the administration of any placebo. Here, we analyze the effects of open (i.e., expected) versus hidden (i.e., unexpected) stimulations of the human subthalamic region on autonomic responses in Parkinson patients. To do this, we mapped the whole subthalamic region, from the dorsal to the ventral part, and recorded both heart rate and sympathetic responses by using spectral analysis of heart rate variability. We found that open stimulations were more effective than hidden ones only in the ventral subthalamic region, whereas no difference between the two conditions was found in the dorsal aspect. By analyzing the stimulus-response curves in the dorsal, middle, and ventral subthalamic regions, we found that the autonomic response threshold was higher in the hidden than open condition for both heart rate and sympathetic responses only in the ventral part. As this ventralmost portion of the subthalamic region is involved in associative-limbic functions, these data suggest that expectation enhances autonomic responses only if these are elicited in the limbic system. These results extend previous findings on the open-hidden paradigm in deep brain stimulation [Benedetti, F., Colloca, L., Lanotte, M., Bergamasco, B., Torre, E., Lopiano, L., 2004a. Autonomic and emotional responses to open and hidden stimulations of the human subthalamic region. Brain Res. Bull. 63, 203-211.], and indicate that expectation plays a major role in the therapeutic outcome. In light of the interactions between the sympathetic adrenergic system and the immune system, the open-hidden difference in autonomic responses might be relevant to the understanding of how expectations might affect the immune system.     

Anodal Transcranial Direct Current Stimulation (tDCS) Over the Motor Cortex Increases Sympathetic Nerve Activity

BackgroundTranscranial direct current stimulation (tDCS) is currently being investigated as a non-invasive neuromodulation therapy for a range of conditions including stroke rehabilitation. tDCS affects not only the area underlying the electrodes but also other areas of the cortex and subcortical structures. This could lead to unintended alteration in brain functions such as autonomic control.ObjectiveWe investigated the potential effects of tDCS on cardiovascular autonomic function in healthy volunteers.MethodsAnodal (n = 14) or cathodal (n = 8) tDCS at 1 mA was applied over the primary motor cortex with the second electrode placed on the contralateral supraorbital region. Subjects visited the department twice and received active or sham tDCS for 15 min. Heart rate, blood pressure and respiration were recorded at baseline, during tDCS and after stimulation. Heart rate variability (HRV) was calculated using spectral analysis of beat-to-beat intervals derived from ECG data. Microneurography was also used to record muscle sympathetic nerve activity (MSNA; n = 5).ResultsAnodal tDCS caused a significant shift in HRV toward sympathetic predominance (P = 0.017), whereas there was no significant change in the cathodal or sham groups. Microneurography results also showed a significant increase in MSNA during anodal tDCS that continued post-stimulation.ConclusionsAnodal tDCS of the motor cortex shifts autonomic nervous system balance toward sympathetic dominance due at least in part to an increase in sympathetic output. These results suggest further investigation is warranted on tDCS use in patient groups with potential autonomic dysfunction, such as stroke patients.     

A meta-analysis of non-invasive brain stimulation and autonomic functioning: Implications for brain-heart pathways to cardiovascular disease

Given the intrinsic connection between the brain and the heart, a recent body of research emerged with the aim to influence cardiovascular system functioning by non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Despite the implications of cardiovascular activity modulation for therapeutic purposes, such effects of NIBS have not yet been quantified. The aim of this study was to meta-analyze studies on NIBS effects on blood pressure (BP), heart rate (HR) and its variability (HRV). PubMed and Scopus databases were searched for English language studies conducted in humans. Twenty-nine studies were eligible for the analyses. Pooled effect sizes (Hedges’ g) were compared. Random effect models were used. NIBS was effective in reducing HR (g = 0.17) and enhancing HRV (g = 0.30). A marginal effect emerged for BP (g = 0.21). Significant moderators were the stimulation technique and the site of stimulation. Results show that NIBS affects cardiovascular and autonomic nervous system activity, confirming a potential pathogenic brain-heart pathway to cardiovascular disease.     

Sympathetic hyperactivity,hypertension, and tachycardia induced by stimulation of the ponto-medullary junction in humans

ObjectiveThe purpose of this study is to investigate changes in autonomic activities and systemic circulation generated by surgical manipulation or electrical stimulation to the human brain stem.MethodsWe constructed a system that simultaneously recorded microsurgical field videos and heart rate variability (HRV) that represent autonomic activities. In 20 brain stem surgeries recorded, HRV features and sites of surgical manipulation were analyzed in 19 hypertensive epochs, defined as the periods with transient increases in the blood pressure. We analyzed the period during electrical stimulation to the ponto-medullary junction, performed for the purpose of monitoring a cranial nerve function.ResultsIn the hypertensive epoch, HRV analysis showed that sympathetic activity predominated over the parasympathetic activity. The hypertensive epoch was more associated with surgical manipulation of the area in the caudal pons or the rostral medulla oblongata compared to controls. During the period of electrical stimulation, there were significant increases in blood pressures and heart rates, accompanied by sympathetic overdrive.ConclusionsOur results provide physiological evidence that there is an important autonomic center located adjacent to the ponto-medullary junction.SignificanceA large study would reveal a candidate target of neuromodulation for disorders with autonomic imbalances such as drug-resistant hypertension.     

Frequency-specific RSA-like hippocampal patterns elicited by septal, hypothalamic, and brain stem electrical stimulation

Hippocampal electrographic patterns comprised of specific frequencies of slow waves electrographically similar to the waves comprising normal hippocampaa rhythmical slow activity (RSA, theta) may be generated by appropriate electrical stimulation of specific septal, hypothalamic, and brain stem sites. The waves elicited from some but not all sites are further similar to normal RSA patterns in that they may be differentiated into atropine-sensitive (immobility-related) and atropine-resistant (movement-related) types by the same criteria used to define atropine-sensitive and atropine-resistant RSA. The high degree of behavioral, pharmacological, and electrographic similarity between the electrically elicited hippocampal activity and normal hippocampal RSA would seem to warrant further use of the present technique in the investigation of hippocampal function.     

Fear recognition is impaired by subthalamic nucleus stimulation in Parkinson's disease

Behavioural disturbances such as disorders of mood, apathy or indifference are often observed in Parkinson's disease (PD) patients with chronic high frequency deep brain stimulation of subthalamic nucleus (STN DBS). Neuropsychological modifications causing these adverse events induced by STN DBS remain unknown, even if limbic disturbances are hypothesised. The limbic system supports neural circuits processing emotional information. The aim of this work is to evaluate changes of emotional recognition in PD patients induced by STN DBS. Thirty PD patients were assessed using a computerised paradigm of recognition of emotional facial expressions [Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press], 15 before STN DBS and 15 after. The two patients groups were compared to a group of 15 healthy control subjects. One series of 55 pictures of emotional facial expressions was presented to each patient. Patients had to classify the pictures according to seven basic emotions (happiness, sadness, fear, surprise, disgust, anger and no emotion). The intact ability to percept faces was firstly assured using the Benton Recognition Test. Recognition of fear expressions was significantly and selectively reduced in the post-operative group in comparison to both pre-operative and control groups. Our results demonstrate for the first time a selective reduction of recognition of facial expressions of fear by STN DBS. This impairment could be the first neuropsychological marker of a more general limbic dysfunction, thought to be responsible for the behavioural disorders reported after STN DBS.     

Acute severe depression induced by intraoperative stimulation of the substantia nigra: a case report

We present a 62 years old man with Parkinson's disease (PD) who underwent bilateral stimulation in the subthalamic nucleus (STN). During the intraoperative evaluation, stimulation through the lowest contact in the right STN area, induced an acute depressive state, during which the patient was crying and expressing that he did not want to live. The patient returned to his normal state of mood within seconds after the cessation of stimulation. Repeated blinded stimulations resulted in the same response. Immediate postoperative magnetic resonance imaging (MRI) revealed that the lowest contact of the right electrode was located in the substantia nigra.     

Autonomic cardiovascular control and responses to experimental pain stimulation in fibromyalgia syndrome

Objective

This study involves a comprehensive investigation of autonomic cardiovascular regulation in fibromyalgia syndrome (FMS) at rest and during painful stimulation and its association with pain indices.

Methods

In 35 patients and 29 healthy controls, electrocardiography, impedance cardiography, and finger continuous blood pressure measurements were conducted. For the purpose of experimental pain induction, a cold pressor test was applied.

Results

FMS patients showed lower pain threshold and tolerance, as well as higher ratings of pain intensity and unpleasantness on visual analogue scales. Resting stroke volume, myocardial contractility, R-R interval, heart rate variability, and sensitivity of the cardiac baroreflex were reduced in the patients, and increases in stroke volume and myocardial contractility during cold pressor stimulation were less pronounced. In the whole sample as well as in the FMS group, baroreflex sensitivity was inversely associated with subjective pain intensity, and a higher number of baroreflex operations per unit of time predicted higher pain tolerance.

Conclusions

The data suggest impaired autonomic cardiovascular regulation in FMS in terms of reduced sympathetic and parasympathetic influences, as well as blunted sympathetic reactivity to acute stress. The association between baroreflex function and pain experience reflects the pain inhibition mediated by the baroreceptor system. Given the reduced baroreflex sensitivity in FMS, one may assume deficient ascending pain inhibition arising from the cardiovascular system, which may contribute to the exaggerated pain sensitivity of FMS.     

Outcome of deep brain stimulation in slowly progressive multiple system atrophy: A clinico-pathological series and review of the literature

ObjectivesTo highlight the risk of clinical worsening after deep brain stimulation in histologically proven multiple system atrophy (MSA) patients presenting slow and relatively benign disease progression mimicking Parkinson's disease (PD). In such cases but also in more typical MSA patients, the results of deep brain stimulation have been mostly reported as case reports and small patient series.MethodsThe present study describes the outcome of the largest series of histologically proven MSA patients who underwent deep brain stimulation (DBS) of the subthalamic nucleus because they were considered as having PD at the time of surgery.ResultsThree patients showed significant improvement of motor signs after surgery while two did not. Clinical improvement was short-lasting and rapidly followed by the occurrence of disabling manifestations of MSA that counteracted DBS benefits.ConclusionsTogether with previous reports, our study demonstrates that DBS should not be recommended for MSA patients. It also underlines that detecting subtle red flags is crucial to avoid DBS surgery in this population.     

A novel approach to investigate neuronal network activity patterns affected by deep brain stimulation in rats

The establishment of new therapeutic indications for deep brain stimulation (DBS) is ambitiously promoted though the underlying mechanisms remain contested. Here, we report that PET-imaging and subsequent c-Fos-immunostaining in rats constitute a new translational approach to further understand DBS-mechanisms and -effectiveness.     

Subthalamic nucleus deep brain stimulation does not alter long-term heart rate variability in Parkinson’s disease

The power spectra of the heart rate variability frequency bands, analyzed from 24-hour ECG recordings, did not change 12 months after bilateral subthalamic nucleus operation in 14 patients with Parkinson’s disease.     

Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate

Background

Optimal parameters of transcutaneous auricular vagus nerve stimulation (taVNS) are still undetermined. Given the vagus nerve's role in regulating heart rate (HR), it is important to determine safety and HR effects of various taVNS parameters.

Electrophysiological signatures predict clinical outcomes after deep brain stimulation of the globus pallidus internus in Meige syndrome

ObjectiveDeep brain stimulation (DBS) of the globus pallidus internus (GPi) has been shown to be a safe and effective alternative therapy for ameliorating medically refractory primary Meige syndrome. However, the associations between DBS target position and surrounding electrophysiological properties as well as patients’ clinical outcomes remains largely unknown. In a large number of patients, we investigated electrophysiological features around stimulation targets and explored their roles in predicting clinical outcomes following bilateral GPi-DBS.MethodsThe locations of DBS active contacts along the long axis of the GPi in a standard space were calculated and compared among three groups with different clinical outcomes. The firing rates of individual neurons within the GPi were calculated for each patient and compared across the three groups.ResultsCompared with the bad group (poor clinical outcome), active contacts in the good group (good clinical outcome) and the best group (best clinical outcome) were located in the more posterior GPi. The average firing rates in the good and best groups were significantly higher than in the bad group, and this difference was pronounced within the ventral GPi. For the bad group, the average firing rates were significantly lower in the ventral than in the dorsal GPi.ConclusionsThis study suggests that DBS of the posterior GPi may produce better clinical outcomes during primary Meige syndrome treatment and that higher GPi neuronal activity, particularly within the ventral part, can be used as a biomarker to guide DBS electrode implantation during surgery.     

Acute severe depression induced by stimulation of the right globus pallidus internus

Depressive symptoms may occur after Deep Brain Stimulation (DBS) in the subthalamic nucleus. This is often explained by reduced pharmacological treatment after surgery, and not as a direct effect of DBS. Pallidal DBS seems not to be associated with such side effects and have not, to our knowledge, previously been reported. We present a patient with acute depressive symptoms induced by pallidal DBS. We believe this case strengthen the hypothesis that the basal ganglia and structures involved in the functional connectome of these nucleuses play a role not only in regulation of movement but also in regulation of mood.