Safety and feasibility of deep brain stimulation of the anterior cingulate and thalamus in chronic refractory neuropathic pain: a pilot and randomized study

Abstract

Background

Deep Brain Stimulation (DBS) of the anterior cingulum has been recently proposed to treat refractory chronic pain but its safety and its efficacy have not been evaluated in controlled conditions. Our objective was to evaluate the respective feasibility and safety of sensory thalamus (Thal-DBS) combined with anterior cingulate (ACC-DBS) DBS in patients suffering from chronic neuropathic pain.

Methods

We conducted a bicentric study (clinicaltrials.gov NCT03399942) in patients suffering from medically-refractory chronic unilateral neuropathic pain surgically implanted with both unilateral Thal-DBS and bilateral ACC-DBS, to evaluate successively: Thal-DBS only; combined Thal-DBS and ACC-DBS; ACC-DBS “on” and “off” stimulation periods in randomized cross-over double-blinded conditions; and a 1-year open phase. Safety and efficacy were evaluated by repeated neurological examination, psychiatric assessment, comprehensive assessment of cognitive and affective functioning. Changes on pain intensity (Visual Analogic Scale) and quality of life (EQ-5D scale) were used to evaluate DBS efficacy.

Results

All the patients (2 women, 6 men, mean age 52,1) completed the study. Adverse events were: epileptic seizure (2), transient motor or attention (2), persistent gait disturbances (1), sleep disturbances (1). No patient displayed significant cognitive or affective change. Compared to baseline, the quality of life (EQ-5D utility score) was significantly improved during the ACC-DBS “On” stimulation period (p = 0,039) and at the end of the study (p = 0,034).

Conclusion

This pilot study confirmed the safety of anterior cingulate DBS alone or in combination with thalamic stimulation and suggested that it might improve quality of life of patients with chronic refractory neuropathic pain.

Trial registration

The study has been registered on 20,180,117 (clinicaltrials.gov NCT03399942).

Background

Moderate to severe neuropathic pain (NP) has a prevalence of 5,1% in the general population [1]. Independently of pain intensity and duration, patients with NP report a huge impairment of quality of life and anxiety/depression scores, significantly higher than patients without pain or than patients suffering from pain without neuropathic component [2]. Only 23% of neuropathic pain patients consulting in tertiary pain treatment centers respond to well-conducted medical treatments, including antidepressants, antiepileptics and opioids [3]. These refractory NP patients [4], and especially central neuropathic pain [5], have a poor quality of life and no conventional therapeutic solution, justifying invasive approaches as deep brain stimulation (DBS).

DBS has been proposed since the 1970s to treat refractory pain using two main targets: regions surrounding the third ventricle and aqueduct of Sylvius, including the grey matter (periventricular grey and periaqueductal grey) and sensory thalamus. Sensory thalamic DBS targeted the ventral posteromedial (VPM) and ventral posterolateral (VPL) nuclei. Sensory thalamic stimulation seems selectively effective to refractory NP and a recent meta-analysis showed VPL demonstrated the largest effect among different brain targets, with significant heterogeneity observed [6]. However, several studies, including controlled trials, reported partial, insufficient [7] or short-lasting [8] efficacy that prevent its common use in daily practice.

Recently, the anterior and dorsal cingulate gyrus (ACC) has been proposed as a target for DBS for refractory pain [9, 10]. Functional brain imaging studies suggest that ACC plays a role in integration and modulation of the cognitive, emotional and affective components of pain [11, 12]. In particular, the ACC is thought to be involved in the process of attributing unpleasantness or “suffering” to the experience of pain perception. Focal neurosurgical lesions of the ACC, namely cingulotomies, have been used to treat chronic pain, with success rates of about 50% [13, 14]. Chronic electrical stimulation of the ACC (DBS-ACC), a non-destructive and reversible technique, was proposed as an alternative to cingulotomy in few open studies or case reports [9, 10, 15–17]. In a series of 22 patients suffering from refractory pain [10], ACC-DBS induced a reduction of pain intensity below a VAS score of 4/10 in one third of the patients. The overall health status (EQ-5D scale) and quality of life (SF-36 scale) improved significantly (respectively by 20% and 7%) after ACC-DBS at a mean follow-up of 13 months. Patients treated by cingulotomy or ACC-DBS reported a dissociation between the persistence of the usual pain perception and a certain indifference to pain linked to the loss of perception of its unpleasant aspect. This point and the dissociation between the significant improvement in quality of life and the lack of improvement in pain intensity suggests that DBS-ACC may modulate more the cognitive and emotional integration of pain rather than the pain itself [9, 14], bringing new therapeutic hope to hopeless chronic refractory pain patients.

However, ACC plays a functional role in other cognitive, motivational and affective functions [18]. Damage to the ACC results in an overall decrease in interest, a decrease in motivation and activity leading to apathy [13, 14]. Cingulotomies’ main adverse effect was apathy, although its incidence in treated pain patients was unclear [14]. These functions have not yet been studied in patients treated with chronic ACC- DBS. Moreover, DBS-induced indifference to pain may be associated with an emotional indifference (anhedonia), loss of motivation (apathy) or cognitive impairment, which may impact on patients’ daily lives.

Moreover, the interest of combining ACC-DBS with thalamic-DBS remains to be clarified, as these two DBS approaches seem to have different mechanisms of action. Thalamic DBS is supposed to modulate the transmission of the nociceptive input and to inhibit the hyperactivity of deafferented thalamic neurons, in order to reduce pain intensity. ACC-DBS is supposed to modulate the emotional integration of pain, without modifying the intensity and the perception of pain.

To answer to these questions, we conducted an exploratory study evaluating the feasibility and safety of combined ACC-DBS and thalamic-DBS, in patients with refractory NP for whom all conventional treatments have failed. This study was focused on the systematical assessment of the possible short-term and long-term cognitive, emotional and affective consequences of DBS. In order to evaluate the cognitive and affective impacts of ACC-DBS, the study also included a randomized phase during which DBS-ACC was alternatively active (“On”) or inactive (“Off”).

Methods

Study design

We conducted a bicentric prospective, feasibility and safety study to evaluate bilateral ACC-DBS combined with unilateral sensory thalamic-DBS in patients suffering from refractory unilateral NP. Study protocol has been previously published [19].

Sensory thalamic and ACC-DBS devices were implanted under local anesthesia in a single stage surgery. During the first month after surgery (M0-M1), only sensory thalamic-DBS was activated (Fig. 1). ACC-DBS was then activated one month after surgery (M1) and parameters settings were optimized during the next 3 months (M1-M4). Four months after surgery, all the patients were randomized in two 3 month-periods (separated by a 2-week wash-out period) organized in a cross-over design, comparing a DBS-ACC sequence on (“On”) and a DBS-ACC sequence off (“Off”). The patients and evaluating neurologists were blinded to the treatment periods and the ACC-stimulation parameters. This randomized period was followed by a 12-months open phase with ACC stimulation On.

Fig. 1.

Study design. The study design consists of a 1-month pre-treatment evaluation phase, a phase of thalamic stimulation alone (1 month), then thalamic and anterior cingulate (ACC) stimulation (3 months), followed by a cross-over randomized phase comparing ACC stimulation “On” (3 months) and “Off” (3 months) periods, and then an open phase (12 months)

Patients

Inclusion criteria were: adult patients (age 18–70 years old) suffering from chronic (duration > 1 year) unilateral NP (DN4 score ≥ 4/10), severe (VAS score ≥ 6/10 at 3 different evaluations during the year preceding inclusion), with high emotional impact (Hospital Anxiety and Depression scale sub-scores ≥ 10), considered as refractory to medication specific to neuropathic pain at sufficient doses and durations (including at least antiepileptics and antidepressants) and not sufficiently improved by rTMS or potentially relevant surgical solutions. Exclusion criteria were: cognitive impairment (MMSE score < 24), DSM-IV axis I psychiatric disorder, contra-indication to surgery, DBS, anesthesia or MRI.

Technical aspects

Details concerning the surgical technique and stimulation parameters for thalamic- and ACC-DBS have been previously published [19]. One lead was implanted in the sensory thalamic nuclei contralateral to pain and two leads were implanted bilaterally and symmetrically in the ACC, and then connected to 2 generators. Sensory thalamic nuclei were targeted stereotactically based on the patient’s MRI and optimal position of the electrode was refined by intraoperative micro-electrode recordings and test stimulation to check that DBS-induced paresthesias were perceived in the painful body area. Stimulation intensity used for chronic stimulation was adapted to ensure that the stimulation-paresthesias were pleasant and felt in the painful region. The dorsal anterior cingulate was targeted on stereotactic MRI, according to the technique and location proposed by [10], approximately 20 mm posterior to the projection of the anterior tip of the frontal horn of the lateral ventricle. We chose to target the ACC bilaterally considering that, in chronic pain patients, ACC activity changes are bilateral [12] and that previous successful therapeutic procedures targeting the ACC, namely cingulotomies [13, 14] and DBS [9, 10, 17] were performed bilaterally. Stimulation of the ACC does not induce any perceptible feeling. The stimulation parameters were based on those used by [9, 10]. To avoid a “kindling” effect and the risk of epilepsy, the chronic stimulation was cyclic, alternating a 5-minute “On” phase and a 10-minute “Off” phase. The stimulation parameters were optimized, depending on the therapeutic or adverse effects observed, during the period between M1 and M4. The parameters found to be the most effective and best tolerated were used for the randomized phase.

Endpoints

Feasibility was evaluated by the proportion of patients undergoing with success the process of surgical intervention, chronic stimulation and evaluation without serious adverse events. Safety profile and efficacy were evaluated 1 month before surgery and 1, 4, 7, 10, 22 months after by independent assessments performed by a neurosurgeon, a neurologist specialized in pain medicine, a psychiatrist and a neuropsychologist, the last three being blind from the randomization. Safety was evaluated by repeated general and neurological examination, psychiatric assessment, assessment of cognitive and affective functioning. The cognitive assessment consisted in several tests: the mini mental status (MMSE) [20] to evaluate global cognition, the French version of the Free and Cued Selective Reminding Test (FCSRT) [21] to assess episodic memory, the Digit Span WAIS-IV subtest to assess working memory, the Digit Symbol-Coding WAIS-IV subtest [22] to assess processing speed and the GREFEX battery [23] to assess executive functions, including the Trail Making Test (TMT), the Stroop test, the 6 element test, the Brixton test, the double task test, the modified card sorting test (MCST) and verbal fluencies. Assessment of affective functions was performed using Hospital Anxiety and Depression (HAD) scale [24] the Lille Apathy rating scale (LARS) [25], the revised version of “Reading the mind in the eyes” test [26] to assess theory of mind and the Facial Expressions of Emotion– Stimuli and Tests (FEEST) test [27] to assess emotion recognition.

DBS efficacy was evaluated using pain intensity on Visual Analogic Scale (VAS), Brief Pain Inventory [28], the QDSA questionnaire (French version of the Short-Form McGill Pain Questionnaire) [29] and quality of life improvement (EQ-5D-3 L health questionnaire) [30].

Statistics

To assess the effects of DBS on cognition we performed paired samples Student’s t-tests on each raw score comparing Baseline to every other time of the study (Post-op, Thalamus only, Thalamus and ACC, Long term). A “p-value” and an “adjusted p-value” were computed using the Benjamini and Hochberg False Discovery Rate to minimize the type I error rate. As we could not identify a pattern in the missing data, no imputing method was used. The effect of DBS on functioning of cognitive domains (episodic memory, executive functions, processing speed, working memory and social cognition) was assessed by grouping relevant standardized scores and computing their mean values. Lastly, we calculated the variation of these scores between baseline and every other time of measure. This new score was called “delta-z”. Descriptive statistics were then computed. Given the design of the study and following appropriate statistical practice, we used linear mixed models (LMMs) [31]. We used linear mixed models with time as a fixed variable, subject as a random variable, and each cognitive variable to be predicted. We also modeled the effect of time and interindividual variability with a multivariate mixed linear model considering the mean standardized scores of the different cognitive domains (episodic memory, executive functions, processing speed, working memory and social cognition). When necessary for mixed linear modeling, mean imputation was performed.

Analyses were performed using the software R Statistical Software (v4.2.2; R Core Team, 2022) and the following R packages: lme4 (v.1.1.33; [32]), mice (v.3 0.16.0; [33]), rempsyc (v.0.1.2 ) [34], tidyverse (v.2.0.0; [35]), zoo (v.1.8.12; [36]).

Concerning the efficacy assessment, due to the small number of subjects in this study, statistical analysis was based on non- parametric tests. Results are presented as means (standard deviation [SD]) for quantitative variables. The scores comparisons between each visit and baseline were performed using the Wilcoxon signed- rank test. Alpha risk was set to 5% (α = 0.05). Statistical analysis was performed with EasyMedStat (version 3.27; www.easymedstat.com).

Results

Patients

Eight patients were included in the study. Patients’ characteristics are detailed in Table 1. There were 6 men and 2 women; mean age was 52,1 years old (range 42–69). Five patients suffered from central neuropathic pain and 3 from peripheral neuropathic pain. Mean pain duration before surgery was 7,1 years (range 2,5–25).

Table 1.

Patients demographics and clinical characteristics. F: face; SL; superior limb, IL: inferior limb

Patient	Gender	Age	Pain mechanism	Location of the Lesion	Pain Location	Pain side	Pain duration
C1P1	M	52	Central neuropathic pain	Tectum mesencephali	Hemibody	L	6
C1P2	F	50	Central neuropathic pain: hemorrhagic stroke	Thalamus, internal capsule	SL, F	R	3
C1P3	M	42	Peripheral pain: sciatic nerve lesion	Sciatic nerve trunk	IL	L	7
CIP4	M	47	Central neuropathic pain: mesencephalic cavernoma	Mesencephalic	hemi body (IL predominant)	R	5
C2P1	M	67	Vestibular schwannoma	Trigeminal nerve lesion	F	L	25
C2P2	M	42	Central neuropathic pain, middle cerebral artery ischemic stroke	Fronto-parieto-insular regions	hemi-body ( SL and IL predominant)	L	3
C2P3	F	48	Trigeminal nerve lesion	Trigeminal nerve	F	R	2,5
C2P4	M	69	Spinal cord injury	Cervical spinal cord	SL, IL	R	5

Safety

All the patients completed the study. Only one patient refused to answer the neuropsychological assessment at the end of the study. Postoperative imaging confirmed the placement of the leads in the thalamus and ACC (Fig. 2). Thalamic stimulation intensity, pulse width and frequency were adapted according to the paresthesias perceived by the patients and varied between 0,4 − 2,5 mA, 120–150 microsecondes and 20–130 Hz, respectively. Due to the lack of efficacy and unpleasant DBS-induced paresthesias, 6 out of 8 patients demanded to stop the thalamic stimulation after 4 months of stimulation. ACC stimulation intensity and pulse width were adapted according to the safety profile and efficacy and varied between 2 and 3,5 mA and 60–450 microsecondes, respectively.

Fig. 2.

Location of electrodes. A. 3D representation of bilateral electrodes within the antérior cingulate cortex (ACC), from a left superior anterior point of view. B, C, D Patient’s C1P2 properative T1 weighted MRI merged with post operative CT showing the respective locations of the electrodes within the left sensory thalamus (B) and the ACC (C, D)

Adverse events are detailed in Table 2. Surgery-related complications consisted in one intraoperative epileptic seizure needing to abort the surgery. The postoperative imaging did not show any complication. The patient recovered without neurological impairment and the surgery was postponed and completed one month later. Most of the adverse events were observed during the ACC stimulation settings optimization period. Several patients presented transient motor or attention disturbances that recovered without sequelae when the ACC stimulation intensity was decreased (Table 2). Two patients displayed persistent adverse effects: one patient complained of gait and balance disturbances, probably related to thalamic stimulation; and one patient complained of sleep disturbances, likely related to ACC stimulation. No patient developed permanent epilepsy.

Table 2.

Adverse events

Peri-operative period
Intraoperative seizure	1
Local pain on générator site	1
Thalamic stimulation périod (1 month)
Pain worsening	1
Gait disturbances	2
Thalamic and ACC stimulation period (3 months)
Pain worsening	1
Gait disturbances	2
Sleep change (insomnia)	1
Attention disturbances	1
Focal seizure	1
Mood worsening	2
ACC “Off” period (3 months)
Sleep change (hypersomnia)	1
Mood worsening	1
ACC “On” stimulation period (3 months)
Gait disturbances	1
Mood worsening	1
Open phase (1 year)
Sleep disorder (insomnia)	1
Mood impairment	1

No patient displayed significant changes in cognitive and affective assessment (Table 3; Fig. 3). Paired t-tests on raw scores and delta-z scores did not change significantly neither between each time of measure compared baseline, nor between On and Off ACC-DBS periods. Linear mixed models confirmed the absence of cognitive and affective worsening over time (data not shown). Psychiatric clinical evaluation revealed no DBS-related impairment of emotional and affective functioning.

Table 3.

Cognitive and affective assessment of the patients according to study period and stimulation status. Values are expressed by means and standard deviations (SD) of the raw scores at each time of measure. TMT: Trail making test, WAIS-IV: Wechsler adult intelligence scale IV, RMET: reading the mind in the eyes task, FR: Free Recall, TR: total recall, FEEST: facial expression of emotion: stimuli and test, M-WCST: modified– Wisconsin Card sorting test, Stroop I-N: Stroop interference– naming

Tests	Baseline	Thalamus	Thalamus and ACC	ACC Off	ACC On	End of Study
MMSE	29.00 (0.82)	29.00 (1.15)	28.57 (1.51)	29.17 (1.17)	28.14 (1.57)	28.00 (1.41)
TMT A	45.75 (28.44)	39.14 (14.21)	43.50 (17.49)	40.50 (19.11)	47.00 (23.9)	38.83 (18.93)
TMT B	89.17 (32.42)	98.40 (62.34)	110.86 (55.73)	122.6 (63.33)	102.50 (59.55)	100.40 (60.47)
TMT B-A	48.33 (23.72)	62.20 (46.79)	69.86 (43.73)	87.8 (49.76)	61.33 (41.15)	67.80 (50.71)
Stroop naming	78.88 (21.89)	75.88 (24.28)	77.62 (19.16)	77.12 (16.6)	76.38 (15.42)	74.43 (14.8)
Stroop reading	58.50 (12.12)	60.25 (14.06)	61.62 (13.55)	62.38 (13.39)	60.62 (16.65)	58.86 (7.88)
Stroop interference	148.12 (39.26)	154.50 (54.27)	147.00 (49.58)	141.62 (42.88)	139.12 (37.43)	127.29 (35.36)
Stroop I-N	69.25 (23.37)	78.62 (41.27)	69.38 (36.45)	63.75 (34.92)	62.75 (30.07)	52.86 (28.93)
Six elements	4.88 (1.25)	5.14 (1.07)	4.88 (1.64)	5.50 (0.84)	5.62 (0.74)	6.00 (0.00)
Phonological fluency (P)	18.62 (6.76)	19.29 (5.96)	20.88 (7.24)	20.67 (8.91)	17.57 (7.28)	22.00 (11.42)
Categorical fluency	23.88 (5.69)	20.57 (7.41)	24.12 (7.20)	28.5 (9.59)	24.86 (11.61)	27.00 (7.38)
M-WCST	3.88 (3.48)	1.57 (1.72)	1.62 (1.92)	1.00 (1.26)	1.00 (1.53)	0.50 (0.55)
Brixton	17.00 (7.86)	15.25 (6.88)	13.75 (4.83)	10.43 (3.21)	11.88 (4.49)	10.00 (3.46)
Double task	97.80 (12.11)	86.88 (9.38)	93.86 (5.30)	89.35 (15.96)	84.80 (10.39)	84.24 (11.83)
FEEST	50.75 (4.17)	48.86 (4.71)	49.38 (3.07)	49.33 (1.97)	51.43 (4.24)	50.67 (2.66)
RMET	19.75 (4.40)	20.57 (2.07)	21.38 (3.42)	20.33 (3.88)	20.29 (3.3)	22.50 (3.27)
FR 1	7.50 (2.20)	9.38 (2.33)	9.50 (2.20)	10.29 (2.43)	9.88 (2.64)	10.33 (2.5)
FR 2	10.12 (3.83)	10.38 (2.45)	9.50 (3.59)	12.14 (3.24)	11.25 (3.11)	11.67 (3.14)
FR 3	11.25 (2.60)	11.75 (3.28)	11.00 (2.62)	12.00 (2.83)	11.50 (2.62)	12.83 (4.45)
FR 4	9.88 (3.98)	11.43 (2.88)	10.75 (2.96)	12.20 (4.32)	12.00 (2.83)	12.67 (2.73)
TR 1	14.38 (1.30)	14.75 (1.49)	13.88 (2.03)	14.86 (0.90)	14.38 (2.07)	13.83 (2.32)
TR 2	14.75 (1.28)	15.38 (0.74)	14.88 (2.23)	15.57 (0.79)	15.12 (0.99)	15.50 (1.22)
TR 3	15.25 (1.16)	15.75 (0.46)	15.00 (1.77)	15.43 (1.51)	15.75 (0.71)	15.83 (0.41)
TR 4	15.00 (1.60)	15.86 (0.38)	14.62 (2.07)	15.20 (1.79)	15.00 (1.53)	15.33 (1.03)
Digit span total	8.75 (3.37)	9.00 (2.16)	9.12 (2.59)	10.00 (2.76)	9.50 (2.93)	9.67 (3.33)
Forward span	8.75 (2.87)	9.00 (2.08)	9.12 (2.30)	9.57 (2.70)	9.75 (2.25)	9.67 (2.80)
Backward span	9.12 (2.59)	8.86 (1.95)	9.12 (2.42)	9.57 (1.90)	9.25 (2.87)	9.67 (1.97)
Ascending span	9.50 (3.82)	9.57 (2.76)	10.38 (3.11)	10.33 (3.61)	10.25 (3.37)	10.50 (4.72)

Fig. 3.

Evolution of main cognitive and affective performances along the study compared to baseline. The graphs indicate the differences of scores between baseline and every other time of measure. Indiviuals patients’ values are indicated by blue points, mean are displayed by red points. No patient showed a variation in performance greater than two standart deviations. Executive function score has been computed by the mean of standardized scores of several test including: the Trail Making Test B, Stroop interference, Stroop Interference– Naming, Six Elements, Phonological fluency, Categorical fluency, Modified Wisconsin card sorting test– perseverative error, Brixton, Double task. Episodic memory has been computed by the mean of standardized scores of the Free recalls 1, 2, 3 and 4 of the Free and Selective Cued Recall Test. The working memory score has been computed by the mean of standardized scores of WAIS IV digit span subtest. The score assessing the “Theory of Mind” has been computed as the mean of standardized score of the Reading the mind in the eyes test. The Emotion Recognition score has been computed as the mean of standardized score of the Facial expression of emotion, stimuli and test (FEEST). Apathy has been assessed by the Lille Apathy Rating Scale

Efficacy

Mean VAS pain intensity did not change significantly according to stimulation periods (Table 4; Fig. 4). However, we observed a significant improvement of the EQ-5D utility index at the end of the ACC ON stimulation period (p = 0,0039) and at the end of the study (p = 0,0034), compared to baseline.  EQ-5D VAS score tended to improve during the same periods, but without statistical significance. No endpoint varied significantly between the On and Off ACC stimulation periods. The affective pain rating index of the QDSA (French version of the McGill Pain Questionnaire) significantly improved between baseline and the end of the study, although the sensory pain rating index of the QDSA did not change significantly. At the end of the study, 4 patients estimated to be improved or very improved compared to baseline, 1 was slightly improved, 1 reported no change and 2 considered that they worsened compared to baseline.

Table 4.

Pain assessment scores of the patients according to study period and stimulation status. Values are expressed by means and standard deviations (SD) at each time of measure. * indicates scores significantly improved compared to baseline. VAS: visual Analogic Scale; BPI: brief Pain Inventory; QDSA: QDSA questionnaire (French version of the short-form McGill Pain Questionnaire); EQ-5D: EuroQoL EQ-5D-3 L health questionnaire

	Baseline	Thalamus	Thalamus and ACC	ACC Off	ACC On	End of study
VAS	70.62 (13.61)	64.62 (21.8)	56.25 (22.47)	64.57 (15)	63.5 (23)	45.57 (22.63)
EQ-5D utility	0.074 ( 0.19)	0.25 ( 0.26)	0.25 ( 0.32)	0.19 ( 0.36)	0.31 ( 0.32) * p = 0.039	0.44 ( 0.41) * p = 0.034
Equation 5D VAS	39 (24.31)	34.38 (19.86)	45.88 (24.08)	38.12 (31.62)	43.88 (29.74)	54.43 (27.04)
BPI Mood	5.88 (3.04)	6.38 (3.16)	6.25 (3.45)	6.235 (3.96)	5.254 (2.82)	4.71 (3.4)
BPI Walking Ability	5.88 (3.0)	5.88 (3.09)	6.12 (3.36)	6.62 (3.2)	5.75 (3.54)	3.57 (3.05)
BPI Normal Work	6.75 (3.33)	6.62 (2.26)	6.5 (3.21)	6.25 (3.88)	5.62 (3.46)	4.29 (3.35)
BPI Relations with other people	8.0 (5.0)	6.0 (2.75)	6.0 (3.75)	4.5 (5.25)	3.0 (6.0)	3.71 (2.87)
BPI Sleep	8.0 (2.25)	8.0 (3.0)	7.5 (4.25)	7 (4.5)	4 (4.0)	6.0 (3.32)
BPI Enjoyment of life	5.0 (3.21)	4.25 (2.92)	4.25 (3.96)	4.62 (4.14)	4.38 (4.07)	4.25 (3.96)
QDSA Affective	23 (4.41)	18.75 (5.8)	16.5 (8.04)	20.75 (5.5)	21.5 (21.5)	12.5 (18.5) * (p = 0.039)
QDSA Sensory	15.38 (6.84)	11.12 (4.05)	12.5 (5.71)	12.0 (5.55)	10.88 (6.24)	9.75 (6.8)
QDSA Total	38.38 (8.38)	29.88 (7.57)	29.0 (11.17)	32.75 (7.78)	27.38 (16.35)* (p = 0.036)	23.25 (7.99) * (p = 0.023)
HAD D	9.12 (5.84)	8.57 (6.16)	9.25 (6.58)	9.62 (7.67)	7.86 (8.8)	7.62 (6.74)
HAD A	8.75 (4.92)	6.43 (4.2)	7.38 (5.73)	8.88 (3.98)	7.86 (4.6)	8.62 (4.53)

Fig. 4.

Evolution of pain intensity and quality of life scores according to study period and stimulation status. VAS: Visual Analogic Scale; EQ-5D: EuroQoL EQ-5D-3 L health questionnaire including two scores: the utility score and the VAS score. QoL: quality of life

Discussion

Our study suggests that ACC-DBS is relatively safe, as it did not induce cognitive or affective side effects. Surgery-related complications were concordant with those usually observed in DBS procedures for movement disorders.

Our initial objective was to evaluate combined ACC and thalamic DBS. However, due to the lack of efficacy and poor tolerance of thalamic-DBS in our patients, most of them demanded to discontinue thalamic stimulation after a few months. These results differed from studies reporting significant improvement of neuropathic pain by thalamic stimulation [6, 37]. Several factors might have contributed to poor efficacy in our study. Most of our patients displayed central neuropathic pain, known to be less responsive to thalamic DBS than peripheral neuropathic pain [38]. In a recent international multicenter study, only 36% of patients suffering from central post-stroke pain did respond to thalamic DBS [39]. Thalamic DBS may be ineffective in central neuropathic pain in case of thalamic destruction; however only one patient (C1P2) in our study had a lesion involving the thalamus. We did not perform an external stimulation trial before complete implantation to select only responders. However, the efficacy of thalamic DBS has been questioned by two randomized studies [7] and is still a matter of debate.

Due to this early thalamic stimulation discontinuation, the safety of combined sensory thalamic and cingulate stimulation could be assessed during 3 months only, but we were able to assess the long-term safety of ACC DBS. In previous studies [10, 16, 17] no ACC DBS- specific complications or side effects were reported, except long term epilepsy [10]. None of our patients developed chronic epilepsy. This might be explained by our shorter follow-up and by different stimulation parameters, especially lower stimulation intensities (2,5 mA maximum in our study compared to 4.5–5 V in previous studies) and cyclic stimulation mode, alternating “On” and “Off” periods to avoid a kindling effect that might favor the development of chronic epilepsy. However, some of our patients displayed transient abnormal motor behaviors, occurring during the ACC stimulation setting period and likely related to excessive stimulation intensity, that were similar to abnormal behaviors induced by anterior cingulate stimulation in epileptic patients explored by stereo-encephalography [40]. We cannot determine whether these transient motor behaviors were focal epileptic seizures or not.

No previous study systematically assessed the potential cognitive and affective consequences of anterior cingulate DBS. We conducted a comprehensive assessment of cognitive and affective functions and detected no significant change over a period of more than one year. This is an important point as this dorsal anterior cingulate area, also called anterior mid-cingulate cortex, is involved in multiple essentials functions, including attention, cognitive control, memory, learning, decision making, social cognition, reward, emotion, negative affects and pain [18, 41]. The absence of adverse effects allows us to consider the further use of anterior cingulum stimulation, provided that it is effective.

Efficacy of ACC DBS has been evaluated only in short cases series [10, 15, 17]. Most of these studies reported a mild or non-significant decrease of mean pain intensity, contrasting with a significant improvement in patients’ quality of life. We observed similar outcomes when comparing the preoperative, baseline pain intensity and quality of life scores with those recorded at the end of the “On” ACC-DBS period and at the end of the study. Those results suggest that ACC-DBS may influence patient’s perception of their own quality of life or health status, independently of pain intensity changes. In addition, considering the changes observed on the McGill Pain Questionnaire, ACC DBS was more efficient on the affective component than on the sensory component of chronic pain. On the other hand, we did not observe significant changes of the HAD depression sub-scores, indicating that the quality-of-life improvement was not related to mood improvement. Changes in ACC activity can be observed in chronic pain patients who experience pain relief, whatever the treatment, including surgery, medication or even placebo [11]. Altogether, these results suggest that ACC-DBS may modulate the affective component of pain and/or emotional perception of pain, leading to an improvement in quality of life.

Recently, Lempka et al. reported that DBS of the ventral striatum / anterior limb of the internal capsule (VS/ALIC), a region targeted by DBS to treat major depressive disorder, improved depressive aspect of patients suffering from chronic pain, but without decreasing pain intensity. VS/ALIC-DBS and ACC-DBS share a common strategy, namely to target the affective component or affective consequences of chronic pain. This strategy could prove more feasible and relevant than targeting the pain intensity itself, in patients suffering from chronic refractory neuropathic pain.

Despite its encouraging results, our study suffered from several limitations. The study lacked adequate statistical power to detect an eventual significant change between ACC-DBS “On” and “Off” conditions, due to the low and insufficient number of patients. These chronic refractory pain patients are usually complex to evaluate, to manage and to treat. VAS score is insufficient to reflect this complexity and the burden of chronic pain. In these patients, pain relief does not necessarily translate into a major change in the VAS score. More relevant and specific endpoints are needed. ACC-DBS efficacy differed across patients and only half of them reported an improvement potentially related to ACC-DBS. Predictors of efficacy are needed to better select future responders. However the safety profile of ACC-DBS allows to study its efficacy in larger controlled studies which are still mandatory.

Conclusions

This pilot study confirmed the safety of anterior cingulate DBS alone or in combination with thalamic stimulation and suggested that it might improve quality of life of patients with chronic refractory pain.

Author contributions

1) conception and design of the study: DF, MLM, AD, ND2) acquisition and analysis of data: DF, AL, AD, ND, AB, BG, RR, BS, PI, JR, MLM.3) drafting of the manuscript and/or figures: DF, AL, ND, AD, AB, BS, PI, MLM. All authors reviewed the manuscript.

Data availability

Anominyzed data is available for research purpose, on request to the corresponding author.

Declarations

Ethics approval and consent to participate

The study was approved by a Ethical Medical Committee (“Comité de Protection de Personnes Sud Méditerranée”, ID-IRB 2017-A00032-51) and registered (clinicaltrials.gov NCT03399942). All the patients signed an informed consent before inclusion. Safety data were supervised by an independent Data Monitoring Committee.

Competing interests

This academic study has been sponsored and funded by the CHU de Nice (grant number: 16-AOIP-01). The hardware (leads and generators) was provided free of charge by Abbott which was not involved in the design and analysis of the study. DF is consultant for Medtronic, Abbott, and Boston Scientific, companies that manufacture and commercialize DBS devices, and received research grant from Medtronic and Abbott. MLM is consultant for Medtronic and received research grant from Medtronic. AL received speaker fees from Boston Scientific. AB has received consultant fees from Medtronic. Other authors declare no conflict of interest related to the study.