Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease Dementia

Abstract

IMPORTANCE Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a treatment option for Parkinson disease dementia. OBJECTIVE To evaluate the safety and potential symptomatic effects of NBM DBS in patients with Parkinson disease dementia. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, crossover clinical trial evaluated the results of 6 patients with Parkinson disease dementia who were treated with NBM DBS at a neurosurgical referral center in the United Kingdom from October 26, 2012, to July 31, 2015. Eligible patients met the diagnostic criteria for Parkinson disease dementia, had motor fluctuations, were appropriate surgical candidates aside from the coexistence of dementia, were age 35 to 80 years, were able to give informed consent, had a Mini-Mental State Examination score of 21 to 26, had minimal atrophy seen on results of brain magnetic resonance imaging, and lived at home with a caregiver-informant. INTERVENTIONS After surgery, patients were assigned to receive either active stimulation (bilateral, low-frequency [20 Hz] NBM DBS) or sham stimulation for 6 weeks, followed by the opposite condition for 6 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was the difference in scores on each item of an abbreviated cognitive battery (California Verbal Learning Test-II, Wechsler Adult Intelligence Scale-III digit span, verbal fluency, Posner covert attention test, and simple and choice reaction times) between the 2 conditions. Secondary outcomes were exploratory and included differences in scores on standardized measurements of cognitive, psychiatric, and motor symptoms and resting state functional magnetic resonance imaging. RESULTS Surgery and stimulation were well tolerated by all 6 patients (all men; mean [SD] age, 65.2 [10.7] years), with no serious adverse events during the trial. No consistent improvements were observed in the primary cognitive outcomes or in results of resting state functional magnetic resonance imaging. An improvement in scores on the Neuropsychiatric Inventory was observed with NBM DBS (8.5 points [range, 4-26 points]) compared with sham stimulation (12 points [range, 8-38 points]; median difference, 5 points; 95% CI, 2.5-8.5 points; P = .03) and the preoperative baseline (13 points [range, 5-25 points]; median difference, 2 points; 95% CI, −8 to 5.5 points; P = .69). CONCLUSIONS AND RELEVANCE Low-frequency NBM DBS was safely conducted in patients with Parkinson disease dementia; however, no improvements were observed in the primary cognitive outcomes. Further studies may be warranted to explore its potential to improve troublesome neuropsychiatric symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01701544

Simultaneous Stimulation of the Globus Pallidus Interna and the Nucleus Basalis of Meynert in the Parkinson-Dementia Syndrome

“…The study reported no consistent improvements in the primary cognitive outcomes after DBS treatment. However, the participants in that study met the criteria for PD dementia, suggesting a more advanced state of neurodegeneration and cortical atrophy [17]. In our study, the patient showed mild cognitive impairments, which might have facilitated obtaining greater improvements after DBS surgery.…”

“…Using fewer leads (2 vs. 4) could be associated with additional cognitive benefits due to less white matter damage, since damaged white matter may lead to a reduced compensation of disconnections in cognitive circuits caused by the implantation of the DBS electrodes or by chronic stimulation [41]. A recent randomized, double-blind clinical trial evaluated 6 patients with PD who underwent DBS and received either active NBM stimulation for 6 weeks followed by sham stimulation for another 6 weeks or those same treatments in reverse order [17]. The study reported no consistent improvements in the primary cognitive outcomes after DBS treatment.…”

“…Likewise, a more complete evaluation of limbic functions under DBS might have enhanced our understanding of the relationship between DBS and the mood effects reported after GPi stimulation. Finally, although the 2 distal contacts of our electrodes were placed in an area corresponding to the location of the NBM complex, they were not at the proposed optimal target for memory, reportedly the laterodorsal portion of the intermediate sector within the NBM (Ch4 intermedius) [10, 17]. …”

“…Stimulation parameters for the monopolar program were 20 Hz, 60 µs and 2 mA bilaterally. The electrode tips were most likely located at the NBM complex but not in the Ch4 intermedius subnucleus, which has been proposed as the optimal target for dementia [10, 17]. …”

Neural signatures of pathological hyperdirect pathway activity in Parkinson’s disease

“…Patients were diagnosed with Parkinson's disease according to the Queen Square Brain Bank criteria 65 . Patients in the GPi DBS subgroup had an additional diagnosis of Parkinson's disease dementia (PDD) and were recruited into a separate trial which involved targeting both the GPi and the Nucleus Basalis of Meynert (NBM) 66 . Clinical characteristics of the patients are presented in Supplementary Table 1.…”