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Cognitive effects of deep brain stimulation: focus on caudal zona incerta for essential tremor and Parkinson´s disease, and on bed nucleus of stria terminalis for obsessive compulsive disorder
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0002-7063-9710
2023 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Kognitiva effekter av deep brain stimulation (djup hjärnstimulering) : fokus på caudal zona incerta vid essentiell tremor och Parkinsons sjukdom, samt på bed nucleus stria terminalis vid tvångssyndrom (Swedish)
Abstract [en]

Preserved cognition is an important determinant for perceived Quality of Life (QoL) and has been found to be essential in order to translate improvements in primary symptoms following Deep Brain Stimulation (DBS) into activities of daily living that drive QoL. Therefore, it is important to evaluate not only the clinical improvement, but also the cognitive impact of DBS.

The aim of this thesis was to evaluate the cognitive effects of DBS in a new target, the caudal Zona incerta (cZi), which has shown promising results in patients with both Parkinson’s Disease (PD) and Essential Tremor (ET). Given that this is a novel target, the effects on cognition were lacking in the literature. In the same manner, the cognitive effects in patients with Obsessive-Compulsive Disorder (OCD) receiving DBS in the Bed Nucleus of Stria Terminalis (BNST) lacked long-term follow-up.

The main findings from the studies included in this thesis, suggest that DBS in the cZi in patients with PD and ET, and in the BNST in patients with OCD, does not generate any major cognitive effects and can be considered safe from a cognitive perspective.However, subtle effects involving aspects of executive function may be present following cZi DBS in patients with PD. Significant results concerned primarily a decrease in selective attention and aspects of inhibition. cZi DBS in patients with ET generated fewer cognitive effects, including a decrease in semantic verbal fluency 12 months after DBS in the cZi. fMRI results evaluating the effects of cZi DBS on brain activity during a working memory task, did not show any significant changes when DBS was ON or OFF. This study also revealed a significant Task-x-DBS interaction, with faster response times during DBS ON relative to DBS OFF for the more cognitively demanding “manipulation” task. In OCD patients with BNST DBS, improved results on the Color-Word Inhibition/switching subtest were found, indicating a possible improvement in cognitive flexibility. However, there was a decrease of performance in visuo-spatial learning at 12 months after surgery.

The studies in patients with PD and ET were the first to report comprehensive neuropsychological data regarding cZi DBS. The fMRI study was the first in patients with ET treated with cZi DBS, focusing on cognitive effects during a working memory task in on/off DBS conditions. The OCD study was the first to report long-term data on cognitive effects after BNST DBS. By showing that DBS in these targets does not produce any major cognitive side effects, valuable knowledge in terms of safety has been added. This will hopefully contribute to increased treatment options in DBS.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2023. , p. 79
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2226
Keywords [en]
Deep brain stimulation. Neuropsychology. Cognition. Parkinson’s disease. Essential tremor. Obsessive-compulsive disorder. Caudal zona incerta. Bed nucleus of stria terminalis. Functional MRI.
National Category
Neurosciences
Research subject
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-204361ISBN: 978-91-7855-995-4 (print)ISBN: 978-91-7855-996-1 (electronic)OAI: oai:DiVA.org:umu-204361DiVA, id: diva2:1733524
Public defence
2023-03-03, Hörsal D, målplan T, plan 9, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Note

Oregelbunden paginering / Various pagings.

Available from: 2023-02-10 Created: 2023-02-02 Last updated: 2023-02-08Bibliographically approved
List of papers
1. Short- and long-term cognitive effects of deep brain stimulation in the caudal zona incerta versus best medical treatment in patients with Parkinson's disease
Open this publication in new window or tab >>Short- and long-term cognitive effects of deep brain stimulation in the caudal zona incerta versus best medical treatment in patients with Parkinson's disease
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2021 (English)In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 134, no 2, p. 357-365Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: A growing number of studies are showing positive effects of deep brain stimulation (DBS) in the caudal zona incerta (cZi) in various tremor disorders, as well as motor symptoms of Parkinson’s disease (PD). The focus of the present study was to evaluate short- and long-term cognitive effects of bilateral cZi DBS in patients with PD.

METHODS: Twenty-five nondemented patients with advanced PD were recruited to participate in a randomized trial of cZi DBS versus best medical treatment (BMT). The patients in the BMT group were offered surgery after 6 months. Neuropsychological evaluations focusing on assessing verbal and visuospatial memory, attention, and executive function were conducted at baseline and at 6 and 24 months after surgery. Self-reported measures of depression, anxiety, and change in "frontal" behaviors were also completed at all assessment points.

RESULTS: Bilateral cZi DBS in patients with PD generated few adverse cognitive effects. At the short-term follow-up after 6 months, no differences were found between patients randomized to BMT and patients randomized to DBS with regard to most of the cognitive domains assessed. A transient improvement in anxiety was, however, found in the surgical group. At the long-term follow-up 24 months after cZi DBS, no major changes in global cognitive functioning were found, although a decline in attention and self-reported executive function was noted.

CONCLUSIONS: With the exception of a decline in attention and self-reported executive function, bilateral cZi DBS for PD in appropriately screened patients appears to be generally safe with regard to cognitive function, both in the short- and long-term perspective.

Place, publisher, year, edition, pages
American Association of Neurological Surgeons (AANS), 2021
Keywords
zona incerta, Parkinson's disease, deep brain stimulation, neuropsychology, cognition, functional neurosurgery
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-170467 (URN)10.3171/2019.12.JNS192654 (DOI)000646422100005 ()32032954 (PubMedID)2-s2.0-85100240654 (Scopus ID)
Available from: 2020-05-06 Created: 2020-05-06 Last updated: 2023-05-03Bibliographically approved
2. Deep brain stimulation in the caudal zona incerta in patients with essential tremor: effects on cognition 1 year after surgery
Open this publication in new window or tab >>Deep brain stimulation in the caudal zona incerta in patients with essential tremor: effects on cognition 1 year after surgery
2021 (English)In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 134, no 1, p. 208-215Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: The ventral intermediate nucleus (VIM) of the thalamus is currently the established target in the use of deep brain stimulation (DBS) to treat essential tremor (ET). In recent years, the caudal zona incerta (cZi), a brain target commonly used during the lesional era, has been revived as the primary target in a number of DBS studies that show evidence of the efficacy of cZi targeting in DBS treatment for controlling the symptoms of ET. The authors sought to obtain comprehensive neuropsychological data and thoroughly investigate the cognitive effects of cZi targeting in patients with ET treated with DBS.

METHODS: Twenty-six consecutive patients with ET who received DBS with cZi as the target at our department from December 2012 to February 2017 were included in this study. All patients were assessed using a comprehensive neuropsychological test battery covering the major cognitive domains both preoperatively and 12 months postoperatively.

RESULTS: The results show no major adverse effects on patient performance on the tests of cognitive function other than a slight decline of semantic verbal fluency.

CONCLUSIONS: This study indicates that the cZi is a safe target from a cognitive perspective in the treatment of ET with DBS.

Place, publisher, year, edition, pages
American Association of Neurological Surgeons (AANS), 2021
Keywords
zona incerta, essential tremor, deep brain stimulation, cognition, functional neurosurgery
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-170465 (URN)10.3171/2019.9.JNS191646 (DOI)000616580000008 ()31860827 (PubMedID)2-s2.0-85098275783 (Scopus ID)
Available from: 2020-05-06 Created: 2020-05-06 Last updated: 2023-03-24Bibliographically approved
3. Evaluation of the effects of DBS in the caudal Zona incerta on brain activity during a working memory task in patients with essential tremor
Open this publication in new window or tab >>Evaluation of the effects of DBS in the caudal Zona incerta on brain activity during a working memory task in patients with essential tremor
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2023 (English)In: Neuroimage: Reports, ISSN 2666-9560, Vol. 3, no 4, article id 100193Article in journal (Refereed) Published
Abstract [en]

Essential tremor (ET) is characterized by bilateral upper limb postural and/or kinetic tremor, but also cognitive deficits. Tremor in ET, as well as aspects of cognitive deficits associated with ET, have been suggested to be linked to dysfunction in the cerebello-thalamo-cerebral circuit. In ET patients with disabling and medically intractable motor symptoms, Deep Brain Stimulation (DBS) is effective in reducing tremor. DBS in the caudal Zona incerta (cZi) has been shown to modulate the activity of the sensorimotor cerebello-cerebral circuit during motor tasks. Whether the activity in the cerebello-cerebral circuit is modulated by DBS during tasks involving working memory is unknown. The present study therefore aimed to investigate the possible effects of cZi DBS on working-memory processing in ET patients by means of task-based blood oxygen level-dependent (BOLD) fMRI.

Thirteen ET patients completed a working-memory task during DBS OFF and ON conditions. The task involved three conditions: maintenance, manipulation, and control. Behaviorally, there was no significant effect from DBS on accuracy, but a marginally significant Task x DBS interaction was detected for response times (RTs). However, post hoc comparisons for each condition failed to reach statistical significance. FMRI analyses revealed that DBS did not alter BOLD signal in regions of interest (lateral prefrontal cortex, parietal cortex, and the cerebellum), or in a complementary whole-brain analysis.

The present study indicates that DBS in the cZi in patients with ET has at most marginal effects on working memory, which is consistent with the results of pre- and post-DBS neuropsychological assessment showing minimal cognitive effects of surgery.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Deep brain stimulation, Essential tremor, Working memory, fMRI
National Category
Neurosciences
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-204363 (URN)10.1016/j.ynirp.2023.100193 (DOI)2-s2.0-85175237822 (Scopus ID)
Funder
Swedish Research Council
Note

Originally included in thesis in manuscript form.

Available from: 2023-02-02 Created: 2023-02-02 Last updated: 2023-11-09Bibliographically approved
4. Deep brain stimulation in the ALIC-BNST region targeting the bed nucleus of stria terminalis in patients with obsessive–compulsive disorder: effects on cognition after 12 months
Open this publication in new window or tab >>Deep brain stimulation in the ALIC-BNST region targeting the bed nucleus of stria terminalis in patients with obsessive–compulsive disorder: effects on cognition after 12 months
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2023 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 165, no 5, p. 1201-1214Article in journal (Refereed) Published
Abstract [en]

Purpose: The aim of this study was to evaluate cognitive effects 12 months after Deep Brain Stimulation (DBS) of the Bed Nucleus of Stria Terminalis (BNST) in patients with refractory Obsessive–Compulsive Disorder (OCD).

Methods: Eight patients (5 female; mean ± SD age 36 ± 15) with OCD were included. A neuropsychological test battery covering verbal and spatial episodic memory, executive function, and attention was administered preoperatively and 12 months after surgery. Medical records were used as a source for descriptive data to probe for any changes not covered by standardized checklists and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the primary outcome measure.

Results: At 12 months, seven patients showed response to DBS: three were full responders (i.e., Y-BOCS ≥ 35% improvement), and four were partial responders (Y-BOCS 25–34% improvement). Relative to baseline, there was a slight decline on visuo-spatial learning (p = 0.027), and improved performance on the Color-Word Interference inhibition/switching subtest (p = 0.041), suggesting improvement in cognitive flexibility.

Conclusions: DBS in the BNST for treatment refractory OCD generates very few adverse cognitive effects and improves cognitive flexibility after 12 months of stimulation. The improvement in Y-BOCS and the absence of major cognitive side effects support the BNST as a potential target for DBS in severe OCD.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Bed nucleus of stria terminalis, BNST, Cognition, Deep brain stimulation, DBS, Obsessive–compulsive disorder, OCD
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-199475 (URN)10.1007/s00701-022-05351-2 (DOI)000849141100001 ()36056244 (PubMedID)2-s2.0-85137480737 (Scopus ID)
Available from: 2022-09-20 Created: 2022-09-20 Last updated: 2023-09-21Bibliographically approved

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