Deep Brain Stimulation Influences Brain Structure in Alzheimer's Disease

Published:December 03, 2014DOI:


      • We examined structural brain changes following DBS of the fornix in AD.
      • In 2 of 6 AD patients, fornix DBS reversed hippocampal atrophy at one year.
      • Across all 6 AD patients, fornix DBS preserved volume in several brain regions.
      • DBS may influence the natural course of brain atrophy in neurodegenerative disease.



      Deep Brain Stimulation (DBS) is thought to improve the symptoms of selected neurological disorders by modulating activity within dysfunctional brain circuits. To date, there is no evidence that DBS counteracts progressive neurodegeneration in any particular disorder.


      We hypothesized that DBS applied to the fornix in patients with Alzheimer's Disease (AD) could have an effect on brain structure.


      In six AD patients receiving fornix DBS, we used structural MRI to assess one-year change in hippocampal, fornix, and mammillary body volume. We also used deformation-based morphometry to identify whole-brain structural changes. We correlated volumetric changes to hippocampal glucose metabolism. We also compared volumetric changes to those in an age-, sex-, and severity-matched group of AD patients (n = 25) not receiving DBS.


      We observed bilateral hippocampal volume increases in the two patients with the best clinical response to fornix DBS. In one patient, hippocampal volume was preserved three years after diagnosis. Overall, mean hippocampal atrophy was significantly slower in the DBS group compared to the matched AD group, and no matched AD patients demonstrated bilateral hippocampal enlargement. Across DBS patients, hippocampal volume change correlated strongly with hippocampal metabolism and with volume change in the fornix and mammillary bodies, suggesting a circuit-wide effect of stimulation. Deformation-based morphometry in DBS patients revealed local volume expansions in several regions typically atrophied in AD.


      We present the first in-human evidence that, in addition to modulating neural circuit activity, DBS may influence the natural course of brain atrophy in a neurodegenerative disease.


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        • Pizzolato G.
        • Mandat T.
        Deep brain stimulation for movement disorders.
        Front Integr Neurosci. 2012; 6 (PMCID: 3265746): 2
        • Mayberg H.S.
        • Lozano A.M.
        • Voon V.
        • et al.
        Deep brain stimulation for treatment-resistant depression.
        Neuron. 2005; 45: 651-660
        • Holtzheimer P.E.
        • Kelley M.E.
        • Gross R.E.
        • et al.
        Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression.
        Arch Gen Psychiatry. 2012; 69: 150-158
        • Jimenez-Ponce F.
        • Velasco-Campos F.
        • Castro-Farfan G.
        • et al.
        Preliminary study in patients with obsessive-compulsive disorder treated with electrical stimulation in the inferior thalamic peduncle.
        Neurosurgery. 2009; 65 (discussion 209): 203-209
        • Greenberg B.D.
        • Malone D.A.
        • Friehs G.M.
        • et al.
        Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder.
        Neuropsychopharmacology. 2006; 31: 2384-2393
        • Lipsman N.
        • Woodside D.B.
        • Giacobbe P.
        • et al.
        Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial.
        Lancet. 2013; 381: 1361-1370
        • Lozano A.M.
        • Lipsman N.
        Probing and regulating dysfunctional circuits using deep brain stimulation.
        Neuron. 2013; 77: 406-424
        • Querfurth H.W.
        • LaFerla F.M.
        Alzheimer's disease.
        N Engl J Med. 2010; 362: 329-344
        • Greicius M.D.
        • Srivastava G.
        • Reiss A.L.
        • Menon V.
        Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI.
        Proc Natl Acad Sci U S A. 2004; 101 (PMCID: 384799): 4637-4642
        • Sperling R.A.
        • Dickerson B.C.
        • Pihlajamaki M.
        • et al.
        Functional alterations in memory networks in early Alzheimer's disease.
        Neuromolecular Med. 2010; 12 (PMCID: 3036844): 27-43
        • Laxton A.W.
        • Tang-Wai D.F.
        • McAndrews M.P.
        • et al.
        A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease.
        Ann Neurol. 2010; 68: 521-534
        • Smith G.S.
        • Laxton A.W.
        • Tang-Wai D.F.
        • et al.
        Increased cerebral metabolism after 1 year of deep brain stimulation in Alzheimer disease.
        Arch Neurol. 2012; 69: 1141-1148
        • Toda H.
        • Hamani C.
        • Fawcett A.P.
        • Hutchison W.D.
        • Lozano A.M.
        The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation.
        J Neurosurg. 2008; 108: 132-138
        • Stone S.S.
        • Teixeira C.M.
        • Devito L.M.
        • et al.
        Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory.
        J Neurosci. 2011; 31: 13469-13484
        • Hamani C.
        • Stone S.S.
        • Garten A.
        • Lozano A.M.
        • Winocur G.
        Memory rescue and enhanced neurogenesis following electrical stimulation of the anterior thalamus in rats treated with corticosterone.
        Exp Neurol. 2011; 232: 100-104
        • Chung M.K.
        • Worsley K.J.
        • Paus T.
        • et al.
        A unified statistical approach to deformation-based morphometry.
        Neuroimage. 2001; 14: 595-606
        • Morris J.C.
        The Clinical Dementia Rating (CDR): current version and scoring rules.
        Neurology. 1993; 43: 2412-2414
        • Folstein M.F.
        • Folstein S.E.
        • McHugh P.R.
        “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician.
        J Psychiatr Res. 1975; 12: 189-198
        • Rosen W.G.
        • Mohs R.C.
        • Davis K.L.
        A new rating scale for Alzheimer's disease.
        Am J Psychiatry. 1984; 141: 1356-1364
        • Wechsler D.
        The Wechsler Abbreviated Scale of Intelligence.
        The Psychological Corporation, San Antonio, TX1999
        • Reitan R.M.
        Trail making test: manual for administration, scoring and interpretation.
        Indiana University Medical Center, Indianapolis, IN1958
        • Wechsler D.
        Wechsler Memory Scale – third edition manual.
        The Psychological Corporation, San Antonio, TX1997
        • Sled J.G.
        • Zijdenbos A.P.
        • Evans A.C.
        A nonparametric method for automatic correction of intensity nonuniformity in MRI data.
        IEEE Trans Med Imaging. 1998; 17: 87-97
        • Boccardi M.
        • Bocchetta M.
        • Apostolova L.G.
        • et al.
        Establishing magnetic resonance images orientation for the EADC-ADNI manual hippocampal segmentation protocol.
        J Neuroimaging. 2014; 24: 509-514
        • Watson C.
        • Cendes F.
        • Fuerst D.
        • et al.
        Specificity of volumetric magnetic resonance imaging in detecting hippocampal sclerosis.
        Arch Neurol. 1997; 54: 67-73
        • Copenhaver B.R.
        • Rabin L.A.
        • Saykin A.J.
        • et al.
        The fornix and mammillary bodies in older adults with Alzheimer's disease, mild cognitive impairment, and cognitive complaints: a volumetric MRI study.
        Psychiatry Res. 2006; 147: 93-103
        • Nugent A.C.
        • Luckenbaugh D.A.
        • Wood S.E.
        • Bogers W.
        • Zarate Jr., C.A.
        • Drevets W.C.
        Automated subcortical segmentation using FIRST: test-retest reliability, interscanner reliability, and comparison to manual segmentation.
        Hum Brain Mapp. 2013 Sep; 34 (PMCID: 3479333): 2313-2329
        • Shrout P.E.
        • Fleiss J.L.
        Intraclass correlations: uses in assessing rater reliability.
        Psychol Bull. 1979; 86: 420-428
        • Hamacher K.
        • Coenen H.H.
        • Stocklin G.
        Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-d-glucose using aminopolyether supported nucleophilic substitution.
        J Nucl Med. 1986; 27: 235-238
        • Takikawa S.
        • Dhawan V.
        • Spetsieris P.
        • et al.
        Noninvasive quantitative fluorodeoxyglucose PET studies with an estimated input function derived from a population-based arterial blood curve.
        Radiology. 1993; 188: 131-136
        • Smith G.S.
        • Kramer E.
        • Ma Y.
        • et al.
        Cholinergic modulation of the cerebral metabolic response to citalopram in Alzheimer's disease.
        Brain. 2009; 132 (PMCID: 2640217): 392-401
        • Collins D.L.
        • Neelin P.
        • Peters T.M.
        • Evans A.C.
        Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space.
        J Comput Assist Tomogr. 1994; 18: 192-205
        • Ishii K.
        • Soma T.
        • Kono A.K.
        • et al.
        Comparison of regional brain volume and glucose metabolism between patients with mild dementia with lewy bodies and those with mild Alzheimer's disease.
        J Nucl Med. 2007; 48: 704-711
        • Chakravarty M.M.
        • Sadikot A.F.
        • Germann J.
        • Bertrand G.
        • Collins D.L.
        Towards a validation of atlas warping techniques.
        Med Image Anal. 2008; 12: 713-726
        • Robbins S.
        • Evans A.C.
        • Collins D.L.
        • Whitesides S.
        Tuning and comparing spatial normalization methods.
        Med Image Anal. 2004; 8: 311-323
        • Borghammer P.
        • Ostergaard K.
        • Cumming P.
        • et al.
        A deformation-based morphometry study of patients with early-stage Parkinson's disease.
        Eur J Neurol. 2010; 17: 314-320
        • Grabner G.
        • Janke A.L.
        • Budge M.M.
        • Smith D.
        • Pruessner J.
        • Collins D.L.
        Symmetric atlasing and model based segmentation: an application to the hippocampus in older adults.
        Med Image Comput Comput Assist Interv. 2006; 9: 58-66
        • Morey R.A.
        • Selgrade E.S.
        • Wagner 2nd, H.R.
        • Huettel S.A.
        • Wang L.
        • McCarthy G.
        Scan-rescan reliability of subcortical brain volumes derived from automated segmentation.
        Hum Brain Mapp. 2010; 31: 1751-1762
        • Falowski S.M.
        • Sharan A.
        • Reyes B.A.
        • Sikkema C.
        • Szot P.
        • Van Bockstaele E.J.
        An evaluation of neuroplasticity and behavior after deep brain stimulation of the nucleus accumbens in an animal model of depression.
        Neurosurgery. 2011; 69: 1281-1290
        • Fotuhi M.
        • Do D.
        • Jack C.
        Modifiable factors that alter the size of the hippocampus with ageing.
        Nat Rev Neurol. 2012; 8: 189-202
        • Barnes J.
        • Bartlett J.W.
        • van de Pol L.A.
        • et al.
        A meta-analysis of hippocampal atrophy rates in Alzheimer's disease.
        Neurobiol Aging. 2009; 30 (PMCID: 2773132): 1711-1723
        • May A.
        Experience-dependent structural plasticity in the adult human brain.
        Trends Cogn Sci. 2011; 15: 475-482