Advertisement

Differential Effects of Deep Brain Stimulation of the Internal Capsule and the Striatum on Excessive Grooming in Sapap3 Mutant Mice

  • Author Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Cindy M. Pinhal
    Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Affiliations
    Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
    Search for articles by this author
  • Author Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Bastijn J.G. van den Boom
    Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Affiliations
    Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands

    Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    Search for articles by this author
  • Fabiana Santana-Kragelund
    Affiliations
    Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
    Search for articles by this author
  • Lizz Fellinger
    Affiliations
    Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
    Search for articles by this author
  • Pol Bech
    Affiliations
    Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
    Search for articles by this author
  • Ralph Hamelink
    Affiliations
    Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands

    Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    Search for articles by this author
  • Guoping Feng
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
    Search for articles by this author
  • Author Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Ingo Willuhn
    Correspondence
    Address correspondence to Ingo Willuhn, Ph.D., the Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105BA Amsterdam, the Netherlands.
    Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Affiliations
    Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands

    Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    Search for articles by this author
  • Author Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Matthijs G.P. Feenstra
    Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Affiliations
    Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands

    Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    Search for articles by this author
  • Author Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Damiaan Denys
    Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.
    Affiliations
    Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands

    Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    Search for articles by this author
  • Author Footnotes
    1 CMP and BJGvdB contributed equally to this work as joint first authors. IW, MGPF, and DD contributed equally to this work as joint senior authors.

      Abstract

      Background

      Deep brain stimulation (DBS) is an effective treatment for patients with obsessive-compulsive disorder (OCD) that do not respond to conventional therapies. Although the precise mechanism of action of DBS remains unknown, modulation of activity in corticofugal fibers originating in the prefrontal cortex is thought to underlie its beneficial effects in OCD.

      Methods

      To gain more mechanistic insight into DBS in OCD, we used Sapap3 mutant mice. These mice display excessive self-grooming and increased anxiety, both of which are responsive to therapeutic drugs used in OCD patients. We selected two clinically relevant DBS targets through which activity in prefronto-corticofugal fibers may be modulated: the internal capsule (IC) and the dorsal part of the ventral striatum (dVS).

      Results

      IC-DBS robustly decreased excessive grooming, whereas dVS-DBS was on average less effective. Grooming was reduced rapidly after IC-DBS onset and reinstated upon DBS offset. Only IC-DBS was associated with increased locomotion. DBS in both targets induced c-Fos expression around the electrode tip and in different regions of the prefrontal cortex. This prefronto-cortical activation was more extensive after IC-DBS, but not associated with behavioral effects. Furthermore, we found that the decline in grooming cannot be attributed to altered locomotor activity and that anxiety, measured on the elevated plus maze, was not affected by DBS.

      Conclusions

      DBS in both the IC and dVS reduces compulsive grooming in Sapap3 mutant mice. However, IC stimulation was more effective, but also produced motor activation, even though both DBS targets modulated activity in a similar set of prefrontal cortical fibers.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Abramowitz J.S.
        • Taylor S.
        • McKay D.
        Obsessive-compulsive disorder.
        Lancet. 2009; 374: 491-499
        • Denys D.
        Pharmacotherapy of obsessive-compulsive disorder and obsessive-compulsive spectrum disorders.
        Psychiatr Clin North Am. 2006; 29: 553-584
        • Nuttin B.
        • Cosyns P.
        • Demeulemeester H.
        • Gybels J.
        • Meyerson B.
        Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder.
        Lancet. 1999; 354: 1526
        • Denys D.
        • Mantione M.
        • Figee M.
        • van den Munckhof P.
        • Koerselman F.
        • Westenberg H.
        • et al.
        Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder.
        Arch Gen Psychiatry. 2010; 67: 1061-1068
        • Alonso P.
        • Cuadras D.
        • Gabriëls L.
        • Denys D.
        • Goodman W.
        • Greenberg B.D.
        • et al.
        Deep brain stimulation for obsessive-compulsive disorder: A meta-analysis of treatment outcome and predictors of response.
        PLoS One. 2015; 10: e0133591
        • Graybiel A.M.
        • Rauch S.L.
        Toward a neurobiology of obsessive-compulsive disorder.
        Neuron. 2000; 28: 343-347
        • van den Heuvel O.A.
        • van Wingen G.
        • Soriano-Mas C.
        • Alonso P.
        • Chamberlain S.R.
        • Nakamae T.
        • et al.
        Brain circuitry of compulsivity.
        Eur Neuropsychopharmacol. 2016; 26: 810-827
        • Figee M.
        • Luigjes J.
        • Smolders R.
        • Valencia-Alfonso C.E.
        • van Wingen G.
        • de Kwaasteniet B.
        • et al.
        Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder.
        Nat Neurosci. 2013; 16: 386-387
        • Haynes W.I.
        • Mallet L.
        High-frequency stimulation of deep brain structures in obsessive-compulsive disorder: The search for a valid circuit.
        Eur J Neurosci. 2010; 32: 1118-1127
        • Feenstra M.G.P.
        • Denys D.
        Animal studies in deep brain stimulation research.
        in: Denys D. Feenstra M.G. Schuurman P.R. Deep Brain Stimulation: A New Frontier in Psychiatry. Springer-Verlag, Berlin2012: 217-224
        • Ahmari S.E.
        • Dougherty D.D.
        Dissecting OCD circuits: From animal models to targeted treatments.
        Depress Anxiety. 2015; 32: 550-562
        • van Kuyck K.
        • Brak K.
        • Das J.
        • Rizopoulos D.
        • Nuttin B.
        Comparative study of the effects of electrical stimulation in the nucleus accumbens, the mediodorsal thalamic nucleus and the bed nucleus of the stria terminalis in rats with schedule-induced polydipsia.
        Brain Res. 2008; 1201: 93-99
        • Winter C.
        • Mundt A.
        • Jalali R.
        • Joel D.
        • Harnack D.
        • Morgenstern R.
        • et al.
        High frequency stimulation and temporary inactivation of the subthalamic nucleus reduce quinpirole-induced compulsive checking behavior in rats.
        Exp Neurol. 2008; 210: 217-228
        • Klavir O.
        • Flash S.
        • Winter C.
        • Joel D.
        High frequency stimulation and pharmacological inactivation of the subthalamic nucleus reduces 'compulsive' lever-pressing in rats.
        Exp Neurol. 2009; 215: 101-109
        • Wu H.
        • Tambuyzer T.
        • Nica I.
        • Deprez M.
        • van Kuyck K.
        • Aerts J.M.
        • et al.
        Field potential oscillations in the bed nucleus of the stria terminalis correlate with compulsion in a rat model of obsessive-compulsive disorder.
        J Neurosci. 2016; 36: 10050-10059
        • Rodriguez-Romaguera J.
        • Greenberg B.D.
        • Rasmussen S.A.
        • Quirk G.J.
        An avoidance-based rodent model of exposure with response prevention therapy for obsessive-compulsive disorder.
        Biol Psychiatry. 2016; 80: 534-540
        • Milad M.R.
        • Rauch S.L.
        Obsessive-compulsive disorder: Beyond segregated cortico-striatal pathways.
        Trends Cogn Sci. 2012; 16: 43-51
        • Robbins T.W.
        • Gillan C.M.
        • Smith D.G.
        • de Wit S.
        • Ersche K.D.
        Neurocognitive endophenotypes of impulsivity and compulsivity: Towards dimensional psychiatry.
        Trends Cogn Sci. 2012; 16: 81-91
        • Figee M.
        • Pattij T.
        • Willuhn I.
        • Luigjes J.
        • van den Brink W.
        • Goudriaan A.
        • et al.
        Compulsivity in obsessive-compulsive disorder and addictions.
        Eur Neuropsychopharmacol. 2016; 26: 856-868
        • Hauser T.U.
        • Eldar E.
        • Dolan R.J.
        Neural mechanisms of harm-avoidance learning: A model for obsessive-compulsive disorder?.
        JAMA Psychiatry. 2016; 73: 1196-1197
        • Welch J.M.
        • Lu J.
        • Rodriguiz R.M.
        • Trotta N.C.
        • Peca J.
        • Ding J.D.
        • et al.
        Cortico-striatal synaptic defects and OCD-like behaviors in Sapap3-mutant mice.
        Nature. 2007; 448: 894-900
        • Burguière E.
        • Monteiro P.
        • Feng G.
        • Graybiel A.M.
        Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors.
        Science. 2013; 340: 1243-1246
        • van Dijk A.
        • Klanker M.
        • van Oorschot N.
        • Post R.
        • Hamelink R.
        • Feenstra M.G.
        • Denys D.
        Deep brain stimulation affects conditioned and unconditioned anxiety in different brain areas.
        Transl Psychiatry. 2013; 3: e289
        • Rodriguez-Romaguera J.
        • Do Monte F.H.
        • Quirk G.J.
        Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear.
        Proc Natl Acad Sci U S A. 2012; 109: 8764-8769
        • Lehman J.F.
        • Greenberg B.D.
        • McIntyre C.C.
        • Rasmussen S.A.
        • Haber S.N.
        Rules ventral prefrontal cortical axons use to reach their targets: implications for diffusion tensor imaging tractography and deep brain stimulation for psychiatric illness.
        J Neurosci. 2011; 31: 10392-10402
        • Greenberg B.D.
        • Rauch S.L.
        • Haber S.N.
        Invasive circuitry-based neurotherapeutics: Stereotactic ablation and deep brain stimulation for OCD.
        Neuropsychopharmacology. 2010; 35: 317-336
        • Albelda N.
        • Joel D.
        Current animal models of obsessive compulsive disorder: An update.
        Neuroscience. 2012; 211: 83-106
        • de Koning P.P.
        • Figee M.
        • Endert E.
        • van den Munckhof P.
        • Schuurman P.R.
        • Storosum J.G.
        • et al.
        Rapid effects of deep brain stimulation reactivation on symptoms and neuroendocrine parameters in obsessive-compulsive disorder.
        Transl Psychiatry. 2016; 6: e722
        • Greenberg B.D.
        • Malone D.A.
        • Friehs G.M.
        • Rezai A.R.
        • Kubu C.S.
        • Malloy P.F.
        • et al.
        Three-year outcomes in deep brain stimulation for highly resistant obsessive–compulsive disorder.
        Neuropsychopharmacology. 2006; 31: 2384-2393
        • Coleman K.A.
        • Baker G.E.
        • Mitrofanis J.
        Topography of fibre organisation in the corticofugal pathways of rats.
        J Comp Neurol. 1997; 381: 143-157
        • Kita T.
        • Kita H.
        The subthalamic nucleus is one of multiple innervation sites for long-range corticofugal axons: A single-axon tracing study in the rat.
        J Neurosci. 2012; 32: 5990-5999
        • Rodriguez-Romaguera J.
        • Do-Monte F.H.
        • Tanimura Y.
        • Quirk G.J.
        • Haber S.N.
        Enhancement of fear extinction with deep brain stimulation: Evidence for medial orbitofrontal involvement.
        Neuropsychopharmacology. 2015; 40: 1726-1733
        • Chang A.D.
        • Berges V.A.
        • Chung S.J.
        • Fridman G.Y.
        • Baraban J.M.
        • Reti I.M.
        High-frequency stimulation at the subthalamic nucleus suppresses excessive self-grooming in autism-like mouse models.
        Neuropsychopharmacology. 2016; 41: 1813-1821
        • Hartmann C.J.
        • Lujan J.L.
        • Chaturvedi A.
        • Goodman W.K.
        • Okun M.S.
        • McIntyre C.C.
        • Haq I.U.
        Tractography activation patterns in dorsolateral prefrontal cortex suggest better clinical responses in OCD DBS.
        Front Neurosci. 2016; 9: 519
        • Reimer A.E.
        • de Oliveira A.R.
        • Diniz J.B.
        • Hoexter M.Q.
        • Chiavegatto S.
        • Brandão M.L.
        Rats with differential self-grooming expression in the elevated plus-maze do not differ in anxiety-related behaviors.
        Behav Brain Res. 2015; 292: 370-380
        • Kalueff A.V.
        • Stewart A.M.
        • Song C.
        • Berridge K.C.
        • Graybiel A.M.
        • Fentress J.C.
        Neurobiology of rodent self-grooming and its value for translational neuroscience.
        Nat Rev Neurosci. 2016; 17: 45-59
        • Fernández-Teruel A.
        • Estanislau C.
        Meanings of self-grooming depend on an inverted U-shaped function with aversiveness.
        Nat Rev Neurosci. 2016; 17: 591
        • Song C.
        • Berridge K.C.
        • Kalueff A.V.
        'Stressing' rodent self-grooming for neuroscience research.
        Nat Rev Neurosci. 2016; 17: 591
        • Tsai H.C.
        • Chen S.Y.
        • Tsai S.T.
        • Hung H.Y.
        • Chang C.H.
        Hypomania following bilateral ventral capsule stimulation in a patient with refractory obsessive-compulsive disorder.
        Biol Psychiatry. 2010; 68: e7-e8
        • Widge A.S.
        • Licon E.
        • Zorowitz S.
        • Corse A.
        • Arulpragasam A.R.
        • Camprodon J.A.
        • et al.
        Predictors of hypomania during ventral capsule/ventral striatum deep brain stimulation.
        J Neuropsychiatry Clin Neurosci. 2016; 28: 38-44
        • Chopra A.
        • Tye S.J.
        • Lee K.H.
        • Sampson S.
        • Matsumoto J.
        • Adams A.
        • et al.
        Underlying neurobiology and clinical correlates of mania status after subthalamic nucleus deep brain stimulation in Parkinson's disease: A review of the literature.
        J Neuropsychiatry Clin Neurosci. 2012; 24: 102-110
        • Mallet L.
        • Polosan M.
        • Jaafari N.
        • Baup N.
        • Welter M.L.
        • Fontaine D.
        • du Montcel S.T.
        • et al.
        • STOC Study Group
        Subthalamic nucleus stimulation in severe obsessive-compulsive disorder.
        N Engl J Med. 2008; 359: 2121-2134
        • Gubellini P.
        • Salin P.
        • Kerkerian-Le Goff L.
        • Baunez C.
        Deep brain stimulation in neurological diseases and experimental models: from molecule to complex behavior.
        Prog Neurobiol. 2009; 89: 79-123
        • Franklin K.B.J.
        • Paxinos G.
        The Mouse Brain in Stereotactic Coordinates.
        Academic Press, Amsterdam2007