The investigators will investigate in a sham controlled design antidepressant effects and safety of DBS to the superolateral branch of the main medial forebrain bundle (slMFB).

The target point for DBS in major depression disorder is located lateral to the ventral tegmental area (VTA) in the midbrain at the branching point of the superolateral branch (slMFB) from the main medial forebrain bundle (MFB).

The exact stimulation coordinates are:

MNI152 coordinates:

left: x(lat.)=-5, y(ap)=-14, z(vert.)=-8 right: x(lat.)=5, y(ap)=-14, z(vert.)=-9

MCP coordinates:

eft: x(lat.)=-6, y(ap)=-1, z(vert.)=-6 right: x(lat.)=4, y(ap)=-1, z(vert.)=-7

All coordinates refer to the MNI152 brain. Legend: slMFB = superolateral branch of medial forebrain bundle, MNI152=Montreal Neurologic Institute brain 152 coordinates, MCP = mid-commissural point coordinates, lat. = lateral, ap= antero-posterior, vert. = vertical.

More information can be found at: http://goo.gl/n9sWV

In addition to the described intervention, we will record EEG activity within the implanted regions during cognitive paradigms (Fell and Axmacher, Nat Rev Neurosci 2011). Specifically, we will investigate the neural mechanisms underlying classification learning, working memory and exploration of rewarded spatial locations and explore oscillatory responses following stimulation of the target regions. These experimental paradigms will be conducted on the first day after electrode implantation.

Inclusion Criteria:

• Major depression (MD), severe, unipolar type

• German mother tongue

• Hamilton Depression Rating Scale (HDRS24) score of > 20

• Global Assessment of Function (GAF) score of < 45

• At least 4 episodes of MD or chronic episode > 2 years

• > 5 years after first episode of MD

• Failure to respond to

  • adequate trials (>5 weeks at the maximum recommended or tolerated dose) of primary antidepressants from at least 3 different classes;
  • adequate trials (>3 weeks at the usually recommended or maximum tolerated dose) of augmentation/combination of a primary antidepressant using at least 2 different augmenting/combination agents (lithium, T3, stimulants, neuroleptics, anticonvulsants, buspirone, or a second primary antidepressant);
  • an adequate trial of electroconvulsive therapy [ECT] (>6 bilateral treatments) and;
  • an adequate trial of individual psychotherapy (>20 sessions with an experienced psychotherapist).

• Able to give written informed consent

• No medical comorbidity

• Drug free or on stable drug regimen at least 6 weeks before study entry

Exclusion Criteria:

• Current or past nonaffective psychotic disorder
• Any current clinically significant neurological disorder or medical illness affecting brain function, other than motor tics or Gilles de la Tourette syndrome
• Any clinically significant abnormality on preoperative magnetic resonance imaging (MRI)
• Any surgical contraindications to undergoing DBS
• Current or unstably remitted substance abuse (aside from nicotine)
• Pregnancy and women of childbearing age not using effective contraception
• History of severe personality disorder