Scientific Stuff

The following is from Winter 2008

Deep Brain Stimulation for Treatment-Resistant Depression

Helen S. Mayberg Andres M. Lozano Valerie Voon Heather E. McNeely David Seminowicz Clement Hamani Jason M. Schwalb Sidney H. Kennedy

Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medica- tions, psychotherapy, and electroconvulsive therapy have failed. Based on our preliminary observation that the sub- genual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six pa- tients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupt- ing focal pathological activity in limbic-cortical circuits using electrical stimulation of the subgenual cingulate white matter can effectively reverse symptoms in otherwise treatment-resistant depression.


Major depression is the most common of all psy- chiatric disorders (Wang, 2003). It ranks among the top causes of worldwide disease burden and is the leading source of disability in adults in North America under the age of 50 (World Health Orga- nization, 2001). While depression can be effec- tively treated in the majority of patients by either medication or some form of evidence-based psy- chotherapy (American Psychiatric Association, 2000), up to 20% of patients fail to respond to standard interventions (Fava, 2003; Keller et al., 1992). For these patients, trial-and-error combina- tions of multiple medications and electroconvulsive therapy are often required (Kennedy and Lam, 2003; Lancet UK ECT Review Group, 2003; Sac- keim et al., 2001). For patients who remain severely depressed despite these aggressive approaches, new strategies are needed. We describe a strategy di- rected at this group of treatment-refractory patients with major depression.

Converging clinical, biochemical, neuroimaging, and postmortem evidence suggests that depression is unlikely to be a disease of a single brain region or neurotransmitter system. Rather, it is now gener- ally viewed as a systems-level disorder affecting

(Reprinted with permission by Neuron, 2005; (45):651– 660)

integrated pathways linking select cortical, subcor- tical, and limbic sites and their related neurotrans- mitter and molecular mediators (Manji et al., 2001; Mayberg, 1997; Nemeroff 2002; Nestler et al., 2002; Vaidya and Duman, 2001). While mecha- nisms driving this “system dysfunction” are not yet characterized, they are likely to be multifactorial, with genetic vulnerability, developmental insults, and environmental stressors all considered impor- tant and synergistic contributors (Caspi et al., 2003; Heim et al., 2000; Kendler et al., 2001). Treatments for depression can be similarly viewed within this limbic-cortical system framework, where different modes of treatment modulate spe- cific regional targets, resulting in a variety of com- plementary, adaptive chemical and molecular changes that re-establish a normal mood state (Vaidya and Duman 2001; Hyman and Nestler, 1996, Mayberg 2003).

Functional neuroimaging studies have had a crit- ical role in characterizing these limbic-cortical pathways (Brody, et al., 2001; Drevets, 1999; May- berg, 1994, 2003). Our own studies have demon- strated consistent involvement of the subgenual cingulate (Cg25) in both acute sadness and antide- pressant treatment effects, suggesting a critical role for this region in modulating negative mood states

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(Mayberg et al., 1999; Seminowicz et al., 2004). In support of this hypothesis, a decrease in Cg25 ac- tivity is reported with clinical response to different antidepressant treatments including specific seroto- nin reuptake inhibitor (SSRI) antidepressant med- ications, electroconvulsive therapy (ECT), repeti- tive transcranial magnetic stimulation (rTMS), and ablative surgery (Dougherty et al., 2003; Goldapple et al., 2004; Malizia, 1997; Mayberg et al., 2000; Mottaghy et al., 2002; Nobler et al., 2001).

In addition, Cg25 connections to the brainstem, hypothalamus, and insula have been implicated in the disturbances of circadian regulation associated with depression (sleep, appetite, libido, neuroendo- crine changes) (Barbas et al., 2003; Freedman et al., 2000; Jurgens and Muller-Preuss, 1977; Maclean, 1990; Ongur et al., 1998). Reciprocal pathways linking Cg25 to orbitofrontal, medial prefrontal, and various parts of the anterior and posterior cin- gulate cortices form the neuroanatomical substrates by which primary autonomic and homeostatic pro- cesses influence various aspects of learning, mem- ory, motivation and reward-core behaviors altered in depressed patients (Barbas et al., 2003; Car- michael and Price, 1996; Haber, 2003; Vogt and Pandya, 1987).

Recent advances in the surgical treatment of Par- kinson’s disease have demonstrated that chronic high-frequency deep brain stimulation (DBS) in pathologically overactive brain circuits produces profound clinical benefits (Benabid, 2003; Lang and Lozano, 1998). We have previously shown that clinically effective DBS in the basal ganglia pro- duces both local and remote changes in neural ac- tivity as assessed by positron emission tomography (PET) (Davis et al., 1997). We have now leveraged these observations to investigate whether DBS could be used to modulate pathological brain cir- cuits in depression.

We tested the hypothesis that the use of chronic stimulation to modulate Cg25 gray matter and in- terconnected frontal and subcortical regions could reverse the pathological metabolic activity in these circuits and produce clinical benefits in patients with treatment-resistant depression (TRD). This study reports the use of high-frequency subgenual cingulate white matter (Cg25WM) DBS in six TRD patients.



All six patients met DSM IV-TR criteria for ma- jor depressive disorder (MDD) with a major de-

pressive episode (MDE) of at least 1 year duration diagnosed by structured clinical interview for DSM IV-TR (First et al., 2001), and all had severe de- pression with a minimum score at entry of 20 on the 17 item Hamilton Depression Rating Scale (HDRS) (Hamilton, 1960). Each met stringent cri- teria for treatment resistance defined as failure to response to a minimum of four different antide- pressant treatments, including medications, evi- dence-based psychotherapy, or electroconvulsive therapy, administered at adequate doses and dura- tion during the current episode (Fava, 2003; Sack- eim et al., 2001; Thase and Rush 1997). Subjects’ demographic characteristics are presented in Table 1.


DBS electrodes were implanted in Cg25WM un- der local anesthesia using MR imaging guidance (Figure 1, row 1: A/B and row 2: C/D) (Schalten- brand and Wahren, 1977). A protocol similar to that used in evaluating stimulation thresholds for efficacy or adverse effects in patients with Parkin- son’s disease was adopted for use in these patients (Benabid, 2003; Davis et al., 1997; Lang and Lozano, 1998). The spontaneous report or occur- rence of any acute behavioral, cognitive, motor, or autonomic effects was sought during blinded, se- quential stimulation of successive, individual con- tacts (monopolar stimulation, 60 􏰀s pulsewidths, 130 Hz). Voltage was progressively increased up to 9.0 V at each of the eight electrode contacts (four per side), as tolerated. Voltage was increased by approximately 1.0 V every 30 s, with a 15–20 s pause between adjustments, allowing time for pa- tients to identify an effect, if present. Patients re- ported no motor or sensory phenomena that cued them as to whether current was either on or off.

All patients spontaneously reported acute effects including “sudden calmness or lightness,” “disap- pearance of the void,” sense of heightened aware- ness, increased interest, “connectedness,” and sud- den brightening of the room, including a description of the sharpening of visual details and intensification of colors in response to electrical stimulation. Reproducible and reversible changes in these phenomena, time locked with stimulation, were observed at specific contacts and parameters for individual patients and not with sham or sub- threshold stimulation at those same sites. Increases in motor speed, volume, and rate of spontaneous speech and improved prosody were observed. In addition, changes in both positive and negative af- fective rating scores (PANAS scale) (Watson and Clark, 1988) occurred coincident with the patients’



spontaneous statements. There were no overt ad- verse affective or autonomic changes with stimula- tion at settings producing these improvements. However, all patients experienced stimulation dose-dependent adverse effects including light- headedness and psychomotor slowing at high set- tings (over 7.0 Volts), most often seen at the supe- rior electrode contact.


Postoperative MR imaging confirmed the place- ment of the DBS electrodes within the subgenual cingulate white matter (Cg25WM) bilaterally as targeted. (Figure 1, row 3: E/F). During the 5 day postoperative period, and prior to placement of the pulse generator, daily short sessions of DBS were used to refine final contact selection and stimula- tion parameters. Systematic testing of individual and paired unilateral and bilateral contacts was per- formed with a variety of parameters (monopolar [contact anode; case cathode] and bipolar, pulse- width of 30 –250 􏰀s, frequency of 10 –130 Hz, progressive increase in voltage from 0.0 –9.0 Volts). Acute behavioral changes were again observed dur- ing these test sessions. Reproducible improvements in interest, motor speed, activity level, and PANAS scores (reduced negative, increased positive scores) were seen during these stimulation sessions gener- ally using the same contacts and parameters that induced effects in the operating room.

To control for the possibility of a placebo effect, patients were blinded as to which contact was being stimulated and to the parameter settings. Sham stimulation using either 0.0 Volts or subthreshold stimulation failed to elicit any changes in behavior. Randomized, acute off-on-off-on trials of varying short periods of stimulation (1–5 min) at optimal settings produced consistent stimulation-locked behavioral improvements. Unexpectedly, with ap- plication of stimulation for progressively longer pe- riods (from 1 to 3 hr), there was an increasing and correspondingly longer carry-over of the beneficial behavioral effects beyond cessation of the stimula- tion. These longer stimulation periods were free of adverse effects and were the basis for selecting the stimulation settings used chronically.

Postoperative Selection of Stimulation Parame- ters Patients were discharged home with stimula- tion “off” following implantation of the pulse gen- erators. One week later, chronic DBS was initiated using the lowest voltage and specific electrode con- tacts that had previously produced acute behavioral effects. Parameters of stimulation were reassessed at weekly intervals with minor adjustments in voltage

made to optimize clinical effects. Following a 4 week period of parameter optimization, settings generally remained stable for the remainder of the 6 month follow-up period. The mean stimulation pa- rameters used in this group at 6 months were 4.0 Volts, 60 􏰀s pulsewidths, at a frequency of 130 Hz.


Standard criteria for antidepressant response and remission were applied (Frank et al., 1991). Re- sponse was defined as a decrease in the HDRS-17 score of 50% or greater from the pretreatment base- line; remission as an absolute HDRS-17 score 􏰁8. One month postop, two patients met criteria for clinical response (Table 2). By 2 months, five of the six patients met the defined response threshold. Continued antidepressant response was seen in four of these subjects, with some variability up to 5 months. At the 6 month study endpoint, antide- pressant response was maintained in four subjects (66%). Moreover, three of these subjects achieved remission or near remission of illness. Consistent with the improvements seen in the HDRS-17 scores, comparable changes were also demonstrated on other quantitative depression scales (see Table 3). Presurgical medications and doses were un- changed throughout the 6 month study.

Normalization of early-morning sleep distur- bance (middle insomnia commonly seen in MDD) occurred in the first week of chronic DBS in four of the six subjects (patients 1, 3, 5, and 6) and was the first notable sustained symptom change. Over the initial few weeks of continuous DBS, increased en- ergy, interest, and psychomotor speed were addi- tionally reported, with effects generally appreciable a day or two following stimulation adjustments. Patients and their families described renewed inter- est and pleasure in social and family activities, de- creased apathy and anhedonia, as well as an im- proved ability to plan, initiate, and complete tasks that were reported as impossible to attempt prior to surgery. While all patients continued to report feel- ing “moderately depressed” for several weeks, sev- eral also indicated that the sensations of “painful emptiness” and “void” remitted almost immedi- ately following onset of stimulation at the optimal contacts.

Two patients failed to show a sustained antide- pressant response at the 6 month time point (Table 2). One of these subjects, patient 2, met criteria for clinical response in the first 4 months; however, the level of improvement fluctuated overtime, and the maximal benefit could not be recaptured with ei- ther a change in the stimulation contact or adjust-

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Table 1. Patient Demographics

Patient# 123 4 5 6 Group


Current age

Age MDD onset

Current episode (yrs)

# Lifetime episodes

Hamilton depression score (17 item)

Past ECT

Past psychotherapy

Family history MDD

DSM IV diagnosis

Melancholic subtype

Current medicationsa



46 􏰃 8 29.5 􏰃 12 5.6 􏰃 3 4.7 􏰃 5 25 􏰃 3 5 of 6

6 of 6

5 of 6

5 UP

4 of 6

48 59 45

18 45 21

1.5 3 6

12 9 3

29 20 27

no yes yes

yes yes yes

yes no yes


yes no yes

1–5 1, 3 1–4

48 37 39

40 19 34

8 10 5

1 2 1

24 26 25

yes yes yes

yes yes yes

yes yes yes


no yes yes

1, 2, 4, 6, 7 1, 7 1, 4, 5, 7

MDD, major depressive disorder; ECT, electroconvulsive therapy; DSM IV, Diagnostic and Statistical Manual of Mental Disorders, Version IV; UP, unipolar; BP, bipolar. a Current medications: 1, SSRI/SNRI; 2, bupropion; 3, atypical antipsychotic; 4, benzodiazepine; 5, stimulant; 6, mood stabilizer; 7, other.

ments in stimulation parameters after 4 months. Patient 4 had no appreciable clinical improvement with chronic stimulation despite trials with various combinations of contacts and stimulation parame- ters. Of note, the prominent sleep disturbances in these two patients (difficulty falling asleep [patient 4] and hypersomnia [patient 2]) were not affected by DBS, unlike the middle insomnia improve- ments seen in the other four subjects.


We next considered that the long-term benefit in the responders could be related to placebo or non- specific factors. To examine this possibility, after a period of continuous stimulation for 6 months, the effects of cessation and reintroduction of stimula- tion was examined in patient 1, who had shown the earliest, most robust, and best-sustained clinical re- sponse (Table 2). Following blinded discontinua- tion of bilateral stimulation (stimulators set at 0.0 V), antidepressant effects were maintained for 2 weeks (HDRS 􏰂 9; PANAS positive score 􏰂 48 of out of a possible 50, PANAS negative score 􏰂 10 out of a possible 50 versus 6 month score positive 􏰂 50, negative 􏰂 10). In weeks 3 and 4 without stim- ulation, the improvements in mood were also sus- tained (HDRS 􏰂 10). In the context of this sus- tained euthymia, however, there was a progressive change in behavior characterized by loss of energy and initiative, impaired concentration, and re- duced activities, reflected by a drop in the PANAS positive score to 37, without appreciable change in the negative score (negative 􏰂 13). At this point, and under continued blinded conditions, the stim- ulator was turned back on to the previous best set- tings (3.5 V, PW 60, 130 Hz). This resulted in normalization of symptoms within approximately 48 hr and return to prediscontinuation activities within 1 week (HDRS 􏰂 6, PANAS positive 􏰂 50, negative 􏰂 10 after 1 week of restarting chronic DBS). This remission was sustained at 6 weeks of resumed stimulation at comparable levels to the

Figure 1. DBS Electrode Placement in the Subgenual Cingulate White Matter

(Row 1) Sagittal (left, [A]) and coronal (right, [B]) views of the subgenual cingulate target (white circles) localized on the Schaltenbrandt neurosurgical atlas. (Row 2) Sagittal (C) and coronal (D) views of the DBS target mapped on a high-resolutin T1 MRI scans for one patient. (Row 3) Sagittal (E) and coronal (F) views of postop MRI scans demonstrating the location of electrodes for a single subject with the ventral contact centered within the predetermined location. sgCg, subgenual cingulate; cc, corpus callosum; g, genu of the corpus callosum; ac, anterior commissure; white circles, electrode target in sgCg white matter; white and black arrows, sgCg gyrus; dotted line, anterior-posterior position of the electrode relative to the ac-g line.

146 Winter 2008, Vol. VI, No. 1



prediscontinuation baseline (HDRS 􏰂 4). Taken together, these findings suggest that stimulation of Cg25WM produces long-term improvements in mood that are sustained beyond the period of active stimulation. The cognitive aspects of depression (i.e., poor concentration, apathy) also show sus- tained improvements, but the observed changes ap- pear to have a different biology and kinetics, decay- ing closer to the cessation of stimulation.


Positron emission tomography was used to char- acterize the activity in brain networks involved in TRD and to provide a quantitative measure of brain changes associated with stimulation. Base- line, resting-state, cerebral blood flow (CBF) PET scans were performed in the first five study subjects and compared to five age- and sex-matched, non- depressed healthy volunteers. Depressed patients showed a unique pattern of elevated subgenual cin- gulate (Cg25) blood flow at pretreatment baseline, not previously reported in studies of nontreatment resistant patients. In addition, and consistent with past studies of depressed patients (reviewed in May- berg, 2003), CBF decreases in prefrontal (BA9/46), premotor (BA6), dorsal anterior cingulate (BA24), and anterior insula were also identified (Figure 2 row 1; Table 4, left). A similar pattern of hyperac- tive Cg25 and hypoactive prefrontal cortex was seen in both the DBS responders and nonre- sponders (data not shown). Responder versus non- responder differences at baseline were seen primar- ily in the magnitude of the prefrontal decreases (responders 􏰄 nonresponders). Responders also showed an area of hyperactivity in the medial fron- tal cortex (BA10) not seen in the nonresponders; however, the small sample size precluded further analysis.

The time course of CBF changes with chronic stimulation of Cg25WM was also examined to es- tablish the relationship of regional brain function- ing to behavioral effects. Serial scans were per- formed after 3 and 6 months in four of the first five patients (1, 2, 3, and 5). Group analyses showed local CBF decreases in Cg25 and adjacent orbital frontal cortex (BA11) after 3 months of stimulation. The long-term responders (patients 1, 3, and 5) showed additional CBF changes at both 3 and 6 months: decreases in hypothalamus, anterior insula, and medial frontal cortex (BA10) as well as increases in dorsolateral prefrontal (BA9/46), dorsal anterior (BA24) and posterior cingulate (BA31), premotor (BA6), and parietal (BA40) regions (Table 4; Figure 2,

rows 2 and 3). Neither the medial frontal (BA10) de- creases nor the dorsal prefrontal (BA9/46), anterior cingulate (BA24), or parietal (BA40) increases were seen in the nonresponder (patient 2) at either 3 or 6 months (data not shown).

The stimulation-induced CBF increases in pre- frontal cortex (BA9/46) normalized pretreatment abnormalities. Similarly, the Cg25 decreases not only normalized pre-treatment dysfunction, but ac- tivity in this region with DBS was actually sup- pressed below that of the controls at both time points, a change also observed in our previous stud- ies of PET scan changes with response to antide- pressant medications (Mayberg et al., 2000). Un- like medication, brainstem changes were not seen early with DBS, although changes in the pons were demonstrated at the 6 month time point. Overall, regional changes seen after 3 months were main- tained at 6 months in all three responders (Table 4, middle and right sections).


A comprehensive neuropsychological battery was performed prior to surgery and after 3 and 6 months of stimulation, coincident with the day of the PET scan sessions. The test battery was de- signed to differentiate dorsolateral, superior me- dial, and ventrolateral/orbital frontal behaviors, po- tentially affected by chronic Cg25WM DBS. Serial testing further allowed differentiation between sub- acute surgical effects, chronic stimulation effects, and correlations with mood change.

At baseline, all patients were functioning intellectu- ally in the average range, consistent with estimates of premorbid IQ. Inspection of results over time indi- cates that surgery itself did not have a negative impact on general cognition (i.e., IQ, language, basic visual- spatial function). Moreover, many specific areas that were below average or impaired at baseline were sig- nificantly improved (or trending due to low power) following 6 months of DBS [responders: visuo-motor function, particularly with the nondominant hand, t(2) 􏰂 5.8, p 􏰂 0.014; dorsolateral frontal function (verbal fluency), t(2) 􏰂 10.0, p 􏰂 0.005; ventral pre- frontal function (fewer errors on object alternation task), t(2) 􏰂 1.7, p 􏰂 0.12; and orbital frontal func- tion (fewer risky choices on the gambling task), t(2) 􏰂 6.3, p 􏰂 0.012]. Importantly, there were no acquired impairments in orbital frontal functioning to indicate local DBS adverse effects (Kartsounis et al., 1991; Dalgleish et al., 2004). Nonresponders had normal performance on all tests at baseline, with the exception of slowed psychomotor speed (consistent with effects of depression). Repeat testing was only available for one of these subjects.

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Table 2. Hamilton Depression Rating Scale, HDRS-17, Scores over Time for Each Subject

Hamilton Scorea


Preop baseline

1 week postop (acute stimulation)

2 weeks postop (DBS off)

1 month

2 months

3 months


5 months


Pt 1b










Pt 2c










Pt 3b










Pt 4c










Pt 5b










Pt 6b










a Clinical response: decrease HDRS score 􏰄50%. Clinical remission: absolute HDRS score 􏰁8. b Clinical responders. c Clinical nonresponders.


Patients 2 and 4 developed local infections related to the connector cable at the chest (patient 2) or scalp (patient 4). Both were treated with intravenous anti- biotics. Because of persistent infection in the absence of clinical benefit, the devices were explanted at ap- proximately 6 months with resolution of their infec- tions. No worsening of depressive symptoms was ob- served in either subject following explantation. Patient 5 developed skin erosion over the hardware and also received antibiotics. While no definitive eti- ology of these infections was identified, the protocol was modified after patient 5 to implant both the elec- trodes and pulse generator in a single surgical session, thus eliminating the several-day period where the elec- trodes remained externalized.


In this study, we have demonstrated that high- frequency DBS of the Cg25WM can produce strik- ing behavioral changes in patients with TRD.

Acute behavioral effects were time locked to stimulation intraoperatively and during short-term testing sessions. Furthermore, sustained clinical im- provements decreased with blinded discontinua- tion of chronic DBS and were recaptured with re- institution of stimulation, providing evidence as to the specificity of DBS-mediated changes. PET scan data further indicate that Cg25WM DBS has pro- found effects on the cerebral networks involved in depression and suggest that reversal of baseline ab- normalities correlates with antidepressant benefits. While the number of subjects is small, four of six patients (66%) achieved sustained clinical response or remission at the end of 6 months without changes in concurrent medications. This response rate is striking given the extreme treatment refrac- toriness of this patient population and the well- documented low and poorly sustained placebo re- sponse rates of such patients (Fava, 2003; Keller, et al., 1992; Kennedy and Lam, 2003; Thase and Rush, 1997; Sackeim et al., 2001).

The identified CBF change pattern associated with DBS-induced antidepressant effects has im-

Table 3. Psychiatric Ratings: Patient Subgroups

All Patients (n 􏰈 6) Mean Scores (SD)

Responders (n 􏰈 4) Mean Scores (Range)

Nonresponders (n 􏰈 2) Mean Scores (Range)






25.8 (2.8)

34. (1.9)

33.3 (4.5)

6.2 (0.4)

1 mo

15.8 (4.7)

25.8 (9.1)

23 (8.5)

5.2 (0.8)

3 mo 6 mo

12.8 (7.8) 11.5 (6.8)

21.2 (8.7) 18.8 (10.6)

17.4 (10.1) 18.5 (10.4)

4.2 (0.6) 4.0 (1.7)


27.3 (2.1)

35.7 (1.5)

33.8 (6.7)

6.3 (0.5)

1 mo

15.3 (5.4)

25 (12.5)

3 mo 6 mo

9.3 (5.9) 7.8 (3.1)

15.3 (3.5) 11.3 (2.9)


23 (22–24)

33 (32–34)

33 (31–34)

6 (6)

1 mo

17 (14–20)

27 (24–30)

27 (25–28)

6 (6)

3 mo 6 mo

20 (15–25) 19 (15–23)

30 (27–33) 30 (27–33)

27 (21–33) 29 (25–33)

6 (6) 6 (6)

20.7 (11.1) 11 (3.6) 9.7 (3.8)

4.7 (0.6) 3.3 (1.0) 3.0 (0.8)

Note. f/u MADRAS and HDRS 24 scores not available for patient 6.



portant similarities to other therapies for depres- sion. The pattern of reduced activity in the Cg25 and hypothalamus together with prefrontal (BA9) and brainstem increases during DBS are identical to changes reported with antidepressant response to medication (Mayberg et al., 2000). On the other hand, the medial frontal (BA10)/ orbital frontal (BA11) decreases and dorsal cingulate (BA24) in- creases are similar to the change pattern observed with response to cognitive behavioral therapy (Goldapple et al., 2004). The observation that the changes with DBS seen here features both the anti- depressant medication and the CBT- induced changes suggests that Cg25WM DBS acts at a crit- ical node of a distributed mood-regulatory network involved in major depression (Mayberg, 2003; Seminowicz et al., 2004).

The baseline pattern of subgenual cingulate hy- peractivity in combination with frontal hypoactiv- ity described here in this TRD patient group is a finding that is in contrast to the hypoactivity re- ported in a more rostral region of subgenual medial prefrontal cortex in familial bipolar and unipolar depressed patients (Drevets et al., 1997). This dis- tinction suggests important differences across sub- types of depression that are potentially relevant to the pathophysiology of major depressive disorders and perhaps their treatment.

Although the mechanisms of action of DBS are incompletely understood, it is clear that stimula- tion produces both local and remote regional effects (Davis et al. 1997). The behavioral and neuroim- aging changes in this study are consistent with sup- pression of the abnormally elevated baseline Cg25 activity (Figure 2). Possible mechanisms include DBS-induced activation of inhibitory GABA-ergic afferents and/or high frequency stimulation in- duced synaptic or metabolic failure (Gabbott et al., 1997; Lozano et al., 2002; McIntyre et al., 2004). The remote cortical and brainstem increases could occur as an indirect consequence of trans-synaptic effects in response to decreased activity in Cg25, or direct anterograde or retrograde activation of WM projections coursing through the stimulation field (Barbas et al., 2003; Carmichael and Price, 1996; Haber, 2003; Freedman et al., 2000; Ongur et al., 1998; Jurgens and Muller-Preuss, 1977; Vogt and Pandya, 1987).

In context of these putative mechanisms, the sud- den mood change seen with stimulation in the op- erating room is consistent with an acute deactiva- tion of a hyperactive Cg25, the region immediately adjacent to the area of stimulation. This region has been previously shown to mediate negative mood (increases with sadness, decreases with alleviation of depressive dysphoria) (Mayberg et al., 1999). Early

Figure 2. PET Scans

Regional cerebral blood flow changes (CBF PET) in TRD patients at baseline (row 1) and after 3 months (row 2) and 6 months (row 3) of successful treatment with con- tinuous DBS. Sagittal (left) and coronal (right) views. Baseline CBF abnormalities are seen relative to age- and gender-matched healthy control subjects (NC): increases in subgenual cingulate (Cg25) and decrease in dorsolateral prefrontal (F9), ventrolateral prefrontal (F47) and anterior cingulate (Cg24) cortices (row 1, patients 1–5). Three months of DBS relative to baseline (row 2, patients 1, 3, and 5): decreases in Cg25, hypothalamus (Hth), anterior insula (ins), medial frontal (mF10) and orbital frontal (oF11); increases in prefrontal (F9/4 and dorsal cingulate (cg24). This same pattern is maintained at 6 months, although additional increases are seen in the brainstem (bs) (row 3). Slice location is in millimeters relative to anterior commissure. Numbers are Brodmann designations. L, left. Significant CBF increases in red; decreases in blue

(p 􏰁 0.001).

effects of DBS on sleep, energy and motivation also suggest changes in activity of the hypothalamus and brainstem, regions monosynaptically connected to Cg25 (Barbas et al. 2003; Freedman et al., 2000; Jurgens and Muller-Preuss, 1977; Ongur et al., 1998). The more global changes in functioning, i.e., resolution of the depressive syndrome, as well as the prolonged washout time and associated per- sistent benefit we have observed beyond the cessa- tion of stimulation, may reflect long-term changes in neural network properties as a consequence of prolonged stimulation (Carmichael and Price, 1996; Vaidya and Duman, 2001; Haber, 2003; Vogt and Pandya, 1987). This phenomenon of on- going benefit after DBS discontinuation has been observed in other disorders targeting different brain circuits, including epilepsy, essential tremor, dysto- nia, and Parkinson’s disease (Hodaie et al. 2002, Kumar et al. 2003; Deep-Brain Stimulation for Parkinson’s Disease Study Group, 2001; Vidailhet et al., 2005).

Despite these encouraging results, there are lim- itations to this first study of Cg25WM DBS for TRD. Sample size was small, follow-up was lim- ited, and no sham surgery or systematic placebo control arm was used. There was also inadequate power to identify demographic, clinical, subtype, neuropsychological, or imaging markers that might predict response. It may be relevant that all four re-

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Table 4. PET Blood Flow Changes

Baselinea Patients (n 􏰈 5) 3 Months DBS vs Baselineb,c 6 Months DBS vs Baselineb,c

vs Controls (n 􏰈 5)c

Responders (n 􏰈 3) Responders (n 􏰈 3)

zxyz zxyz zxyz

Region BA

sgCg 25



mFr 10

pCg 31



dCg 24b



n. acc


Score Coordinates Region BA 􏰉

Score Coordinates Region BA 􏰉

Score Coordinates

L 2

􏰅4.68 􏰅4 10 􏰅4

5.16 􏰅1028􏰅12

25 2 􏰅4.75 􏰅28􏰅10 sgCg Hth

32/10 2 􏰅5.1 0 34 􏰅8 OrbF 32/10 R 2 􏰅4.84 6462 10 R 2 􏰅3.98 22 60 􏰅10

R 2 􏰅3.76 60 10 􏰅6 Ins

L 2 􏰅5.74 􏰅50 16 􏰅16 10 L 2 􏰅4.19 􏰅22 62 22 mFr 10 R 2 􏰅5.95 34 56 26 24 R 2 􏰅5.86 12 22 26

9 R 2 􏰅5.57 12 46 34 mFr L 2 􏰅4.87 􏰅5 56 34

9 L 2 􏰅5.96 􏰅28 54 43 R 2 􏰅5.19 185234

2 􏰅3.88 1020􏰅4

2 􏰅4.63 􏰅2 2 􏰅4 L 2 􏰅4.97 􏰅10 30 􏰅10

L 2 􏰅4.41 􏰅20 36 􏰅10 R 2 􏰅4.07 58 16 􏰅6 L 2 􏰅5.67 􏰅50 20 􏰅6 L 2 􏰅3.53 􏰅14 56 38

L 2 􏰅4.27 􏰅28 56 32 R 2 􏰅4.19 12 20 20 L 2 􏰅3.79 􏰅16 24 22 R 2 􏰅3.95 6 52 30

R 2 􏰅3.34 2 46 40

L 1 2 􏰅3.67 0 4 􏰅12






Fr pole





















6.05 􏰅38 22 14

6.22 26 42 16

L 1

R 1

L 1 R 1 L 2 􏰅7.07 􏰅38 28 30 R 2 􏰅4.92 40 20 30 L 2 􏰅4.66 􏰅52 42 2 R 2 􏰅4.98 32 26 0 L 2 􏰅5.39 􏰅2 18 28

R 2 􏰅4.69 14 2 12 R 2 􏰅4.58 12 􏰅6 14

4.65 􏰅10􏰅7220 3.51 24 􏰅68 14 4.05 􏰅26 16 30 DLPF

4.73 􏰅38 32 18 4.91 34 22 16

4.06 􏰅2 10 28 dCg 4.21 􏰅52 􏰅4 32 PM 5.71 50 0 30

4.43 􏰅8􏰅5426 3.88 10 􏰅56 26

31 L 1 31 R 1 9 L 1

46 L 1 46 R 1 24b L 1 6L 1 6R 1

a Patients 1–5 versus five age- and gender-matched healthy controls. b Patients 1, 3, and 5. c SPM t maps. Significance threshold: p 􏰁 0.001 uncorrected (t 􏰄 3.27); cluster size 􏰄50 voxels.

Par 39

4.13 􏰅36 􏰅56 18 4.01 44 􏰅56 10



R 1 L 1 R 1 L 1 L 1 L 1 R 1 L 1 R 1 R 2 􏰅4.66 6 􏰅36 􏰅10

4.63 38 12 34

3.79 􏰅34 18 24 4.13 32 24 10

3.84 􏰅38 26 10 3.58 􏰅4 4 34 3.34 􏰅48 2 22 5.92 50 4 28

sponders had their first major depressive episode (MDE) before age 35 and had predominant melan- cholic features whereas the two nonresponders had first episodes in their 40s and had more atypical symp- toms (Table 1). Differences in electrode targeting and placement and stimulation parameters may have also contributed to the observed response variance. The

relative contribution of these various factors will re- quire testing of additional subjects. In the future, the possible interactions between DBS and antidepressant medications need to be examined.

In conclusion, Cg25WM DBS appears to be ef- ficacious for TRD. The treatment is titratable; there are objective imaging correlates of response



effects; and the procedure is well tolerated. This approach may represent an effective, novel inter- vention for severely disabled patients with treat- ment-resistant depression.



This pilot study included six patients with treat- ment-resistant major depression, referred by mood disorder specialists (Table 1). The clinical diagnosis of major depressive disorder, major depressive epi- sode (MDD-MDE) was independently confirmed by two psychiatrists and a research coordinator us- ing the Structured Clinical Interview for DSM-IV (First et al., 2001). Patients were selected for sur- gery because they were resistant to all available ther- apeutic options. All had failed to respond to a min- imum of four different classes of antidepressant medications, prescribed at maximal tolerable doses. Failed treatments included SSRI, venlafaxine, bu- propion, monoamine oxidase inhibitor, and tricy- clic antidepressants, as well as augmentation strat- egies using lithium, atypical antipsychotics, and anticonvulsants. Five of the six patients had re- ceived electroconvulsive therapy, and all had at- tempted cognitive behavioral therapy without clin- ical improvement. Patients with cerebrovascular risk factors or a previous stroke; documented head trauma or neurodegenerative disorders; other Axis I psychiatric diagnoses including schizophrenia, bi- polar disorder, panic disorder, obsessive compul- sive disorder, or evidence of global cognitive im- pairment were excluded. Patients with psychotic symptoms, current history of substance abuse, daily use of alcohol in the previous 3 months, or active suicidal ideations were also excluded. Other exclu- sion criteria included age over 60, pregnancy (risk of radiation exposure from the PET scans), general contraindications for DBS surgery (cardiac pace- maker/defibrillator or other implanted devices), and inability or unwillingness to comply with long- term follow-up. Final selection was made by con- sensus of the investigator team. Additional subjects were screened but either did not meet inclusion/ exclusion criteria or were accepted but declined.


The study protocol was reviewed and approved by three separate ethics committees at the Univer- sity of Toronto: Toronto Western Hospital, Centre for Addiction and Mental Health, and Baycrest Centre for Geriatric Care. All potential subjects

were referred by a psychiatrist that was not involved in the research protocol. They were then seen inde- pendently by two psychiatrists (V.V. and S.K.) for diagnostic assessment and if potentially eligible, in- troductory discussions took place. In all cases, the referring psychiatrist was involved in discussions of the potential benefits and the potential risks associ- ated with DBS. During subsequent meetings with one of the principal investigators (H.S.M.), a fam- ily member was invited to attend and did so in all cases. Only after these discussions, were interested candidates referred to the neurosurgical principle investigator (A.L¿), who explained the surgical pro- cedure. Interested candidates were offered in- formed consent forms to read and further discuss as needed. The average time from initial assessment to signing consent was 6 – 8 weeks.


The general surgical procedure for the implanta- tion of DBS electrodes has been previously de- scribed (Abosch and Lozano, 2003). A stereotactic frame (Leksell G; Elekta, Inc., Atlanta, GA) was affixed to the patient’s head on the morning of sur- gery, and preoperative MR images were obtained (Signa, 1.5 tesla; General Electric, Milwaukee, WI). The x, y, and z coordinates of the anterior (AC) and posterior commissures (PC) were deter- mined using axial 3D T1 MR images. To target the subgenual cingulate white matter target, a midline T2 sagittal image was chosen, and the cingulate gyrus below the genu of the corpus callosum was identified (Figure 1, row 1) (Schaltenbrand and Wahren, 1977). A line was traced from the most anterior aspect (genu) of the corpus callosum to the anterior commissure and the midpoint was selected (Figure 1, row 2, left). The T2 coronal section cor- respondent to the plane of this midpoint was iden- tified, and the coordinates of the transition between the gray and white matters of area 25 were calcu- lated (Figure 1, row 2, right).

In the operating room under local anesthesia, a burr hole was drilled 2 cm from the midline in front of the coronal suture. The underlying dura mater was opened, and the exposed pial surface coagu- lated. Tisseal (Immuno, Vienna, Austria) was used to prevent cerebrospinal fluid egress and minimize brain shift. The Leksell arc was attached to the head frame and set to the target coordinates. Microre- cordings were started 10 mm above the target using electrodes made from parylene-C-insulated tung- sten wires and plated with gold and platinum. Tip lengths ranged from 15 to 40 􏰀m and impedances ranged from 0.2 to 1.5 􏰆. Cell activity was ampli- fied (DAM 80 WPI Instruments) with a gain of

FOCUS Winter 2008, Vol. VI, No. 1 151



1000 and initially filtered to 0.1–10 kHz. The sig- nal was displayed on an oscilloscope and directed to a window discriminator (Winston Electronics) and an audio monitor (Grass AM 8, with noise clipping circuit). In the present study, microelectrode map- ping was mainly used to confirm the anatomic lo- cation of the gray and white matters of area 25, characterized respectively by the recording of neu- ronal activity and cell sparse areas. The transition between these two regions was chosen as the final target for the implantation of the electrodes. Final electrode location was confirmed by postoperative MRI (example, Figure 1, row 3).

DBS quadripolar electrodes (Medtronic 3387; Medtronic, Inc., Minneapolis, MN) were im- planted bilaterally. Each of the four electrode contacts was tested for adverse effects and clinical benefits. These contacts were numbered from 0 to 3 (right hemisphere) and 4 to 7 (left hemi- sphere), 0 and 4 being the most ventral and 3 and 7 the most dorsal contacts. The electrodes re- mained externalized for 5–7 days for clinical test- ing. They were then connected to a pulse gener- ator (Kinetra, Medtronic, Minneapolis, MN) that was implanted in the infraclavicular region under general anesthesia. Prophylactic antibiot- ics were used for 24 hr after each of the surgical procedures.


Clinical efficacy was evaluated using standardized ratings by the study psychiatrist blinded to the current stimulus parameters and/or changes. Standardized ratings included the Hamilton Depression Rating Scale (HDRS-17 and 24 item versions) (Frank, et al., 1991), the Montgomery Asberg Depression Scale (MADRS) (Montgomery and Asberg, 1979), the Clinical Global Impressions Scale (CGI) (National Institute of Mental Health, 1970), and the Positive and Negative Affective Scale (PANAS) (Watson and Clark 1988) (Table 3). Ratings were performed weekly for the first 3 months and biweekly until the study endpoint at 6 months, following baseline assess- ments at enrollment and 1 week prior to surgery. Medications were unchanged throughout the 6 month follow-up period.


Regional cerebral blood flow PET scans (rCBF) were acquired preoperatively and after 3 and 6 months of chronic DBS (Fox et al., 1984). Five CBF scans were acquired in each subject at each time point. A comparative scan-set (one time point

only) was also acquired under identical scanning conditions in a group of five age-and sex-matched healthy volunteers. All scans were acquired with subjects resting, with eyes closed and no explicit cognitive or motor instructions. Scans were ac- quired on a GEMS/Scanditronix 2048b camera (15 parallel slices; 6.5 mm center-to-center inter- slice distance) using measured attenuation correc- tion (68G¿\68Ga transmission scans). rCBF was measured using the bolus [15O]-water technique (35 mCi 15O-water dose/scan; scan duration 60 s) (Mayberg et al., 1999). Scans were spaced a mini- mum of 11 min apart to accommodate radioactive decay to background levels. Mood state (sadness and anxiety) was assessed at the end of each scan using a seven-point analog scale and the PANAS to verify behavioral stability over the course of the five scans (Watson and Clark, 1988).

Statistical analyses were performed using SPM99 (Wellcome Department of Cognitive Neurology, London, UK) implemented in Matlab (version 5.3, Mathworks Inc., Sherborn, MA). PET scans were first realigned and then spatially normalized into standard three-dimensional space relative to the an- terior commissure using the MNI ICBM 152 ste- reotactic template within SPM99. The images were then corrected for differences in the whole-brain global mean, and smoothed using a Gaussian ker- nel to a final in-plane resolution of 10 mm at full- width at half-maximum. Baseline abnormalities (patients versus controls) and changes with chronic DBS (3 months versus baseline, 6 months versus baseline) were assessed using general linear models (peak voxel threshold p 􏰂 0.001; cluster threshold 50 voxels (voxel 􏰂 2 mm3) (Worsley et al., 1996). Resulting t values were lastly converted to z scores for interpretation. Brain locations are reported as x, y, z coordinates in MNI space with approximate Brodmann areas (BA) identified by mathematical transformation of SPM99 coordinates into Ta- lairach space ( Imaging/) (Table 3).


A comprehensive battery of neuropsychological tests was administered at three time points to estab- lish baseline intellectual and cognitive abilities prior to surgery/stimulation and to monitor for changes over time (3 months, 6 months). Tests were chosen to tap general cognitive and intellectual function, as well as four domains of frontal function (Bechara et al. 1994; Freedman et al., 1998; Lang et al., 1999; Spreen and Strauss, 1998). Parallel versions were used where possible to minimize effects of repeti- tion, and scores are corrected for effects of age, gen-



der, and education, where appropriate. The follow- ing tests were administered: Wechsler Adult Intelligence Scale-III; North American Adult Reading Test; Trail Making Tests A and B; Boston Naming Test; Benton Judgment of Line Orienta- tion Test; Hopkins Verbal Learning Test; Brief Vi- sual Spatial Memory Test, Revised; Finger Tapping Test; Grooved Pegboard Test; Controlled Oral Word Association Test; Wisconsin Cart Sorting Test; Stroop Color Word Test; Emotional Stroop Task; Object Alternation Test; Iowa Gambling Task; and the International Affective Picture Sys- tem Ratings. A subset of tests is presented. Paired t tests were used to compare differences between the baseline and 6 months data to determine the prob- ability that the actual mean difference is consistent with zero. This comparison is aided by the reduc- tion in variance achieved by taking the differences, and thus is a good choice for use with a small sam- ple. A more detailed discussion of neuropsycholog- ical results will be published separately.


Abosch, A., and Lozano, A.M. (2003). Stereotactic neurosurgery for movement disorders. Can. J. Neurol. Sci. 4, S72–S82.

American Psychiatric Association, A.M. (2000). Practice guideline for the treatment of patients with major depressive disorder (revision). Am. J. Psychiatry 157, 1–45.

Barbas, H., Saha, S., Rempel-Clower, N., and Ghashghaei, T. (2003). Serial pathways from primate prefrontal cortex to autonomic areas may influ- ence emotional expression. BMC Neurosci. 4, 25.

Bechara, A., Damasio, A.R., Damasio, H., and Anderson, S.W. (1994). Insen- sitivity to future consequences following damage to human prefrontal cortex. Cognition 50, 7–15.

Benabid, A.L. (2003). Deep brain stimulation for Parkinson’s disease. Curr. Opin. Neurobiol. 13, 696–706.

Brody, A.L. Barsom, M.W., Bota, R.G., and Saxena, S. (2001). Pre-frontal- subcortical and limbic circuit mediation of major depressive disorder. Semin. Clin. Neuropsychiatry 6, 102–112.

Carmichael, S.T., and Price, J.L. (1996). Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys. J. Comp. Neurol. 371, 179–207.

Caspi, A., Sugden, K., Moffitt, T.E., Taylor, A., Craig, I.W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., and Poulton, R. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389.

Dalgleish, T., Yiend, J., Bramham, J., Teasdale, J.D., Ogilvie, A.D., Malhi, G., and Howard, R. (2004). Neuropsychological processing associated with recovery from depression after stereotactic subcaudate tractotomy. Am. J. Psychiatry 161, 1913–1916.

Davis, K.D., Taub, E., Houle, S., Lang, A.E., Dostrovsky, J.O., Tasker, R.R., and Lozano, A.M. (1997). Globus pallidus stimulation activates the cortical motor system during alleviation of parkinsonian symptoms. Nat. Med. 3, 671– 674.

Deep-Brain Stimulation for Parkinson’s Disease Study Group (2001). Deep- brain stimulation of the subthalamic nucleus or the pars interna of the globus pal¿f¡dus in Parkinson’s disease. N. Engl. J. Med. 345, 956 –963.

Dougherty, D.D., Weiss, A.P., Cosgrove, R., Alpert, N.M., Cassem, E.H., Nier- enberg, A.A., Price, B.H., Mayberg, H.S., Fischman, A.J., and Rauch, S.L. (2003). Cerebral metabolic correlates as potential predictors of response to cingulotomy for major depression. J. Neurosurg. 99, 1010–1017.

Drevets, W.C. (1999). Prefrontal cortical-amygdalar metabolism in major de- pression. Ann. N Y Acad. Sci. 877, 614–637.

Drevets, W.C., Price, J.L., Simpson, J.R., Jr., Todd, R.D., Reich, T., Vannier, M., and Raichle, M.E. (1997). Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386, 824–827.

Fava, M. (2003). Diagnosis and definition of treatment-resistant depression. Biol. Psychiatry 53, 649–659.

First, M.B., Spitzer, R.L., Gibbon, M., and Williams, J.B.W. (2001). Clinical Interview for DSM-IVTR (SCID-I): User’s Guide and Interview-Research Version (New York: New York Psychiatric Institute Biometrics Research Department).

Fox, P.T., Mintun, M.A., Raichle, M.E., and Herscovitch, P. (1984). A noninvasive approach to quantitative functional brain mapping with H2 (15)O and positron emission tomography. J. Cereb. Blood Flow Metab. 4, 329–333.

Frank, E., Prien, R.F., Jarrett, R.B., Keller, M.B., Kupfer, D.J., Lavori, P.W., Rush, A.J., and Weissman, M.M. (1991). Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remis- sion, recovery, relapse, and recurrence. Arch. Gen. Psychiatry 48, 851– 855.

Freedman, M., Black, S., Ebert, P., and Binns, M. (1998). Orbitofrontal function, object alternation and perseveration. Cereb. Cortex 8, 18–27.

Freedman, L.J., Insel, T.R., and Smith, Y. (2000). Subcortical projections of area 25 (subgenual cortex) of the macaque monkey. J. Comp. Neurol. 421, 172–188.

Gabbott, P.L., Jays, P.R., and Bacon, S.J. (1997). Calretinin neurons in human medial prefrontal cortex (areas 24a,b,c, 32􏰇, and 25). J. Comp. Neurol. 381, 389–410.

Goldapple, K., Segal, Z., Garson, C., Lau, M., Bieling, P., Kennedy, S., and Mayberg, H. (2004). Modulation of cortical-limbic pathways in major depression: treatment specific effects of cognitive behavioral therapy. Arch. Gen. Psychiatry 61, 34–41.

Haber, S.N. (2003). The primate basal ganglia: parallel and integrative net- works. J. Chem. Neuroanat. 26, 317–330.

Hamilton, M.A. (1960). Rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62.

Heim, C., Newport, D.J., Heit, S., Graham, Y.P., Wilcox, M., Bonsall, R., Miller, A.H., and Nemeroff, C.B. (2000). Pituitary-adrenal and autonomic re- sponses to stress in women after sexual and physical abuse in childhood. JAMA 284, 592–597.

Hodaie, M., Wennberg, R.A., Dostrovsky, J.O., and Lozano, A.M. (2002). Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 43, 603–608.

Hyman, S.E., and Nestler, E.J. (1996). Initiation and Adaptation: a paradigm for understanding psychotropic drug action. Am. J. Psychiatry 153, 151–162. Jurgens, U., and Muller-Preuss, P. (1977). Convergent projections of different limbic vocalization areas in the squirrel monkey. Exp. Brain Res. 29,

75– 83. Kartsounis, L.D., Poynton, A., Bridges, P.K., and Bartiett, J.R. (1991). Neuro-

psychological correlates of stereotactic subcaudate tractotomy. A pro-

spective study. Brain 114, 2657–2673. Keller, M.B., Lavori, P.W., Mueller, T.I., Endicott, J., Coryell, W., Hirschfeld,

R.M., and Shea, T. (1992). Time to recovery, chronicity, and levels of psychopathology in major depression. A 5 year prospective followup of 431 subjects. Arch. Gen. Psychiatry 49, 809– 816.

Kendler, K.S., Thornton, L.M., and Gardner, C.O. (2001). Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am. J. Psychiatry 158, 582–586.

Kennedy, S.H., and Lam, R.W. (2003). Enhancing outcomes in the management of treatment resistant depression: a focus on atypical antipsychotics. Bipolar Disord. 158, 36–47.

Kumar, R., Lozano, A.M., Sime, E., and Lang, A.E. (2003). Long-term follow-up of thalamic deep brain stimulation for essential and parkinsonian tremor. Neurology 9, 1601–1604.

Lancet UK ECT Review Group (2003). Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 361, 799–808.

Lang, A.E., and Lozano, A.M. (1998). Parkinson’s disease. Second of two parts. N. Engl. J. Med. 339, 1130–1143.

Lang, P.J., Bradley, M.M., and Cuthbert, B.N. (1999). International Affective Picture Rating System (IAPS): Instruction Manual and Affective Ratings. Technical Report A-4 (Gainseville, FL: The Centre for Research in Psycho- physiology, University of Florida).

Lozano, A.M., Dostrovsky, J., Chen, R., and Ashby, P. (2002). Deep brain stimulation for Parkinson’s disease: disrupting the disruption. Lancet Neurol. 1, 225–231.

Maclean, P.D. (1990). The Triune Brain in Evolution: Role in Paleocerebral Function (New York, NY: Plenum).

Malizia, A. (1997). Frontal lobes and neurosurgery for psychiatric disorders. J. Psychopharmacol. 11, 179–187.

FOCUS Winter 2008, Vol. VI, No. 1 153



Manji, J.K., Drevets, W.C., and Charney, D.S. (2001). The cellular neurobiology of depression. Nat. Med. 7, 541–547.

Mayberg, H.S. (1994). Frontal lobe dysfunction in secondary depression. J. Neuropsychiatry Clin. Neurosci. 6, 428–442.

Mayberg, H.S. (1997). Limbic-cortical dysregulation: a proposed model of depression. J. Neuropsychiatry Clin. Neurosci. 9, 471– 481.

Mayberg, H.S. (2003). Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br. Med. Bull. 65, 193–207.

Mayberg, H.S., Liotti, M., Brannan, S.K., McGinnis, S., Mahurin, R.K., Jerabek, P.A., Silva, J.A., Tekell, J.L., Martin, C.C., and Fox, P.T. (1999). Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675–682.

Mayberg, H.S., Brannan, S.K., Mahurin, R.K., McGinnis, S., Silva, J.A., Tekell, J.L., Jerabek, P.A., Martin, C.C., and Fox, P.T. (2000). Regional metabolic Effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol. Psychiatry 48, 830–843.

McIntyre, C.C., Savasta, M., Kerkerian-Le Goff, L., and Vitek, J.L. (2004). Uncovering the mechanism(s) of action of deep brain stimulation: activa- tion, inhibition, or both. Clin. Neurophysiol. 115, 1239–1248.

Mottaghy, F.M., Keller, C.E., Gangitano, M., Ly, J., Thall, M., Parker, J.A., and Pascual-Leone, A. (2002). Correlation of cerebral blood flow and treatment effects ofrepetitive transcranial magnetic stimulation in depressed pa- tients. Psychiatry Res. 115, 1–14.

Montgomery, S.A., and Asberg, M. (1979). A new depression scale designed to be sensitive to change. Br. J. Psychiatry 134, 382–389.

National Institute of Mental Health, M. (1970). CGI: Clinical global impressions. In Manual for the ECDEU Assessment Battery. 2, W. Guy and R.R. Bonato, eds. (Chevy Chase, MD: National Institute of Mental Health).

Nestler, E.J., Barrot, M., DiLeone, R.J., Eisch, A.J., Gold, S.J., and Monteggia, L.M. (2002). Neurobiology of depression. Neuron 34, 13–25.

Nemeroff, C.B. (2002). Recent advances in the neurobiology of depression. Psychopharmacol. Bull. 36 (Suppl.), 6–23.

Nobler, M.S., Oquendo, M.A., Kegeles, L.S., Malone, K.M., Campbell, C.C., Sackeim, H.A., and Mann, J.J. (2001). Decreased regional brain metab- olism after ECT. Am. J. Psychiatry 158, 305–308.

Ongur, D., An, X., and Price, J.L. (1996). Prefrontal cortical projections to the hypothalamus in Macaque Monkeys. J. Comp. Neurol. 401, 480–505.

Sackeim, H.A., Rush, A.J., George, M.S., Marangell, L.B., Husain, M.M., Nahas, Z., Johnson, C.R., Seidman, S., Giller, C., Haines, S., et al. (2001). Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 25, 713–728.

Schallenbrand, G., and Wahren, W. (1977). Atlas for Stereotaxy of the Human Brain, Second Edition (Stuttgart, Germany: Thieme Verf¡llåg).

Seminowicz, D.A., Mayberg, H.S., McIntosh, A.R., Goldapple, K.K., Kennedy, S., Segal, Z., and Rafi-Tari, S. (2004). Limbic-Frontal Circuitry in Major Depression: A Path Modeling Metanalysis. Neuroimage 22, 409–418.

Spreen, O., and Strauss, E.A. (1998). Compendium of Neuropsychological Tests, Second Edition (New York, NY: Oxford University Press).

Thase, M.E., and Rush, A.J. (1997). When at first you don’t succeed: Seuqntial strategies for antidepressant nonrsponders. J. Clin. Psychiatry 58 (Suppl.), 23–29.

Vaidya, V.A., and Duman, R.S. (2001). Depresssion-emerging insights from neurobiology. Br. Med. Bull. 57, 61–79.

Vidailhet, M., Vercueil, L., Houeto, J.L., Krystkowiak, P., Benabid, A.L., Cornu, P., Lagrange, C., Tezenas du Montcel, S., Dormont, D., Grand, S., et al. (2005). Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N. Engl. J. Med. 352, 59–67.

Vogt, B.A., and Pandya, D.N. (1987). Cingulate cortex of the rhesus monkey II: Cortical afferents. J. Comp. Neurol. 262, 271–289.

Wang, P.S. (2003). National Co-morbidity survey replication. The epidemiology of major depressive disorder: results from the National co-morbidity Survey Replication (NCS-R). JAMA 289, 3095– 3105.

Watson, D., and Clark, L.A. (1988). Development and validation of brief measures of positive and negative affect: the PANAS scales. Personality Soc. Psychol. 6, 1063–1070.

World Health Organization. (2001). Chapter 2: Burden of Mental and Behavioral Disorders. In The WHO Report 2001: Mental Health, New Understanding, New Hope. chapter2/en/f¡ll dex3.html.

Worsley, K.J., Marrett, S., Neelin, P., Vandal, A.C., Friston, K.J., and Evans, A.C. (1996). A unified statistical approach for determining significant signals in images of cerebral activation. Hum. Brain Mapp. 4, 58–73.



The following is a reprint of articles and blogs from the internet discussing bipolar disorder, it’s relationships to epilepsy and to schizophrenia.

11/8/10 8pm

Research Topic: Similarity between bipolar disorder and epilepsy

Research by:Ocavan Internet Research Specialists,

From: Bipolar World

Q:  Temporal Lobe Epilepsy (TLE) or Bipolar?
I am confused and frustrated…My seven year old son was diagnosed with bipolar by a psychiatrist and several therapists; the neurologist has diagnosed him with temporal lobe epiliepsy.  Do both conditions appear they same on a SPECT scan and who should make the determination what he has?  I feel like I am stuck in the middle and I don’t know which diagnosis to believe.  My son is on Zoloft, Remeron, Rispedel and has several violent rages in a week.  He has been hospitalized twice in the last month and now attends a partail hospitlazation program for school.  I need to know what I should do, he has been seen by so many doctors and no on seems to agree on a diagnosis.  One of the biggest problems is that he was being abused by his father and he has problems from that but everyone seems to agree that there is an underlying condition.  Where else can I go for help?
Dear Sandy —
Sounds very confusing and frustrating, all right.  And yet there’s an unfortunate irony here:  the treatment for both conditions is very similar, in some ways nearly identical.  In both conditions you’d want to rely on anti-seizure medications (“anticonvulsants”).  They are standard medications for the treatment of bipolar disorder (here’s a list of the “mood stabilizers” we use; notice Depakote, Tegretol, lamotrigine are on that list.  In many cases they act like lithium, the old standard for bipolar disorder).In addition, medications that make seizure disorders worse (though only slightly in most cases) can make bipolar disorder worse also (more than slightly in many cases).  These include antidepressant medications and antipsychotic medications, because they “lower seizure threshold”; that is, they make it slightly easier for an underlying seizure condition to express itself.  And the antidepressants at least are widely recognized to have the potential to make bipolar disorder worse — not always, and in some versions of bipolar disorder they’re the standard thing to use, so your son may well have been treated in a very standard way.  However, it is possible, and needs to be considered, that the antidepressant medications (Zoloft, Remeron) could be making things worse, even at the same time as they are making things better, perhaps, in terms of less depressive symptoms (I presume they’re doing something good or being examined for discontinuation, given the known risk that they present in bipolar disorder).

The Risperdal (risperidone) is trickier but the same logic might apply to some degree.  Risperidone can occasionally make bipolar disorder worse (it acts too much like an antidepressant, bringing on cycling or manic-side symptoms — perhaps even at the same time as it’s helping treat some other aspect of the illness).  And risperidone can lower seizure threshold (not as much as some other antipsychotics, but some, e.g. Hedges et al 2003.  If you use this reference, here are some thoughts on talking to doctors about what you’ve learned).

The thing is, temporal lobe epilepsy and bipolar disorder are indeed very much alike.  In fact, there is so much overlap between the two conditions, it sure seems like there must be some direct relationship there — e.g. severe TLE, coming from just the right spot in the temporal lobe, could effectively “be” bipolar disorder, if we knew more about exactly how bipolar disorder works, which as you’ve probably learned, we don’t.   Here’s the most recent article I could find on how researchers are looking at the relationship of TLE and bipolar, finding them similar yet distinguishable (at least in this article, which to me also shows how little we know, i.e. the best we can do is assemble 13 patients and try to tell who’s who?)

The thing is, temporal lobe epilepsy and bipolar disorder are indeed very much alike.  In fact, there is so much overlap between the two conditions, it sure seems like there must be some direct relationship there — e.g. severe TLE, coming from just the right spot in the temporal lobe, could effectively “be” bipolar disorder, if we knew more about exactly how bipolar disorder works, which as you’ve probably learned, we don’t.   Here’s the most recent article I could find on how researchers are looking at the relationship of TLE and bipolar, finding them similar yet distinguishable (at least in this article, which to me also shows how little we know, i.e. the best we can do is assemble 13 patients and try to tell who’s who?)

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Is bipolar disorder a form of epilepsy?

Posted on August 6, 2007 by Seaneen

A lot of the medications used to treat bipolar disorder are also used in the treatment of epilepsy, notably sodium valproate, lamictal and carbamazepine (anticonvulsants).

There is some discussion in the medical community that bipolar is a form of temporal lobe epilepsy, and that the extreme mood states are in fact a form of seizure.

Here is a short study of thirteen patients with bipolar I disorder and epilepsy. There are overlaps- mood swings for a start, although it has been shown that manic episodes of bipolar I are more severe than those witnessed in temporal lobe epilepsy.

It was suggested when I was seventeen that I suffered from Temporal Lobe Epilepsy as I was experiencing psychosis. If you ever think it’s easy to be diagnosed with a mental illness, you’re wrong, it’s extremely difficult. After running through the gamut of being called an attention seeker, doctors will try to rule out other causes. For example, physical illnesses such as Multiple Sclerosiscan present symptoms that need psychiatric treatment. But my symptoms overlapped with TLE. It was eventually ruled out, but you can see why they tested me.

If you look at the symptoms of TLE, they do correspond with symptoms of bipolar I disorder:

Simple partial seizures:

Simple Partial Seizures (SPS) involve small areas of the temporal lobe and do not affect consciousness. These are seizures which primarily cause sensations. These sensations may be mnestic such as déjà vu (a feeling of familiarity), jamais vu (a feeling of unfamiliarity), a specific single or set of memories, or amnesia. The sensations may be auditory such as a sound or tune, or gustatory such as a taste, or olfactory such as a smell that is not truly present. Sensations can also be visual or involve feelings on the skin or in the internal organs. The latter feelings may seem to move over the body. Dysphoric or euphoric feelings, fear, anger, and other sensations can also occur during SPS. Often, it is hard for persons with SPS of TLE to describe the feeling. SPS are often called “auras,” and are sometimes thought to be preludes to actual seizures. The latter is incorrect. SPS are seizures.

The experiences in simple partial seizures are similar to those experienced in mania- for example, hallucinations, dysphoria and euphoria, fear and anger.

Of course, do look further than wikipedia, I’m merely using that page as a summary. I have read further but wiki is good for summing things up. The page for the seizure touches on something interesting:

*amnesia around the seizure event and sometimes events which occurred before the seizure

Something rarely discussed is the cognitive impact of bipolar disorder, such as problems with memory. I experience this, and over years of episodes, my ability to recall events (especially when it comes to things that have been said) and to think clearly has been corroded. I also experience memory blanks when in episodes. I can’t clearly remember any of my manic episodes and with rapid-cycling, short manic or depressive episodes yield blanks for me.

Then there is complex partial seizures which touches on something very interesting:

Signs may include motionless staring, automatic movements of the hands or mouth, inability to respond to others, unusual speech, or unusual behaviors.

Doesn’t that sound like severe catatonic depression and the negative symptoms of schizophrenia?

The similarities end at the point of tonic-clonic seizures.

Remember that bipolar disorder I is not just experiencing severe mood swings. There is a whole host of physical and cognitive symptoms. Mania and depression both involve physical tics such as restlessness, twitching and repetive movement for mania to lack of response in depression. The brain processes things at different speeds in different mood states- too fast in mania, too slow in depression. Memory is impaired, the ability to concentrate is destroyed and at both ends of the rainbow there is psychosis.

There is also some discussion that temporal lobe epilepsy can result in hyperreligiousity, which is also a feature of mania.

Don’t overlook that these are extremely generalised symptoms, though.

So why are bipolar disorder and TLE often treated with the same medications? Something massively overlooked by those who don’t believe in mental illness is that in a lot of cases, the medication works. There is some biological basis to bipolar disorder, or else medication would have no effect. ECT would be rendered useless.

It isn’t a case of simply numbing the person. I take a combination of medication because I have just been diagnosed but my situation isn’t at all representative. Quite a lot of people take one drug- a mood stabiliser or an antipsychotic, and many people take two (those with bipolar II generally take an antidepressant and a mood stabiliser). I started at one- Lithium for mania. My secondary problem, because I experience mania often, is psychosis, so an antipsychotic was added. Then an antidepressant for depression, which was then taken away and Depakote was added for rapid-cycling. All my medications seek to stabilise me. Antidepressants can help depression. Antipsychotics can help psychosis. Antimanics can help mania.

It’s keeping a balance rather than seeking to destroy the feelings and functions of the patient. A lot of people manage to function normally on medications whereas they weren’t able to before. Some people don’t, and some people do not take medication for their illness, either out of unwillingness or because they have a mild form of bipolar disorder. However, there is always the risk that mild will become full blown. Is it behavioural or is it biological? Why does it become worse unmedicated?

The thing is, nobody knows why bipolar medication works. Lithium, one of the oldest drugs for bipolar mania, was discovered by accident and doctors still have no idea how it works. So it’s pretty obvious as to why people won’t take medication. Do you really want to put a drug in your body when you have no idea how it works? There’s more concrete evidence on the mechanics of heroin than on the mechanics of psychiatric medication.

They may be treated with similar drugs because they present similiar symptoms. However, the overlaps in no way mean that they are similiar illnesses. The symptoms of mental illness displayed in TLE are not the whole story.

However, it were proven that bipolar (and possibly even schizophrenia) were forms of epilepsy then it would revolutionise the way they are treated. Physical illnesses garner more sympathy and understanding than mental illnesses. The psychiatric symptoms of physical illnesses are unfortunate side effects of the illness, whereas when the symptoms are the unfortunate illness, the view is quite different.

For example, take the criticism people like me who write about our mental illnesses receive (just cast your eyes over the comments and I could share e-mails I get). I am told often that my illness isn’t real and that I am, as a person, flawed for having this illness. It is unlikely that if I wrote about these symptoms- and symptoms is what they are- while suffering from a physical illness that encompassed these symptoms it would be different. Because physical illnesses are provable, whereas mental illnesses are not. Therefore the physical illness will always be more credible than the mental illness.

If mental illnesses were provable and partially attributed to a biological cause like epilepsy, then the treatment of mental illness and those who have it would change drastically. People who have epilepsy aren’t viewed as burdens to society. People would finally understand that we mean it when we say that we don’t do this to ourselves. The suffering caused by it to ourselves and loved ones isn’t something we embrace and encourage. The opinion of diagnosis of mental illness as a societal tool for cataloguing and catergorising behavioural problems would be dismissed as physical illnesses do present the same symptoms. It would be nice not to be seen as psychos and fuck ups to be seen as people who have an illness that needs treatment as any other.


Bipolar Disorder and Epilepsy: A Bidirectional Relation? Neurobiological Underpinnings, Current Hypotheses, and Future Research Directions

  1. Marianna Mazza1,
  1. Marco Di Nicola2,
  2. Giacomo Della Marca3,
  3. Luigi Janiri4,
  4. Pietro Bria5 and
  5. Salvatore Mazza6


Author Affiliations

  1. 1Institute of Psychiatry, Bipolar Disorders Unit, Catholic University of Sacred Heart, Rome, Italy,
  2. 2Institute of Psychiatry, Bipolar Disorders Unit, Catholic University of Sacred Heart, Rome, Italy
  3. 3Department of Neurosciences, Epilepsy Center, Catholic University of Sacred Heart, Rome, Italy
  4. 4Institute of Psychiatry, Bipolar Disorders Unit, Catholic University of Sacred Heart, Rome, Italy
  5. 5Institute of Psychiatry, Bipolar Disorders Unit, Catholic University of Sacred Heart, Rome, Italy
  6. 6Department of Neurosciences, Epilepsy Center, Catholic University of Sacred Heart, Rome, Italy


A number of studies have demonstrated that affective disorders in epilepsy represent a common psychiatric comorbidity; however, most of the classic neuropsychiatric literature focuses on depression, which is actually prominent, but little is known about bipolar depression, and very little about mania, in epilepsy. Biochemical, structural, and functional abnormalities in primary bipolar disorder could also occur secondary to seizure disorders. The kindling paradigm, invoked as a model for understanding seizure disorders, has also been applied to the episodic nature of bipolar disorder. In bipolar patients, changes in second-messenger systems, such as G-proteins, phosphatidylinositol, protein kinase C, myristoylated alanine-rich C kinase substrate, or calcium activity have been described, along with changes in c-fos expression. Common mechanisms at the level of ion channels might include the antikindling and the calcium-antagonistic and potassium outward current-modulating properties of antiepileptic drugs. All these lines of research appear to be converging on a richer understanding of neurobiological underpinnings between bipolar disorder and epilepsy. Mania, which is the other side of the coin in affective disorders, may represent a privileged window into the neurobiology of mood regulation and the neurobiology of epilepsy itself. Future research on intracellular mechanisms might become decisive for a better understanding of the similarities between these two disorders. NEUROSCIENTIST 13(4):392—404, 2007. DOI: 10.1177/1073858407301117


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