Functional topography of the ventral striatum and anterior limb of the internal capsule determined by electrical stimulation of awake patients

Clinical Neurophysiology 120 (2009) 1941–1948

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Functional topography of the ventral striatum and anterior limb of the internal capsule determined by electrical stimulation of awake patients Andre Machado a,*, Suzanne Haber b, Nathaniel Sears c, Benjamin Greenberg d, Donald Malone e, Ali Rezai f a

Center for Neurological Restoration, Department of Neurosurgery, Cleveland Clinic, 9500 Euclid Ave., Desk S31, Cleveland, OH 44195, USA Department of Pharmacology and Physiology, University of Rochester, Medical Center, USA c Department of Psychiatry and Human Behavior, Brown University, USA d Brown University, USA e Psychiatry Neuromodulation Center, Cleveland Clinic, USA f Department of Neurosurgery, Ohio State University, USA b

See Editorial, pages 1879–1880

a r t i c l e

i n f o

Article history: Accepted 11 May 2009 Available online 24 September 2009 Keywords: Deep brain stimulation Major depressive disorder Orbitofrontal cortex Ventral striatum Internal capsule

a b s t r a c t Objective: To assess the behavioral and subjective effects of acute electrical stimulation along the anterior limb of the internal capsule (ALIC) and ventral striatum (VS). Methods: Intraoperative awake electrical stimulation and postoperative programming was performed in a group of 6 patients with major depressive disorder (MDD) undergoing bilateral deep brain stimulation of the ALIC and VS areas. Results: Electrical stimulation of the VS area acutely produced changes in mood as well as alertness, anxiety, dizziness, sensation of warmth and ‘‘flushing”. Stimulation of the ventral capsule area just dorsal to the anterior commissure was associated with increments in mood, sensation of energy and alertness, laughing, calmness and talkative behavior. Behavioral effects were less commonly observed with stimulation of the dorsal region of the ALIC. Conclusion: Acute behavioral and subjective responses can be consistently obtained from stimulation in the ventral ALIC and VS region. Positive changes in mood and anxiety were reproducibly elicited in the ventral ALIC area. Significance: Intraoperative awake stimulation and postoperative programming of patients undergoing DBS for MDD provide unique opportunities to explore the subjective responses and behavioral phenomena related to electrical stimulation of the area spanning from the dorsal ALIC to the ventral striatum. Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Stereotactic neurosurgical procedures have been considered as an option in the treatment of severe and resistant forms of psychiatric disorders for several decades. Thermocoagulation or radiosurgical ablative procedures of the cingulum (Ballantine et al., 1967, 1987; Dougherty et al., 2002; Cosgrove and Rauch, 2003), subcaudate region (Knight, 1965; Goktepe et al., 1975; Bridges et al., 1994; Hodgkiss et al., 1995) and the anterior limb of the internal capsule (ALIC) have been reported (Leksell and Backlund, 1978; Fodstad et al., 1982; Mindus and Meyerson, 1982; Lippitz et al., 1999; Ruck et al., 2008), with long term outcomes. * Corresponding author. Tel.: +1 216 444 4270; fax: +1 216 636 2989. E-mail address: [email protected] (A. Machado).

Stereotactic procedures targeting the ALIC have been performed for a variety of psychiatric disorders, ranging from obsessive compulsive disorder to schizophrenia. Capsulotomies were reported to be efficacious and safe for alleviating the symptoms of obsessive compulsive disorder (Mindus and Meyerson, 1995). The safety of these procedures has been recently revisited and the risk associated with large lesions or repeated thermocapsulotomy procedures may have been underestimated (Ruck et al., 2003, 2006). During the past two decades a gradual shift has occurred in the field of stereotactic and functional neurosurgery, as deep brain stimulation became an established method for chronic alleviation of medically refractory essential tremor, Parkinson’s disease and dystonia. Reversibility and adjustability are fundamental safety features of this technology. Nutin and collaborators Nutin and collaborators (1999) reported positive results in the first series of OCD patients

1388-2457/$36.00 Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2009.05.030

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undergoing DBS instead of ablation of the ALIC. Subsequently, other groups have also reported similar outcomes, further corroborating to the safety and efficacy of DBS of the ALIC and ventral striatum (VS) for the treatment of OCD (Gabriels et al., 2003; Aouizerate et al., 2004; Abelson et al., 2005; Greenberg et al., 2006, 2008). Prospective follow-up of theses patients allowed the investigators to note mood enhancement along with improvements in obsessive compulsive symptoms. This finding led to the exploration of this target in patients with disabling refractory major depressive disorders (MDD) (Greenberg et al., 2003). A prospective Ventral Anterior Limb of the Internal Capsule/Ventral Striatum (VC/VS) deep brain stimulation trial for intractable major depressive disorder is currently in progress at three United States centers. Preliminary results suggest that the therapy is safe and effective (Malone et al., 2009). During the implant procedure and post-implantation programming sessions individual contacts were tested with cathodic electrical stimulation. Although exploration of the effects of electrical stimulation at the targeted areas had a clear therapeutic intent, it also provided a unique opportunity to assess the functional topography of the VC/VS in this group of patients. In the present study, we report the behavioral and subjective effects described during acute intraoperative and postoperative programming sessions and correlate these to the topography of the contacts from which the effects were elicited. 2. Patients and methods 2.1. Patients Six patients for whom adequate postoperative imaging for electrode localization was available were included in the study. All patients were participants in investigator initiated studies of DBS for refractory depression at the Cleveland Clinic. Informed consent was obtained along with appropriate IRB and FDA (IDE) approvals. Inclusion criteria were strict, to ensure that patients enrolled were severe, refractory and without other significant treatment options. All subjects had failed extensive medication and psychotherapy treatment regimens along with at least six bilateral ECT treatments. At least four failed trials of antidepressants plus two combination/augmentation trials were required for inclusion. At the time of data analysis for this report, all patients had been followed for at least six months after DBS implantation and programming was considered optimized. Intraoperative testing and postoperative programming data from the 6 patients contributed to the data analysis. All patients had undergone intraoperative stimulation testing and postoperative programming in a standard fashion, performed by the same psychiatrist. All data regarding behavioral and subjective responses to stimulation were recorded by the same investigator in order to minimize the variance of interpretation of these subjective effects. 2.2. Surgical procedure All patients underwent bilateral stereotactic implantation of deep brain stimulation electrodes under local anesthesia and sedation. Stereotactic volumetric magnetic resonance images for surgical planning were acquired prior to the day of surgery and a volumetric computed tomographic scan was obtained in the day of surgery with the stereotactic headframe (G model, Elekta, Stockholm) placed. Image fusion was always performed, preceding target determination and trajectory selection (Stealth Station Treon, Medtronic). The stereotactic target was planned so that the ventral contacts of the electrode would be located at the ventral striatum and ventral ALIC. On the antero-posterior plane, the electrodes were aimed at the anterior commissure (AC) or at a maximum of

Fig. 1. Coronal MRI (T1 weighed) view at the level of the anterior commissure (AC). The DBS leads are targeted at the striatum ventral to the AC. The trajectory for implantation is planned such that it follows the slope of the anterior limb of the internal capsule. Contact 0 on the right side and contact 1 on the left side are labeled, as well as the head of the caudate nucleus on the left side (arrowhead) and the globus pallidum on the right (arrow). The surgical goal is to position the ventralmost contact in the ventral striatal area while positioning the other contacts along the ALIC. Surgical considerations that limit symmetry include avoidance of blood vessels along the trajectories. The preference is to penetrate the brain at the crown of a gyrus rather than a sulcus.

3 mm anterior to the posterior edge of the AC. Fig. 1 exemplifies a typical implant. The trajectory was planned so that the more dorsal contacts (contacts 2 and 3) would be positioned along the main axis of the ALIC. The trajectory was also planned so that it would avoid any sulcus or major vessels. Once each electrode was implanted on either side, intraoperative stimulation was initiated with an external pulse generator (model 3625 Medtronic, Minneapolis). All patients were implanted with the modified 3387 INS (Medtronic, Minneapolis) DBS electrodes except for 1 patient that received a standard 3387 electrode on the left side and the 3387 INS on the right side. The quadripolar 3387 INS electrode has 3 mm long contacts separated by 4 mm interspaces, covering a total span of 24 mm. The standard 3387 lead has 1.5 mm long contacts separated by 1.5 mm interspaces, for a total span of 10.5 mm. The contact closest to the tip of the electrode (and consequently implanted most ventrally in the targeted area) is labeled contact 0. The most dorsal of the four contacts is labeled 3. Contacts 1 and 2 are in between. A cathodal survey was performed for each electrode, assessing the effects of each contact as an independent cathode. Frequency was set at 130 Hz and pulse width at 90 and 210 ls. The patient was blinded to the amplitude and sham stimulation was frequently used (0 V) while asking for possible effects. Amplitude was titrated at increments of 1–2 V and the effects recorded on standardized forms. Upon verification of the effects, the electrode was anchored to the burr hole with the StimLock device and the wounds closed. Internalization of the system with subclavicular implantation of Soletra implantable pulse generators (Medtronic, Minneapolis) was performed on a second surgical day, under general anesthesia.

2.3. Postoperative localization of the electrodes A post-operative volumetric T1 MRI or stereotactic high resolution CT scan was performed in all patients. The images were fused with the preoperative MR and the AC and PC were identified. The

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images were re-formatted to triplanar views orthogonal to the AC– PC line. In reformatted MR images, each contact was individually located and triplanar coordinates obtained in relation to the AC. In postoperative reformatted CT scans, the tip of the electrode was identified and the slope of angulation of the electrode determined by selecting a second arbitrary point along the electrode trajectory. The coordinates for each contact centroid were then determined based on the calculated slope in relation to the intercommissural line and the known distances between the tip and contacts. 2.4. Programming Postoperative programming was aimed at maximizing the effects of DBS in alleviating the symptoms of MDD while avoiding side effects such as hypomania, anxiety, and sensation of warmth. In order to identify the stimulation effects elicited by each contact, a systematic cathode review was performed in a similar fashion to intraoperative testing, activating one electrode as the cathode at a time on either side. Outpatient programming strategy was based on identifying cathodes and stimulation parameters that created the most positive effects with minimal side effects. These settings were then applied to chronic stimulation with the intent of enhancing mood and alleviating the symptoms of depression. On several occasions, a given response was elicited several times from the same cathode, either intraoperatively or postoperatively. Often, this was an attempt of the programmer to validate a finding and confirm its occurrence at a given stimulation threshold. In order to avoid redundancy and over-representation when correlating stimulation effects to an anatomical region, given responses from each cathode (i.e. mood enhancement) were only counted once. In reporting the effects observed during either intraoperative or postoperative stimulation, we classified the effects as consistent (when at least 4 patients reported the effect); frequent (when 2 or 3 patients reported the effect) or isolated (when only 1 patient reported the effect). 2.5. Clustering of proximate contacts The stereotactic coordinates of each electrode contact in relation to the AC was plotted in a single data set. The average location of each electrode contact on either side across all patients was calculated. Then, all contacts within a Euclidian distance of 3 mm from the average location of a given contact (i.e. contact 1 on the right side) were clustered together. Those contacts that laid outside this maximum distance were considered not to belong to the same cluster and were excluded from this analysis. 2.6. Comparison of intraoperative and postoperative effects As described above, individual contacts from each electrode were activated with cathodic stimulation during surgery and in the post-operative period. During surgery, the investigators were interested in target verification with macrostimulation. The goals were to ascertain that at least one contact on each side would provide positive effects (i.e. mood improvement or lower anxiety) and to identify the stimulation threshold for possible side effects (i.e. increased anxiety, autonomic activation, mood worsening). During the implant procedure, although patients were typically very cooperative, the extent of testing was somewhat limited. Post-operatively, during outpatient programming sessions, cathodal surveys were more detailed and redundant. The effects observed intraoperatively and postoperatively were compared. All effects were grouped and normalized to 100%. We report and compare the fre-

quency of subjective responses obtained intraoperatively and postoperatively.

3. Results 3.1. Contact clusters Clustering of the electrode contacts from all 6 patients located within 3 mm radius of the average contact location resulted in three contact clusters: Contact Cluster 0 (CC0), Contact Cluster 1 (CC1) and Contact Cluster 2 (CC2). Contacts 3 across the different electrodes were not clustered because of greater variability of stereotactic location across the patients, creating an incohesive group. All coordinates are reported in millimeters and relative to the posterior inferior margin of the anterior commissure. The coordinates of the clusters are listed in Table 1 and graphically displayed in space in Fig. 2. Fig. 3 shows the cluster contacts superimposed on images adapted from the Mai Atlas (Mai, 1998). The behavioral and subjective responses to stimulation in each cluster are reported, per side. Table 2 summarizes the effects of electrical stimulation of each cluster. Table 3 lists uncommon subjective responses to stimulation. Contact Cluster 0 had average location (X, Y, Z) on the right side (7.7, 1.1, 2.8) and on the left side ( 5.0, 1.6, 2.6). This location corresponds anatomically to a point 2.5 mm inferior to the anterior half of the anterior commissure, lying in the topography of the ventral striatum. On the left side, the cluster is more medial and hence closer to the hypothalamus. Stimulation on the right side consistently resulted in acute mood enhancement. Dizziness, anxiety, alertness and increased energy were frequently reported. Stimulation on the left side consistently resulted in enhancement of mood as well as a sensation of warmth. Dizziness and anxiety were also frequently reported. Uncommon effects for both sides were reduced mood, laughter, sensation of ‘‘flushing”, increased talking and nausea (Table 2). Cluster contact 1 had an average location on the right side of (11.6, 3.5, 2.7) and on the left ( 7.9, 4.0, 2.6). The electrodes were typically implanted from a pre-coronal burrhole, often close to the hairline in the frontal region. In the medial–lateral orientation, the trajectory followed the anterior limb of the internal capsule (Fig. 1). Consequently, CC1 is located dorsal, rostral and lateral to CC0 and is rostral and dorsal to the anterior commissure. Stimulation with these contacts on the right side resulted in similar effects to CC0, with increased mood and, frequently, increased energy, laughter, alertness, dizziness and increased talking. On the left side, frequent (but not consistent) responses were increased mood and energy, alertness, warmth, a sensation of calmness and nausea. Uncommon effects at this topography were also similar to those found in contact 0, except for a sensation of fatigue that was reported once on both sides (Tables 2 and 3). Cluster Contact 2 was located on the right at coordinates (15.6, 5.1, 7.9) and left ( 11.0, 6.3, 7.6). Again, as a result of the planned trajectory, the contacts are more rostral and lateral then the ventral contacts. The average location corresponds to the middle third of the ALIC in the dorsoventral direction, between the caudate nucleus and the putamen as visualized in Fig. 3. Stim-

Table 1 Cluster contact locations. Cluster Contact

0 1 2 3

Right

Left

X

Y

Z

7.7 11.6 15.6 19.1

1.1 3.5 5.1 8.8

2.8 2.7 7.9 13.8

X 5.0 7.9 11.0 13.9

Y

Z

1.6 4.0 6.3 10.3

2.6 2.6 7.6 12.7

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Fig. 2. Trajectory through the ALIC. Leads 0, 1 and 2 are the averaged locations through the ALIC. Shaded squares represent the actual locations of leads included in the analysis. The remaining not shaded squares are outliers and not included in the analysis.

ulation with this cluster of contacts on the right side resulted in no consistent responses. Mood enhancement was only reported by 1 patient, a significant disparity from the ventral contacts. Frequent responses were dizziness, anxiety and reduced mood. Fatigue was reported frequently on the right side at this location, compared to only in 1 patient at CC1. There were no consistent or frequent effects generated with CC2 on the left side. Uncommon effects were sensations of warmth or energy and dizziness. 3.2. Comparison of intraoperative and postoperative findings Contact 0 on the right side produced an increase in mood more frequently during the intraoperative phase (50%) than during the postoperative phase (40%). On the left side, there was a decline in the reported increase in mood going from an intraoperative frequency of 60% to a postoperative frequency of 44%. Contact 1 on the right side improved mood in 33% of cases intraoperatively

and 42% postoperatively. On the left side, CC1 showed only a minimal (2% points) variation in the reported mood increase. Stimulation with CC2 on the right was associated with a 50% decrease in mood during surgery and dropped to 22% responsiveness postoperatively. The data on left side CC2 was not sufficient for comparison. Globally, the responses generated with stimulation at CC0 on the right changed an average of 5% between the intraoperative and postoperative phase. The responses associated with CC0 on the left changed an average of 12% comparing the intraoperative period to the postoperative period. There was a 6% difference between the intraoperative and postoperative stimulation at CC1 on the right and 12% on the left. Overall there was an average variability of 11% – a concurrence of 89% – between the intraoperative and postoperative stimulation periods at all contacts. Table 4 summarizes the comparison between intraoperative and postoperative stimulation effects.

Fig. 3. Cluster contacts plotted on the Mai Atlas of the human brain. The AP (Y) coordinates are as follows: left: Y = 1.3 mm (Plate 20); Center: Y = 4.2 mm (Plate 17); Right: Y = 5.8 mm (Plate 16). The squares represent the locations of the contacts in the right hemisphere, while the circles represent contact locations in the left hemisphere. The solid shapes represent the locations of the cluster contact. The open shapes represent individual patient contact locations contributing to each cluster contact.

A. Machado et al. / Clinical Neurophysiology 120 (2009) 1941–1948 Table 2 Summary of responses associated with stimulation at each contact. Cathode

Number of PTs reporting

Right

Left

0

4–6 patients; consistent 2–3 patients; frequent 1 patient; isolated

Up mood

Warmth, up mood

Dizzy, anxious, alert, energetic Down mood, laughter, talkative, flushed

Dizzy, anxious, flushed Down mood, laughter, talkative, calm, nausea

4–6 patients; consistent 2–3 patients; frequent

Up mood

1

1 patient; isolated 2

4–6 patients; consistent 2–3 patients; frequent 1 patient; isolated

Up mood, energetic, alert, laughter, dizzy, talkative Anxious down mood, tired, warmth, calm, alert, nausea

Dizzy, anxious, calm, mood down, tired Warmth, up mood

Up mood, energetic, alert, warmth, calm, nausea Anxious down mood, tired, dizzy, talkative

Warmth, energetic, dizzy, calm

Deep brain stimulation is a promising therapy for patients disabled by medically refractory MDD. Patients that contributed data to this study were enrolled in a trial of DBS of the VC/VS for severe and otherwise intractable MDD. Our initial data indicates that this therapy is safe and effective even in this very refractory population (Malone et al., 2009), suggesting that this line of investigation is likely to proceed into larger trials The development of this emerging therapy depends not only on advances in surgical technique and patient selection but also in furthering our understanding of the circuitry involved in the targeted region and how focal electrical stimulation may affect it. The results of this study, although derived from a limited sample, provide an initial understanding of the functional topography of the VC/VS region and indicate behavioral and subjective responses that may be elicited from discrete topographical locations within the targeted region. The choice of electrodes used in this trial, with 24 mm of active array length,

Table 3 Uncommon responses recorded with stimulation at different locations along the ALIC. Cluster Contact

R

L

0

Motor effect: left face pulled

Nasal tingling. Sweeping. facial pulling Dry mouth, shoulders feel heavy

Left nasal tingling Dry mouth shoulders heavy

2

allowed for exploration of stimulation effects throughout a relatively large region, spanning from the ventral striatum to the middle third of the ALIC. 4.1. Correlation between cluster location and effects

4. Discussion

1

1945

Pressure at higher voltage Tingling, improved fogginess Initial sweeping sensation Sweeping sensation, unusual taste Ears cogged Some shivering

Some shaking Initial sweeping sensation Some visual disturbance Clogged ears

No noted effect through 7 volts Right nostril pulled to the right Visual blurring Nasal sensation Bilateral frontal temporal HA, heaviness

Initial sweeping sensation Shoulders heavy

Heaviness

4.1.1. Contact Cluster 0 Stimulation of the region of the ventral striatum and nucleus accumbens in patients with deep brain stimulation for obsessive compulsive disorder has been reported to generate sensations of fear and panic attacks (Shapira et al., 2006; Okun et al., 2007). In these studies, the events were well documented and temporally related to turning the stimulation ON. Shutting the stimulation OFF resulted in cessation of the effects as well as normalization of heart rate. These effects corroborate data from animal models that have indicated that the nucleus accumbens has a role in processing fear and conditioned aversive learning (Haralambous and Westbrook, 1999; Reynolds and Berridge, 2001, 2002; Pezze et al., 2002). Temporary blockade of the nucleus accumbens in a rodent model has been shown to completely block the acquisition of conditioned fear. It is possible that electrical stimulation of this region in patients with OCD activated these circuits. However, in contrast to this finding, observed in a few OCD patients, stimulation of the region of the nucleus accumbens/ventral striatum in the present study elicited anxiety in some patients but no sensation of fear or panic attacks. This region, a relatively compact area, has been shown to have topographical organization and segregation of function (Kirouac and Ganguly, 1995; Reynolds and Berridge, 2001). It is possible that variations in targeting of the DBS electrodes or the variation in stimulation parameters that were used between the present series and the previous series reporting panic attacks account for the differences in responsiveness to acute electrical stimulation. Alternatively, the difference in disease states may also play a role in the disparity of effects as patients with severe depressive disorders may have abnormal neuropharmacological function of the nucleus accumbens (Zangen et al., 2001; Malkesman et al., 2007) which may, consequently, not respond to electrical stimulation in the same fashion as in patients with OCD. In the present study, stimulation of CC0 in the region of the ventral striatum and ventral pallidum on either side resulted in reports of positive mood and laughter (Table 2). Similar effects have been previously reported by acute stimulation of this region (Okun et al., 2004, 2007). It is possible that stimulation of this region modulates behavior specific cortico-subcortical systems. The existence of five parallel cortico-striatal–pallidal–thalamo-cortical (CSPTC) pathways conveying segregated motor, oculomotor, executive and behavioral information was proposed by Alexander and DeLong (Alexander and Crutcher, 1990). This classic publication is one of the foundations of our current understanding of the basal ganglia. It is particularly important in the surgical treatment of movement disorders, providing a rational model to explain how lesions or stimulation outside the motor subregion of a given subcortical nucleus (i.e. the subthalamic nucleus) may influence executive or behavioral functions (Bejjani et al., 1999; Dujardin et al., 2001; Moretti et al., 2002; Francel et al., 2004). The first indications that the CSPTC system could have non-motor information segregated in parallel to the classic motor pathway were observed in projections from the ventral parts of the striatum (Heimer and Wilson, 1975). These findings later gave rise to the definition of the ventral striatopallidal system (Haber and Lu, 1995; de Olmos and Heimer, 1999; Haber and Gdowski, 2003; Heimer, 2003) mediating information with behavioral relevance. In this study, the electrical field generated by stimulation of CC0 is likely to have affected the ventral striatal and/or its projections into the ventral pallidal region. The ventral pallidum receives inputs from the orbitofrontal cortex via the ventral striatum and projects to the cortex via the medial–

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Table 4 Response frequency at each lead during intraoperative and postoperative stimulation. The value N signifies the total number of contributing responses. The values represent the contribution (as a fraction of 1) that each response made to that stimulation session. The value ‘‘delta” shows the difference between intraoperative stimulation and post operative stimulation. It should be noted that the total number of contributing responses recorded intraoperatively are less than during the post operative period because of the time constraints during awake neurosurgery. 0R – contact 0, right side; 0L – contact 0, left side; 1R – contact 1, right side; 1L – contact 1, left side; 2R – contact 2, right side; 2L – contact 2, left side; IO – intraoperative; PO – postoperative. Lead

Time period

N

0R

IO PO

0L

IO PO

8 15 Delta 5 9 Delta

0.50 0.40 0.10 0.60 0.44 0.16

0.00 0.07 0.07 0.00 0.11 0.11

0.13 0.20 0.07 0.20 0.00 0.20

0.00 0.00 0.00 0.00 0.00 0.00

0.13 0.13 0.00 0.20 0.33 0.13

0.25 0.20 0.05 0.00 0.11 0.11

9 12 Delta 7 11 Delta

0.33 0.42 0.09 0.29 0.27 0.02

0.11 0.08 0.03 0.00 0.09 0.09

0.22 0.25 0.03 0.14 0.27 0.13

0.00 0.08 0.08 0.00 0.09 0.09

0.22 0.08 0.14 0.43 0.09 0.34

0.11 0.08 0.03 0.14 0.18 0.04

2. 9 Delta 0 2 Delta

0.00 0.11 0.11 0.00 0.00 0.00

0.50 0.22 0.28 0.00 0.00 0.00

0.00 0.00 0.00 0.00 0.50 0.50

0.50 0.11 0.39 0.00 0.00 0.00

0.00 0.22 0.22 0.00 0.00 0.00

0.00 0.33 0.33 0.00 0.50 0.50

0.08

0.10

0.16

0.09

0.14

0.18

1R

IO PO

1L

IO PO

2R

IO PO

2L

IO PO

Overall average delta

Up mood

Down mood

Up energy

dorsal nucleus of the thalamus (Heimer, 2003). The ventral striatopallidal system has been thoroughly linked to the processing of reward related inputs (Haber et al., 2000; Nicola et al., 2005; Ikemoto, 2007) and how these may influence the individual’s behavioral response to these inputs (Haber et al., 2006). The ventral striatopallidal projections may have functional relevance analogous to the dorsal (motor) striatopallidal projections, in selecting behaviors that are appropriate for the situation while inhibiting inadequate behaviors (Haber and Gdowski, 2003). As with stimulation of the ventral striatum, stimulation of the ventral pallidal area may elicit the behavioral responses observed in this group of subjects. In fact, these are two components of the same striatopallidal circuit and high frequency stimulation of either the striatal origin or the pallidal connection may have resulted in the observed effects. In addition to possible CC0 stimulation effects upon the ventral striatopallidal nuclear structures, it is also possible that the acute changes in mood observed in these subjects resulted from stimulation spread to neighboring white matter bundles such as the fornix, anterior commissure, internal capsule or the extended amygdala. Stimulation of the anterior commissure or internal capsule can lead to antidromic and orthodromic activation of the orbitofrontal cortex. The anterior commissure (AC) is located immediately superior to CC0 in this group. This commissural bundle connects the inferior temporal regions of each hemisphere and the parahippocampal gyri. Previous studies have demonstrated that fibers from the orbitofrontal cortex also contribute to the AC (Pandya et al., 1973; Demeter et al., 1990). Recent work using tracing techniques in non-human primates has corroborated these findings and indicates that fibers originating in the oribitofrontal areas cross the midline on the anterior half of the AC (Schmahamann and Pandya, 2006). Electrical stimulation of CC0 in this series may have resulted in orthodromic or antidromic effects upon the orbitofrontal regions connected via the AC resulting in mood augmentation. The close proximity of the AC to the division of the fornix in two anterior columns suggests that if the electrical field from CC0 was large enough to influence the AC fibers, it likely influenced fornicial fibers as well. Human diffusion-weighed imaging tractography studies have indicated a high probability of connections be-

Down energy

Up anxiety

Down anxiety

?

0.05

?

0.12

?

0.07

?

0.12

?

0.22

?

0.17

?

0.13

tween the fornix and the medial orbital cortex (Croxson et al., 2005). Consequently, electrical stimulation of the fornicial fibers may affect the orbital medial cortex or may directly influence the classic Papez circuitry (Papez, 1995). The medial and lateral bed nuclei of the stria terminalis are located immediately dorsal to the AC, near the crossing point of the ventral ALIC to the AC. Stimulation of CC0 may have extended to these nuclei, which are part of the extended amygdala (de Olmos and Heimer, 1999). The extended amygdala is directly involved in behavior, receiving inputs from the limbic lobe and projecting to the autonomic and endocrine hypothalamic nuclei. These connections may in part explain the autonomic related effects reported by some patients during stimulation. The ventral capsule is dorsal to CC0 and may have been affected with higher amplitude stimulation, although it is more closely related to CC1. The topography of CC0 corresponds to an area densely populated by nuclear structures and white matter fiber bundles functionally related to behavior. This study is limited to discriminate the relative contributions of stimulation of the AC, anterior fornix, extended amygdala or ventral capsular fibers in eliciting the behavioral responses observed in this group of patients. 4.1.2. Contact Cluster 1 Mood elevations were consistently reported with stimulation of CC1 on the right side and frequently on the left side (Table 2). Although it is possible that mood elevation from CC1 region stimulation is mediated by ventral current spread to the AC fibers projecting to and from the orbitofrontal cortex, effects upon the larger bundle of axons projecting through the ventral capsule have to be taken in consideration. Tracing studies have shown that fibers from the orbitofrontal cortex project to the thalamus and to the hippocampus via the ventral ALIC (Schmahamann and Pandya, 2006). Consequently, stimulation of this region may antidromically activate the orbitofrontal cortex. Alternatively, stimulation may orthodromically augment the output to the ventral corticostriatal–pallido-thalamocortical loop originating at the prefrontal and orbital cortical areas. The orbitofrontal cortex is believed to be involved in the pathogenesis of major depression and obsessive compulsive disorder. Functional imaging studies have indicated

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changes in activity of the orbitofrontal cortex in individuals undergoing a paradigm of humor perception (Lee et al., 2007). In patients with severe depression, reaction to negative emotional stimuli has been shown to result in activation of the orbitofrontal cortex, which did not occur in normal individuals. Other imaging studies have also demonstrated the involvement of the orbitofrontal cortex in mood and smiling (Gosain et al., 2001). Flushing or facial warmth sensation was related to activation of CC0 and CC1 on either side (Table 2). These effects, as well as nausea, are suggestive of involvement of the autonomic nervous system. The hypothalamus is within a 3 mm radius of the left CC0 (Mai, 1998) and it is possible that direct current spread affected the lateral region of the hypothalamus, which is involved in cardiovascular regulation (Smith et al., 1990; Haibara et al., 1994; Pajolla and de Aguiar Correa, 2004). Alternatively, hypothalamic stimulation could have been mediated by direct dense projections from the nucleus accumbens to the lateral hypothalamic area (Kirouac and Ganguly, 1995). As discussed previously, stimulation at the level of the anterior commissure may have spread into the neighboring extended amygdala (bed nuclei) and, in turn, modulate autonomic hypothalamic centers. 4.1.3. Contact Cluster 2 Stimulation of the middle and dorsal areas of the ALIC has been reported since the earlier days of stereotactic surgery for psychiatric disorders. A classic paper by Laitinen in 1979 reports on the intraoperative effects of acute stimulation performed prior to thermocoagulation of a number of stereotactic targets, including the anterior limb of the internal capsule, for a heterogeneous group of diagnosis ranging from neurosis to schizophrenia (Laitinen, 1979). Acute responses from the ALIC were not common. In fact, 68% of patients reported no effects. The majority of the responses were obtained from the dorsal areas of the ALIC, where the permanent lesion was planned. In that location, only some of the patients reported ‘‘positive” responses to stimulation, defined as a ‘‘feeling of well being and relaxation”. Our observation of inconsistent and relatively uncommon responses from stimulation of the middle and dorsal areas of the ALIC are in agreement with Laitinen’s pioneering report. Dizziness was occasionally reported with stimulation of CC1 and CC2 and was considered by the investigators as a vague response, hard to attribute to a specific circuitry. 4.2. Intraoperative stimulation vs. postoperative programming The combined concordance between intraoperative stimulation and postoperative programming results was 89% (Table 4). Interestingly, discrepancy was more common on the left side than on the right side. The high overall concordance corroborates the stability of the DBS electrode after fixation to the skull. Large shifts in localization could have caused the effects to diverge more. The reproducibility of effects also supports the investigators belief that these were not placebo effects. Although the investigators tended to use cathodes that caused acute mood increments for chronic stimulation, it is still unclear whether the acute changes in mood are indeed correlated to the chronic benefits observed in alleviation of depression and improvements in quality of life. Of note, acute mood enhancements were consistently observed during intraoperative testing and programming sessions. However, not not all patients responded to the chronic therapy (Malone et al., 2009). 5. Conclusion The majority of the acute behavioral responses elicited by stimulation with the long quadripolar leads used in this study were

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associated with activation of the ventral electrode contacts – CC0 and CC1. These clusters are located in areas densely populated by different nuclei and white matter bundles, including the nucleus accumbens, ventral pallidal complex, extended amygdala, anterior commissure, fornix and ventral ALIC. Mood modulation, laughter, flushing or other effects suggestive of autonomic involvement may not result from isolated effects upon one of these structures. Instead, it is possible that some behavioral responses resulted from a composite effect. This may be particularly true given the remarkable increments in mood observed in most patients with CC0 and CC1 stimulation. The large magnitude of the effect may potentially be supraphysiological in nature, resulting from combined activation of multiple pathways associated with the orbitofrontal cortex and ventral striatopallidal circuit. Deep brain stimulation of the VC/VS is a promising therapy for patients with otherwise intractable and disabling depression. Acute stimulation is performed intraoperative and postoperatively for the purpose of electrode location verification and programming optimization. The data obtained during these clinically oriented trials are valuable opportunities for assessing the functional anatomy, topography and physiology of this region of the brain and related circuits. This line of investigation is not purely exploratory in nature as it may contribute to advances in surgical targeting of this region for the management of intractable affective disorders. References Abelson JL, Curtis GC, Sagher O, Albucher RC, Harrigan M, Taylor SF, et al. Deep brain stimulation for refractory obsessive–compulsive disorder. Biol Psychiatry 2005;57(5):510–6. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990;13(7):266–71. Aouizerate B, Cuny E, Martin-Guehl C, Guehl D, Amieva H, Benazzouz A, et al. Deep brain stimulation of the ventral caudate nucleus in the treatment of obsessive– compulsive disorder and major depression. Case report. J Neurosurg 2004;101(4):682–6. Ballantine Jr HT, Cassidy WL, Flanagan NB, Marino Jr R. Stereotaxic anterior cingulotomy for neuropsychiatric illness and intractable pain. J Neurosurg 1967;26(5):488–95. Ballantine Jr HT, Bouckoms AJ, Thomas EK, Giriunas IE. Treatment of psychiatric illness by stereotactic cingulotomy. Biol Psychiatry 1987;22(7):807–19. Bejjani BP, Damier P, Arnulf I, Thivard L, Bonnet AM, Dormont D, et al. Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med 1999;340(19):1476–80. Bridges PK, Bartlett JR, Hale AS, Poynton AM, Malizia AL, Hodgkiss AD. Psychosurgery: stereotactic subcaudate tractomy. An indispensable treatment. Br J Psychiatry 1994;165(5):599–611 [discussion 612–3]. Cosgrove GR, Rauch SL. Stereotactic cingulotomy. Neurosurg Clin N Am 2003;14(2):225–35. Croxson PL, Johansen-Berg H, Behrens TE, Robson MD, Pinsk MA, Gross CG, et al. Quantitative investigation of connections of the prefrontal cortex in the human and macaque using probabilistic diffusion tractography. J Neurosci 2005;25(39):8854–66. de Olmos JS, Heimer L. The concepts of the ventral striatopallidal system and extended amygdala. Ann NY Acad Sci 1999;877:1–32. Demeter S, Rosene DL, Van Hoesen GW. Fields of origin and pathways of the interhemispheric commissures in the temporal lobe of macaques. J Comp Neurol 1990;302(1):29–53. Dougherty DD, Baer L, Cosgrove GR, Cassem EH, Price BH, Nierenberg AA, et al. Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive–compulsive disorder. Am J Psychiatry 2002;159(2):269–75. Dujardin K, Defebvre L, Krystkowiak P, Blond S, Destee A. Influence of chronic bilateral stimulation of the subthalamic nucleus on cognitive function in Parkinson’s disease. J Neurol 2001;248(7):603–11. Fodstad H, Strandman E, Karlsson B, West KA. Treatment of chronic obsessive compulsive states with stereotactic anterior capsulotomy or cingulotomy. Acta Neurochir (Wien) 1982;62(1–2):1–23. Francel P, Ryder K, Wetmore J, Stevens A, Bharucha K, Beatty WW, et al. Deep brain stimulation for Parkinson’s disease: association between stimulation parameters and cognitive performance. Stereotact Funct Neurosurg 2004;82(4):191–3. Gabriels L, Cosyns P, Nuttin B, Demeulemeester H, Gybels J. Deep brain stimulation for treatment-refractory obsessive–compulsive disorder: psychopathological and neuropsychological outcome in three cases. Acta Psychiatr Scand 2003;107(4):275–82. Goktepe EO, Young LB, Bridges PK. A further review of the results of stereotactic subcaudate tractotomy. Br J Psychiatry 1975;126:270–80.

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