Other neurosurgical interventions for treatment-resistant depression

Acknowledgments

Interventional Psychiatry Program in the Department of Psychiatry and Behavioral Science at the University of Minnesota.

Introduction

The use of somatic interventions to control or treat mental symptoms dates back to ancient times ( ; ; ). Evidence for burr holes drilled into the skull to “cure the demons” goes back to the Neolithic age. The notions that convulsions and fever may help mental disorders have been known since Hippocrates, while in medieval times, make-believe surgeries were performed to extract the “stone of madness.”

In the 17th century, Descartes hypothesized that the ventricles were the reservoir of vital fluids and basis for the rational mind. This deemphasized the brain’s role. Conversely, modern somatic treatments for mental illness are rooted in the conceptualization that neural tissue is responsible for behavior. This started in 1796, when Gall proposed that different brain regions were responsible for different functions, a system he called phrenology. Although this notion was revolutionary and would prove essential to our current understanding of brain function, he and his followers were later involved in pseudoscience and contributed little to the functional neuroanatomy of the mind ( ).

Almost a decade later, modern scientific conceptualization of brain functions and localizations began to emerge from animal experiments, cadaver dissections, and clinical observations conducted by , , and others. Also, the notion of neuronal transmission based on electrochemical signals replaced the 19th century hydraulic neuronal transmission model ( ). These ideas of regional brain functional localization and electrochemical neuronal transmission would later evolve into the contemporary neuronal network models that guide and inform much of the current applications of somatic treatments in disorders such as obsessive compulsive disorder and depression. As the biological underpinnings of the complexity of the mind are still being worked out, current somatic interventions are being used both for understanding the neurobiology of mental illness as well as for treating disease ( ).

Treatment-resistant depression (TRD) patients have long lasting depressive episodes, are prone to frequent relapses and have limited treatment options ( ). They are unable to effectively situate themselves in relation to others, to control negative emotions and divert attention from negative experiences to cope with daily life. They present us with major clinical and socioeconomic challenges with cost estimates exceeding $44 billion ( ). A better understanding of the functional neuroanatomy of mood regulation and socialization will lead to optimal and effective treatments. The success rate with pharmacological treatments for TRD is low ( ). Even after achieving relief from depressive symptoms, 35%–70% will relapse often precipitated by medication poor compliance or discontinuation of therapy. These patients become more vulnerable to stress ( ) and the course of their illness worsens leading to longer episode durations and shorter interepisodes periods in between. Brain stimulation therapies (BSTs) directly modulate brain function and regulate mood. Each presents with unique characteristics that define its role in the TRD therapeutic landscape. These various therapies have been discussed in more details in previous chapters (ADD number for chapters on ECT, MST, rTMS, tDCS, VNS, and DBS respectively). This chapter will discuss the current applications of other neurosurgical procedures not otherwise discussed, focusing on prefrontal cortical stimulation (PCS) and neurosurgery for psychiatric conditions.

PCS: The over simplification of the functional neuroanatomy of mood regulation may lead to missed opportunities in treatment development

Epidural cortical stimulation

Epidural cortical stimulation involves the placement of multicontact stimulating paddles over specific cortical regions and connected to a pacemaker-like generator. Chronic epidural cortical stimulation of the motor (EmCS) or sensory areas has been used over a decade to treat intractable pain syndromes, enhance recovery from stroke and for motor disorders like Parkinson’s disease ( ). EmCS induces its therapeutic effects at stimulation intensities below the threshold for overt motor responses. These results rule out the activation of large corticospinal cells, with possible candidates being nonpyramidal intracortical axons ( ). The prefrontal cortex similar to the motor cortex is a six-layered structure that contains cell bodies and axons that run tangentially or perpendicular to its surface. Axons are better than neurons as the targets of cortical stimulation because membrane properties allow fibers to be more excitable than cell bodies ( ). These axons could be short fibers of small inhibitory interneurons within the frontal cortex, as well as afferent or efferent fibers connected with distant cortical or subcortical structures ( ). Various cortical inhibitory neurons are good for local activation owing to their low threshold for electrical stimulation ( ). These cells exert strong inhibition on the underlying cellular network in the prefrontal cortex itself, locally modulating its output. Reciprocal connections between cortical and limbic regions could increase the responsiveness of neural circuits by generating a positive feedback loop. This echoes prefrontal TMS functional neuroimaging dosing studies, where local and distal effects in subcortical brain regions appear to be both intensity ( ; ; ) and frequency dependent ( ).

Epidural prefrontal cortical stimulation (EpCS): Mayberg proposed that illness remission occurs when there is appropriate modulation of dysfunctional limbic-cortical interactions, an effect facilitated by various forms of treatment ( ). Antidepressant drugs or DBS may initially regulate subcortical areas and later lead to a modulation of prefrontal regions (down-top model). The reverse may be observed with cognitive psychotherapy (top-down model), TMS, ECT, or EpCS. EpCS is an innovative new treatment through adaptive prefrontal governance of limbic structures. Two regions of the prefrontal cortex are prime candidates for cortical brain stimulation to treat depression through modulation of local and subcortical activity.

1.

The frontopolar region [Brodmann Area (BA) 10] has distinctly higher number of dendritic spines per cell and lower density of cell bodies than any other prefrontal region ( ). Its rich connections are directed to the cingulate cortex (including subgenual cortex or BA25 and precuneus/posterior cingulate), the orbitofrontal and the dorsolateral prefrontal cortex. It integrates higher level cognitive and emotional processing. It controls emotions, memory and motivation. It is also involved in self-reference, reflective self-awareness ( ) and in attributing mental states to others (“the theory of mind”) ( ). High activity of BA10 is associated with depression.
2.

The midlateral frontal regions [BA9 and 46] maintain preferential bidirectional connections with multimodal temporal areas on the one hand, and with paralimbic areas, such as the cingulate, the retrosplenial and the rostral temporal cortex, on the other hand ( ). They play a critical role in organizing, monitoring, verification of information, attending to emotion stimuli and in reappraisal. The dorsal regions are involved in the monitoring of information in working memory and the ventral regions are involved in active judgments on information held in posterior cortical association regions that are necessary for active retrieval and encoding of information. Depression is associated with gray matter thinning in nearby BA45.

The experience with EpCS for treatment of depression remains very limited. Aside from our work targeting bilateral prefrontal stimulation with four leads, an industry sponsored small trial with unilateral left DLPFC was also carried out. When we began the EpCS work, our primary objective was to pilot its potential safety and therapeutic benefits in TRD patients. We also set out to support our choices of stimulation sites (BA10 and 46) and better characterize their specific roles in mood regulation and socialization. We also were interested in exploring the bilateral hemispheres lead placements, the frequency and most critically, the intermittent on/off duty cycle. The bilateral four paddles EpCS approach we pioneered in 2008 showed significant improvements in depressive symptoms and a number of behavioral measures associated with in self-awareness, internal monitoring and regulatory executive functions. At 7-month follow-up, the average improvement from preimplant baseline on the Hamilton Rating Scale for Depression (HRSD ₂₄ ) ( ) was 54.9% (± 37.7). Three implanted subjects reached full remission and maintained their clinical status at 5 years follow up (this study will be discussed in more details below). Separately from our work, an industry-sponsored study (North Star) reported on the feasibility of unilateral left dorsolateral prefrontal EpCS ( ). Twelve MDD TRD patients were randomized to active or sham single blind for 8 weeks treatment with an adaptive open design follow up. No significant difference across conditions was noted after 2 months. Active left DLPFC EpCS proceeded to have a gradual improvement from 8 to 16 weeks with 21% ± 23 and 26% ± 29 changes from baseline. The results also showed that the placement of their single cortical lead paddle over left DLPFC was critical for their response rate. The more anterior the paddle was, the better the response. Interestingly, we had shown a similar relationship in a larger cohort of 59 patients enrolled in an RCT with noninvasive left DLPFC rTMS ( ).

As mentioned earlier, the bilateral medial and lateral EpCS we undertook was an open study and included five participants. All implants took place within a period of 9 months. The mean age was 44.2 (± 9.4). Four were women and three were diagnosed with recurrent Major Depressive Disorder whereas two others had Bipolar Affective Disorder I, depressed type. All were unemployed and three were receiving disability. The average length of depressive illness was 25.6 (± 8.3) years. The average length of the current depressive episode was 3 years, 7 months (± 38 months). It is noteworthy that participants had received an average of 9.8 (± 5.3) unsuccessful clinical treatments during the current MDE. Of these CNS-active compounds, an average of 6.2 (± 2.1) were classic antidepressant treatments of which 5.8 (± 2.05) met ATHF criteria for trial adequacy. Two had failed a trial of a monoamine oxidase inhibitor or buprenorphine augmentation, one failed intravenous ketamine infusion, a trial of clozapine and another trial of mifepristone for nonpsychotic depressive symptoms. Four of the patients received prior treatments with ECT, TMS, or VNS. They enrolled the study taking on average 6 (± 2.3) psychotropic drugs which were held constant. An expert psychiatrist, independent of the study team, evaluated all patients to insure they were well-informed of their clinical options. Consents were obtained in the presence of a patient advocate also independent of the study team. All subjects underwent comprehensive repeated assessments. A postoperative spiral CT scan confirmed accuracy of lead placements. We allowed 2–3 weeks for surgical recovery before initiating therapy.

(a)

EpCS intraoperative testing under controlled conditions: Once all four leads were stereotactically in place over bilateral anterior prefrontal pole (BA10) and midlateral prefrontal cortex (BA46), they were connected to external stimulators. Discontinuing the propofol infusion then lifted the moderate sedation. With the patient fully alert, we conducted a single-blind sham-controlled parametric testing of bilateral anterior or midlateral leads at 0, 2, and 4–5 V and 60 Hz. Order was randomized. Each train of stimulation lasted about 2–3 min and patients were instructed to record their subjective experience by responding to 13 questions in the form of a visual analog scale. Questions were presented on a laptop computer placed on the patient’s abdomen and were typically phrased “I feel SAD,” “I feel ANXIOUS,” “I feel SETTLED emotionally,” “I feel ATTENTIVE to my surroundings,” etc. ( Fig. 23.2 ). Active EpCS was associated with significant decreases compared to baseline in patients’ subjective sadness (mean change = 34.65%; P = .05) and anxiety levels (mean change = − 45.81%; P = .034) despite this small sample size. Active stimulation was also associated with over 100% improvement in self-ratings of “improved pleasure,” “sense of involvement,” and “attention,” but these effects were specifically pronounced in two subjects which led to a large standard deviation and were not statistically significant. None of the sham conditions led to significant changes from baseline. Two patients distinctly noted improved attention, increased brightness and alertness with lateral stimulation. They commented: “I feel attentive,” “feel better and I can talk now,” “I can think clearer.” A patient noted during anterior frontal pole stimulation as if a “weight is lifting off my shoulder,” “I feel calm,” and another stated “and although I am worried, I feel dissociated from it. I can think back at my worry.” Subject 2 failed to notice any positive changes across all tested parameters, became very discouraged and dysphoric. His testing was interrupted early. This TRD patient is now in full remission with chronic EpCS ( Fig. 23.1 ).

Fig. 23.1

Stereotactic identification of right Brodmann Area 46: BrainLab pointer guides the lead placement with visualization of cortical region of interest in 3D surface render mode (A), in transverse (B), sagittal (C), and coronal (D) views. Brodmann Area 46 is in Yellow and Brodmann Area 10 in Green .
(b)

Clinical outcomes: Patients did not improve clinically 2–3 weeks postoperatively with the EpCS leads turned off as often seen in DBS studies due to local inflammation around implanted electrodes in subcortical regions, but rather showed a 5% worsening of symptoms associated with postoperative recovery. However, once the leads were activated, patients showed a significant improvement over time ( df = 4, F = 4.867, P = .009). After 4 months of active stimulation the group showed a mean HDRS ₂₄improvement of 36% (± 39) which increased to 55% (± 38) at 7 months. Two patients achieved remission at 4 months and three out of five were remitted at 7 months. Mean scores of the MADRS at baseline, 4 and 7 months were 32 ± 7.6, 22 ± 6.6, and 14.6 ± 6.1 respectively. MADRS percent change from baseline significantly improved over time (ANOVA: df = 4, F = 3.886, P = .022). The IDS-SR scores at baseline, 4 and 7 months were 45.8 ± 16.2, 31.4 ± 25.3, and 19 ± 18.48. They also were significantly improved (ANOVA: df = 4, F = 4.419, P = .014). One patient reached remission after 2 weeks of stimulation based on IDS-SR ≤ 15 and remained well until her 7 month follow up. Two additional patients reached remission (HRSD < 10 for 2-week period); one at 4 months and the second at 7 months follow up. Last observation carried forward data at 5 years remains encouraging with three patients still in remission ( ).

Disrupted emotion regulation in depression and EpCS

Emotion regulation involves the ability to modulate the intensity and quality of responses to emotional stimuli, involving both automatic and controlled regulatory processes. It involves an executive control of the limbic structures by the prefrontal cortex. Disruptions of emotional control are associated with poor inhibitory feedback between medial and dorsal frontal cortex, and limbic subcortical and medial temporal structures ( ). They play a central role in mood and anxiety disorders. In fact, a feature of depression is the inability to disengage from negative memories, feelings and thoughts and engage the outside world with flexibility. Negative emotions can also distract away from other cognitive demands and make patients not able to cope with daily life needs ( ). The late positive potential (LPP) reflects an early electrocortical response to emotional stimuli that indexes sustained attention. It is sensitive to both relatively automatic ( ) and conscious emotion regulation strategies. To examine the influence of EpCS on emotional appraisal, we recorded the ERPs caused by viewing emotional taken from the International Affective Picture System (IAPS) during stimulation under single-blind cross-randomized across five conditions (bilateral 60 Hz BA10 or BA46 @ 2 or 4 V and no stimulation). In a series of studies ( Fig. 23.2 ), we demonstrated that the amplitude of the LPP is sensitive to changes in meaning and to emotion regulation instructions. Most importantly, we have also demonstrated that direct bilateral (and not bimedial) EpCS acts similarly to cognitive reappraisal and significantly reduces LPP ( ) making the lateral prefrontal cortex a good anatomical target for future EpCS studies.