Overview of MDD

Major depressive disorder (MDD) is a common psychiatric complaint with a lifetime prevalence of 17% ( ), affecting some 5% of the world’s population at any given time ( ). It is characterized by one or more prolonged episodes of severe sadness and/or melancholia with a tendency to relapse over time ( ), and is associated with significant morbidity and mortality (including a 10%–15% suicide rate) which persists in periods of euthymia ( ). The resulting costs to both the patient and society, including direct medical costs, suicide-related costs, unemployment, absenteeism, and reduced performance at work, are staggering. According to a recent study, the incremental economic burden of MDD in the United States alone was greater than $80 billion in 2010; when comorbid conditions were included, this estimate surpassed $210 billion ( ). Moreover, MDD is the second-highest cause of years lived with disability worldwide, after low-back pain ( ). Thus timely, effective, and durable treatments for MDD are needed to defray these substantial human and monetary costs.

Diagnosis of MDD

MDD is a heterogeneous syndrome which is thought to be the common final pathway of multiple pathophysiological processes. Studies to date have failed to identify biomarkers which might reliably distinguish subtypes of MDD. Thus, its diagnosis remains phenomenological—determined by the presence of a particular clinical phenotype. According to the recently released fifth edition of the Diagnostics and Statistics Manual (DSM-V) ( ), the diagnosis of MDD is defined by one or more major depressive episodes, the criteria for which are the presence of five or more of nine specified symptoms over the same 2-week period: depressed mood, markedly diminished interest or pleasure, significant change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, and recurrent thoughts of death or suicidal ideation with or without a specific plan or suicide attempt; at least one of the symptoms must be either depressed mood or anhedonia. Moreover, these symptoms must represent a change from previous functioning, be present most of the time nearly every day, cause clinically significant distress or impairment in social, occupational, or other important areas of activity, and not be attributable to the physiological effects of a substance or another medical condition. Lastly, MDD can only be diagnosed in the lifetime absence of mania or hypomania, and provided depressive episodes cannot be better explained by the diagnosis of a schizophrenia spectrum or psychotic disorder.

Antidepressants and Psychotherapy

For the majority of patients with MDD, treatment consists of lifelong antidepressant pharmacotherapy and/or cognitive behavior therapy (CBT) ( ). Timing is critical, in that early intervention improves long-term outcomes while multiple untreated episodes may worsen the course of the illness such that it becomes resistant to treatment as the disease progresses ( ). Unfortunately, incomplete response to first-line measures occurs in up to one-third of patients and is predictive of poor response to additional treatments, including switching medications or augmentation with medications of the same or different class ( ). Underscoring this problem, a large multicenter clinical trial was conducted to determine whether response rates improved with a structured, stepwise approach to the treatment of MDD—the sequenced treatment alternatives to relieve depression (STAR∗D) trial ( ). Patients were initially treated with the selective serotonin reuptake inhibitor (SSRI) citalopram, and those who failed to achieve remission or were unable to tolerate this medication were offered a choice between switching to a different medication or adding on to their existing therapy (including the option of switching to or adding CBT) in three subsequent steps. Citalopram was sufficient for remission in only 28% of patients and the rates of remission diminished with each subsequent step, such that by the fourth trial of antidepressant pharmacotherapy remission was achieved in only an additional 6% of patients ( ). Similarly, patients requiring successive pharmacological or psychological interventions to achieve remission had a higher rate of relapse, while those who exited the study without having achieved remission were at the greatest risk of recidivism ( ).

Treatment-Resistant Depression

Treatment-resistant depression (TRD) is generally defined as failure to respond to at least two antidepressant treatments, as well as augmentation therapies and behavioral adjuncts, that have been administered at an effective dose for a sufficient duration ( ). As indicated above, this population appears to comprise at least two subsets of patients: those who truly fail to achieve remission of their depressive symptoms despite extensive trials, and others who relapse after achieving remission. Compared to MDD in general, TRD is associated with increased morbidity, mortality, and societal costs ( ). For these patients, electroconvulsive therapy (ECT) remains the most effective intervention currently available, with remission rates of 40% ( ). However, it is associated with cognitive side-effects including short-term memory impairment, and relapse is common ( ). As an alternative to ECT, repetitive transcranial magnetic stimulation (rTMS) is associated with minimal side-effects but has modest short-term antidepressant effects ( ), particularly in patients with demonstrated failure to respond to conventional antidepressant medications ( ). Finally, vagal nerve stimulation appears to be effective in a small but significant subset of patients with TRD ( ). However, for patients where all options have failed, a surgical intervention to target abnormal nuclei, tracts, or networks in the brain directly may be considered.

Ablative Surgery

The surgical management of depression is fraught with controversy. The first explicit attempt to treat mental illness surgically in the modern surgical era was made in 1888 by the psychiatrist Gottlieb Burkhardt, who performed cortical excisions in one patient with mania, one with dementia, and four with primary paranoid psychosis, or schizophrenia, with decidedly mixed results ( ). In John Fulton and Carlyle Jacobson presented their seminal findings following ablation of the frontal cortices in primates, demonstrating that the animals showed less “experimental neurosis” to task failures, although they were also less able to complete the tasks successfully. Based on this work, Egaz Moniz, working in collaboration with the surgeon Pedro Almeida Lima, introduced prefrontal leucotomy/lobotomy for the treatment of psychotic disorders in 1936 ( ). This procedure initially entailed injecting pure ethyl alcohol into the prefrontal cortex (PFC) through bifrontal burr-hole craniostomies to interrupt the connections between the thalamus and the PFC; subsequent procedures involved the use of a leucotomy for the same purpose. At a time when few alternatives existed for these severe mental illnesses, they described “worthwhile improvement” in 14 of 20 severely ill patients ( ). The frontal lobotomy was further refined by , and in an effort to make the surgery more accessible, Freeman went on to develop and popularize transorbital leucotomy for the treatment of a diverse array of psychiatric disturbances on an outpatient basis ( ). This procedure involved inserting an ice pick through the orbital roof into the basal frontal lobe, and sweeping it in a defined manner to sever the same thalamo–cortical and cortico–thalamic connections. Well over 50,000 such procedures were conducted worldwide in the decade following 1945 despite numerous side-effects, including epilepsy, personality changes, urinary incontinence, and a mortality rate of approximately 4% ( ). Reportedly, some measure of improvement was seen in 60% of patients with affective, psychotic, and other mental disorders, although these studies are limited by the absence of well-defined diagnostic groups. By the late 1950s overuse and unacceptably high long-term morbidity drove this procedure out of favor, and it was eventually abandoned with the advent of antipsychotic and antidepressant medications ( ).

Despite the notoriety of these interventions, interest in the surgical management of severe refractory mental illness persisted, with authors seeking to refine the extent of the disconnection to limit complications and side-effects. Stereotactic techniques were pioneered in the early 1900s ( ), and in 1949 William Scoville described a technique for sectioning the orbitofrontal cortex to a thickness of 1 cm from the base of the skull ( ). This disconnection was subsequently refined by Geoffrey Knight into the procedure known as subcaudate tractotomy, corresponding to bifrontal lesions located beneath and in front of the head of the caudate nucleus. Initially this procedure entailed the stereotactic insertion of radioactive yttrium rods into the brain ( ), and resulted in complete recovery or marked improvement in 68% of patients with severe depression ( ). Later, radiofrequency ablation was employed with comparable results ( ).

Another target for ablative surgery is the cingulate gyrus—either alone, or combined with subcaudate tractotomy in a procedure called limbic leucotomy. The cingulate gyrus is a key element of the limbic system, which was first described in by James Papez as being integral to emotional experience and expression. This suggested its importance in affective disorders, and thereafter Fulton proposed the anterior cingulate as a potential target for psychosurgical intervention ( ). Ablative surgeries soon followed, with Jacques Le Beau being the first to describe cingulotomy as a treatment of psychiatric disorders in 1949. This procedure constitutes the creation of a lesion in a region approximately 15–20 mm posterior to the anteriormost point of the frontal horns of the lateral ventricles ( ). Interestingly, using this technique Le Beau found no improvement in five depressive patients with anxiety and pain, but good results in three out of four patients with depression and obsessive neurosis ( ). Thomas Ballantine, who was the first to describe stereotactic anterior cingulotomy for psychiatric disorders, found that 62% of patients with severe affective disorders comprising unipolar ( n = 83) or bipolar ( n = 23) depression and schizoaffective disorder ( n = 14) had worthwhile improvement following this procedure ( ), with personality changes, epilepsy, weight gain, and urinary incontinence as potential side-effects ( ). A more recent study suggests that as many as 76% of carefully selected MDD patients may derive at least some benefit from anterior cingulotomy ( ). The most common target for these procedures is typically the dorsal anterior cingulate gyrus, corresponding to Brodmann’s area (BA) 24, and the adjacent fibers of the cingulum. Interestingly, better outcomes have been associated with smaller, more rostral lesions ( ). Subrostral cingulotomies, consisting of lesions to the cingulate gyrus ventral to the genu of the corpus callosum, have also been conducted over the years with variable outcomes in patients with depression ( ).

Deep Brain Stimulation

In comparison to ablative surgery, which is permanent and unforgiving, electrical stimulation of specific nuclei or tracts via stereotactically implanted electrodes is particularly attractive in that its effects are reversible and dose dependent—albeit with an ongoing risk of infection or hardware failure, and at greater expense. The implantation of intracranial electrodes in humans was first described by José Delgado et al. in ; he went on to place electrodes attached to a receiver located within the subcutaneous tissues of the scalp in patients with various psychotic disorders, including schizophrenia and epilepsy. In parallel, Robert Heath, a psychiatrist at Tulane University, initiated a series of controversial studies into the surgical control of behavior and emotion using chronic DBS ( ). In the modern era, DBS involves the implantation of an electrode with four contacts into the brain parenchyma and its connection via a subcutaneous extension wire to an implantable pulse generator positioned in the infraclavicular region. Biphasic electrical pulses are delivered at a preset amplitude (current or voltage), pulse width, and frequency to one or more contacts, which then induce an electrical field in a given volume of surrounding brain tissue, known as the volume of tissue activated (VTAct). The electrical parameters and the contact(s) can be adjusted to maximize benefits and minimize side-effects on an ongoing basis. The approved indications for DBS currently include Parkinson’s disease, dystonia, and obsessive–compulsive disorder. Its application in numerous other medical conditions, including MDD, is currently under investigation. A number of loci have been proposed as targets for DBS in MDD, including the subgenual (or subcallosal) cingulate (SCC), ventral capsule/ventral striatum/nucleus accumbens, medial forebrain bundle, inferior thalamic peduncle, lateral habenular nucleus, and rostral cingulate gyrus.

Rationale

A Network Model of MDD

Although the pathophysiology of MDD remains under investigation, it is increasingly understood as a disturbance of a functional network linking many brain regions ( ). Neuroimaging and postmortem studies of patients with MDD have identified structural and functional changes within a number of regions comprising the fronto-limbic system, including the cingulate cortex ( ), PFC ( ), amygdala ( ), hippocampus ( ), and nucleus accumbens ( ). Of note, various types of pharmacological, cognitive, and somatic antidepressant treatments appear to modulate the activity of these regions in modality-specific patterns ( ). For instance, normalization of frontal cortex activity ( ) and decreased activity in limbic and subcortical regions, including the subgenual cingulate, amygdala, hippocampus, posterior cingulate cortex, and insula ( ), are commonly seen with antidepressant pharmacotherapy. In contrast, while CBT normalizes activity in the PFC ( ), it also leads to different changes in other brain regions—including decreased metabolism in posterior cingulate, dorsomedial frontal, and orbital frontal cortices as well as increased metabolism in anterior midcingulate cortex and parahippocampal regions ( ).

Based on these findings, Mayberg et al. proposed a network model of MDD wherein neuroanatomical regions are clustered into four main functionally related groupings recapitulating the core symptoms of MDD (sustained mood, motor, cognitive, and circadian dysfunction), as well as the processes mediating normal responses to emotional stimuli ( Fig. 91.1 ) ( ). According to this model, mood state is a function of the reciprocal interactions between ventral limbic regions involved in interoceptive visceral-motor activity (drive states, autonomic function, and circadian rhythms) and dorsal cortical regions mediating exteroceptive cognitive activity (attention, appraisal, and action) ( ). Negative mood state is associated with increased limbic activity and decreased cortical activity, while reversal of this pattern characterizes mood improvement ( ); affective disturbances such as those seen in MDD are therefore presumed to derive from sustained loss of coordination between these regions. Active cognitive regulation of mood state is mediated by regions of the medial frontal cortex ( ), while subconscious processing of novel emotional stimuli, evaluation of salience, and conditioning to these stimuli are performed by subcortical regions including the amygdala, basal ganglia, and thalamus ( ). The various components of the cingulate cortex are distinguished as nodes connecting regions both within and between these compartments ( ).

(A) Anatomical locations of key brain regions implicated in MDD. Midline, sagittal view of the brain, with subsections of the anterior cingulate cortex highlighted by coloring. A-Hc , amygdala hippocampus; BS , brainstem; C. callosum , corpus callosum; dMF9 , dorso-medial frontal cortex BA9; MCC24 , midcingulate cortex BA24 (blue); OF11 , orbital frontal cortex BA11; pACC24 , pregenual anterior cingulate cortex BA24 (yellow); PCC23 , posterior cingulate cortex BA23; SCC24/25 , SCC BA24 and BA25 (red); vMF10 , ventro-medial frontal cortex BA10. (B) Circuit model of MDD. Regions with known anatomical interconnections that show consistent changes across converging imaging experiments form the basis of this model. Regions are grouped into four main compartments, reflecting general behavioral dimensions of MDD and regional targets of various antidepressant treatments. Regions within a compartment all have strong anatomical connections to one another. Black arrows identify cross-compartment anatomical connections. Solid colored arrows identify putative connections between compartments mediating a specific treatment: green indicates CBT; blue indicates pharmacotherapy; red indicates SCC DBS. a-ins , anterior insula; amg , amygdala; dm-Th , dorsomedial thalamus; dp-Hc , dorsal-posterior hippocampus; mb-vta , midbrain-ventral tegmental area; mF10/9 , medial frontal cortex BA10 and BA9; mOF11 , medial orbital frontal cortex BA11; Par40 , parietal cortex BA40; PF46/9 , prefrontal cortex BA46 and BA9; PM6 , premotor cortex BA6; va-HC , ventral-anterior hippocampus; vst-cd , ventral striatum-caudate.

From Mayberg, H.S., 2009. Targeted electrode-based modulation of neural circuits for depression. J. Clin. Invest. 119, 717–725.

The SCC as a Critical Region in the Regulation of Mood

The SCC is an area of white matter below the corpus callosum with widespread connectivity to cortical, limbic, striatal, thalamic, mesial temporal, hypothalamic, brainstem, and insular regions whose functioning is affected in depression, causing vegetative, somatic, cognitive, motor, and affective symptoms ( Fig. 91.2 ) ( ). Independent of the evidence supporting a role for cingulotomy in the surgical treatment of depression, the rationale behind SCC DBS for MDD derives from careful evaluation of functional imaging studies. Based on the network model of MDD, a series of experiments implicated the SCC as a critical node within the fronto-limbic network ( ). Specifically, Mayberg et al. demonstrated that cerebral blood flow is increased to the SCC (BA 25) and decreased to the dorsolateral PFC (BA 9/46) in healthy individuals who are induced into a negative mood state by thinking of prior sad events, exposure to sad or negative stimuli, or tryptophan depletion ( ). This same pattern of blood flow (hypofrontality with limbic hyperactivity) was observed in patients with active depression ( ). Critically, these changes are reversed with treatment of depression by diverse modalities, including antidepressants, CBT, sleep deprivation, ECT, rTMS, vagal nerve stimulation, and ablative surgery, leading to decreased blood flow and glucose metabolism within the SCC ( Fig. 91.3 ) ( ). This work strongly implicated the SCC in modulating negative mood state, and suggested this region as a potential target for efforts to regulate mood state.

(A) Afferent and (B) efferent connections of the SCC in nonhuman primates. Acb , nucleus accumbens; ACC , anterior cingulate cortex; amygdala: AB , accessory basal nucleus; Bl , basolateral nucleus; Co , cortical nucleus; I , intercalated nucleus; L , lateral nucleus; Me , medial nucleus; BA25 , Brodmann area 25; BST , bed nucleus of the stria terminalis; Cd , caudate nucleus; CnF , cuneiform nucleus; DB , diagonal band of Broca; EC , entorhinal cortex; hypothalamus: DH , dorsal hypothalamus; DMH , dorsomedial hypothalamus; LH , lateral hypothalamus; PH , posterior hypothalamus; Mpre , medial preoptic area; TM , tuberomammillary nucleus; VMH , ventromedial hypothalamus; Ia , agranular insular cortex; LC , locus coeruleus; LS , lateral septal nucleus; OFC , orbitofrontal cortex; PAG , periaqueductal gray; PB , parabrachial nucleus; PHC , parahippocampal cortex; PPN , pedunculopontine nucleus; SI , substantia innominata; TP , temporal pole; thalamus: AM , anteromedial nucleus; MD , mediodorsal nucleus; MDpc , parvicellular portion of the mediodorsal nucleus; PT , paratenial nucleus; Re , nucleus reuniens; CL , central lateral nucleus; lim , nucleus limitans; PF , parafascicular nucleus; PV , paraventricular nucleus; VTA , ventral tegmental area.

From Hamani, C., Mayberg, H.S., Stone, S.S., Laxton, A.W., Haber, S.N., Lozano, A.M., 2011. The subcallosal cingulate gyrus in the context of major depression. Biol. Psychiatry 69, 301–308.

Converging evidence implicating the SCC region in MDD. (A–E) Common pattern of changes in glucose metabolism or blood flow in the SCC with antidepressant response to various interventions. Images demonstrate group change patterns relative to the baseline depressed state for each treatment. (A) Metabolic decreases with the SSRI fluoxetine; (B) metabolic decreases with a placebo pill; (C) metabolic decreases with the serotonin-norepinephrine reuptake inhibitor venlafaxine; (D) blood flow decreases with ECT; (E) metabolic increases with CBT. (F–J) Images demonstrate elevated resting-state SCC25 activity in various groups of patients with TRD. (F) Metabolic increases in CBT and venlafaxine (V) nonresponders (NRs) relative to both healthy subjects and similarly depressed patients who responded to either treatment; (G) resting-state fMRI increases in pharmacotherapy (Med) nonresponders relative to healthy controls; (H) glucose metabolic increases in patients with TRD who later responded to cingulotomy (CGT) relative to those that failed to respond; (I) blood flow increases in patients with TRD enrolled in a DBS treatment trial relative to healthy controls; (J) SCC blood flow increases with induction of transient sadness induced by recollection of a personal sad memory in healthy subjects, a pattern similar to that seen in patients with TRD. Red indicates increased activity (white arrows) and blue indicates decreased activity (black arrows). Images are courtesy of Mitch Nobler (D), Michael Greicius (G), and Darin Dougherty (H). Panels A and J are generated from data published in American Journal of Psychiatry. Panels B and D are adapted with permission from American Journal of Psychiatry. Panel I is adapted with permission from Neuron. Panels C and E are adapted with permission from American Journal of Psychiatry. Panel F is generated from data published in American Journal of Psychiatry. Panel G is adapted with permission from Biological Psychiatry. Panel H is adapted with permission from Journal of Neurosurgery.

From Mayberg, H.S., 2009. Targeted electrode-based modulation of neural circuits for depression. J. Clin. Invest. 119, 717–725.

Feasibility Study of SCC DBS

Based on the evidence outlined above, proposed and conducted a feasibility study of SCC DBS in six patients with TRD. Individual contacts were successively interrogated intraoperatively with monopolar stimulation at 60 ms and 130 Hz, with voltage progressively increased by 1 V every 30 s to a maximum of 9 V, and a 15–20 s pause between adjustments in a modification of the protocol used for evaluating stimulation thresholds for efficacy and adverse effects in patients with Parkinson’s disease. Interestingly, all patients reported reproducible and reversible acute effects with stimulation, including “sudden calmness or lightness,” “disappearance of the void,” “increased connectedness,” and a sense of heightened awareness, and described sudden brightening of the room, intensification of colors, or otherwise more vivid perception. Concomitant changes in the rate and prosody of spontaneous speech and both positive and negative affect as assessed using the Positive and Negative Affect Schedule scale ( ) were also observed intraoperatively. With respect to outcome measures, response was defined as a decrease of 50% or greater in the Hamilton Depression Rating Scale (HAMD-17) score ( ), with remission corresponding to an absolute HAMD-17 score of 8 or less. At the study endpoint of 6 months, four of the six subjects (66%) had sustained response to chronic SCC DBS, with two of these (33%) achieving remission. Notably, the patients in this study demonstrated increased baseline blood flow to BA 25 and hypometabolism in BA 9/46, the premotor cortex (BA 6), and the dorsal ACC (BA 24); this pattern was reversed in long-term responders, similar to the previously observed changes with response to antidepressant and psychotherapeutic treatment. Of note, eventual responders were distinguished from nonresponders by an additional area of baseline hyperactivity in the medial frontal cortex (BA 10), which was also reversed with chronic SCC DBS.

Efficacy and Safety of SCC DBS

Based on the encouraging findings of the initial pilot study, the study was continued to 12 months postoperatively with open-label stimulation and an additional 14 patients were recruited. Of the total cohort of 20 patients, 11 (55%) responded to SCC DBS, of whom 7 (35%) achieved or were within one point of remission. To date the efficacy of subgenual cingulate gyrus DBS in TRD has been reported in six open-label studies, totaling at least 76 patients ( Table 91.1 ). Rates of response, defined as at least a 50% reduction in HAMD-17 from baseline, have varied from 29% to 62.5%, while rates of remission, defined as a HAMD-17 of less than 8, have varied from 35% to 50% ( ). For those who respond, chronic stimulation has been shown to provide continued benefit over time ( ). Data has been published for patients with up to 6 years of follow-up ( ). Improvements were seen in HAMD-17 subscales, including mood, anxiety, somatization, and insomnia ( ). In addition, patients who responded experienced improvements in quality of life, subjective improvements in depressive symptoms, were able to resume working in some cases ( ), and became more socially active ( ). Most patients continued with antidepressant pharmacotherapy and/or psychotherapy in addition to ongoing chronic SCC DBS ( ); thus stimulation does not replace other forms of treatment entirely. There are also reports of at least two patients who successfully received ECT following DBS implantation, after symptom recurrence ( ).

Based on the promising results from open-label studies of SCC DBS in TRD and its own multicenter Canadian pilot study ( ), a pivotal industry-sponsored multicenter blinded clinical trial (BROADEN) was initiated by St. Jude Medical Corp. (Plano, TX) as a step toward obtaining regulatory approval for this intervention. Unfortunately, this trial was halted early after a futility analysis ( ), and the results have not yet been published or publicized. The most commonly cited issues include patient selection and targeting. As indicated previously, the diagnosis of MDD is phenomenological and likely encompasses a collection of pathoetiologically distinct entities which may respond heterogeneously to interventions. However, recent work combining MR tractography and modeled volumes of activation have suggested that it is necessary for electrodes to stimulate specific white-matter tracts actively to achieve clinical benefit (see below) ( ). Combining this knowledge with studies of the acute intraoperative effects of stimulation in properly selected patients may ultimately improve our ability to target more effectively within the SCC ( ). Finally, a major critique of these reported trials is that they are small and for the most part open label in format, and therefore are inherently susceptible to bias. Despite these issues, however, it is highly unlikely that the effects of SCC DBS can be exclusively attributed to placebo and observer bias. The acute effects are reproducible in responders and specific to electrode location ( ). In the long term, discontinuation of stimulation in responders leads to recurrence of symptoms (either in the context of blinded discontinuation or when the pulse generator becomes depleted) ( ); in these patients, benefits are recaptured when stimulation is resumed ( ). While studies in TRD patients appear to suggest a lower rate for the placebo effect in this patient population ( ), one cannot eliminate the possibility of placebo effects in short-term trials. However, evidence of clear loss of antidepressant effects with depletion of batteries or device malfunctions in recovered patients receiving active DBS suggests the placebo effect is unlikely to explain the sustained long-term responses demonstrated in these studies ( ).

Safety of SCC DBS

Chronic SCC DBS has not been shown to impact cognitive functioning negatively in preoperative and postoperative neuropsychological testing ( ), and indeed has led to improved cognitive functioning in some patients ( ). Adverse events reported have consisted of infections, in many cases requiring hardware explantation (although this was reduced when pulse generator implantation was performed on the same day as electrode implantation, eliminating a period of externalized hardware in one series) ( ), isolated perioperative seizure ( ), worsened mood or irritability ( ), perioperative headaches ( ), pain at pulse generator or extension cable sites ( ), nausea and vomiting ( ), and extension cable malfunction requiring revision ( ). There are no reports of hypomania or mania induced by stimulation, including in patients with bipolar disorder who were treated in one series ( ). However, there have been reports of suicidality after SCC DBS implantation, although these did not appear to be directly related to stimulation and are not incompatible with the natural history of TRD ( ). Puigdemont et al. reported one suicide attempt in a patient 4 months into treatment who was classified as a nonresponder ( ). Kennedy et al. reported three responders who were hospitalized with recurrence and suicidality, and two patients died due to probable suicide ( ). Holtzheimer et al. reported two suicide attempts, one after 1 week and one after 1 year of stimulation; and Lozano et al. reported one suicide attempt and one suicide ( ). These incidents emphasize the need for continued close psychiatric monitoring and treatment even in those patients who respond to SCC DBS.

Patient Selection for SCC DBS

Patient selection has long been identified as a concern in studies of psychiatric illness. Owing to our imperfect understanding of the underlying anatomy, etiology, and pathophysiology of the disorders, classification has been similarly imperfect, resulting in an unavoidable degree of patient heterogeneity even in highly selected populations such as patients with TRD. This issue is especially important in investigational therapies, where patient selection, sample size, and consistency of the intervention are critical in determining the outcome of the study. In the first feasibility study of SCC DBS in patients with TRD, patients were carefully selected based on stringent inclusion criteria. All six patients in this study met DSM version IV text revised (DSM IV-TR) criteria for MDD, with a current major depressive episode of at least 1 year in duration diagnosed by structured clinical interview for DSM IV-TR (SCID-1) ( ). Additionally, all had severe depression, with a minimum score of 20 on the HAMD-17, and a Global Assessment of Function score no greater than 50. All patients were classified as treatment resistant based on documented failure to respond to at least four different antidepressant treatments, including medications administered at adequate doses for a sufficient time interval and evidence-based psychotherapy, with most having had prior ECT as well. Moreover, all patients were free of significant medical or psychiatric comorbidities, and had a low risk of imminent suicide. Inclusion criteria were similarly stringent in follow-on studies conducted at Emory University; in fact, documented failure or intolerance to ECT was required in later studies ( ).

To confirm that patients satisfy these criteria, it is essential that a psychiatrist is involved in patient assessment. This process will often entail a detailed review of medical records, including medication adjustment visits, psychotherapy sessions, discharge summaries, and ancillary medical tests ( ). Given the need for close follow-up postoperatively, prospective patients must also be assessed for reliability, compliance, therapy-interfering behaviors, and dysfunctional interpersonal relationships. Finally, there is the issue of Axis I and II comorbidities such as anxiety and personality disorders, whose symptomatology is reflected in currently extant rating scales for depression. In these patients, the specific efficacy of SCC DBS on the primary diagnosis of depression may be confounded by the persistence of such symptoms postoperatively, and the response rate in patients with these comorbidities is unknown. Moreover, this therapy routinely unmasks personality disorders in patients who do not have a clear diagnosis on their presurgical SCID interview ( ). For these reasons, while presence of personality disorders is not necessarily an absolute contraindication to DBS surgery for depression, at this stage of development SCC DBS is most safely tested in patients without these confounds. Similarly, it is clear in the published studies that clinically significant anxiety disorders have not been shown to respond to SCC DBS, mirroring what has been shown with cingulotomy. Thus patients with anxiety disorders independent of their depression should be actively excluded ( ). Given the complexity of these issues, psychiatrists with expertise in the assessment and management of refractory mood disorders are critical to the successful enrollment of patients in this investigational therapy, and due diligence in applying these criteria will often require extensive communication with past and present psychiatrists, primary caregivers, family, and friends. It should be noted that a thorough application of these criteria will invalidate many patients for implantation; in our center, over 1200 patients were screened for SCC DBS and only 17 were implanted—an implantation rate of roughly 1.5% ( ).

Even after the stringent application of enrollment criteria, however, a homogeneous patient population is not guaranteed. Through extensive experience spanning some 8+ years of SCC DBS, three factors have been identified as characterizing a DBS-responsive patient: a history of clear antidepressant response in early depressive episodes with evidence of interepisode functional recovery (job, family, activities); transformation from treatment-responsive to treatment-resistant depression; and lack of emotional reactivity at presentation ( ). Moreover, a number of targets for DBS in patients with MDD have been proposed, and recent clinical experience suggests that different targets may be effective in patients with different symptom clusters. Following SCC DBS, clusters of depressive symptoms appeared to improve at different rates, with normalization of insomnia occurring in the first week of stimulation, whereas improvement in concentration and apathy emerges later ( ). Thus SCC DBS may result in more rapid improvements in core mood as compared to neurovegetative symptoms of depression ( ), while DBS of the ventral capsule/ventral striatum/nucleus accumbens may be more effective in ameliorating anhedonia ( ). Should this be borne out in future studies, symptomatology may prove to be an additional criterion for specific DBS targets.

Neuroimaging has been proposed as an alternative or adjunct to symptomatology in stratifying patients by likely response to various therapies, including SCC DBS ( ). For instance, higher pretreatment metabolic activity in the right dorsoanterior insula—a region involved in monitoring for and orienting to potentially relevant internal and external stimuli including the processing of risk and reward ( )—predicted response to antidepressant therapy, while lower activity in this region was associated with response to CBT ( ). Similarly, high baseline SCC activity is predictive of poor response to traditional therapies for MDD ( ), but may also be predictive of response to interventions such as rTMS, DBS, or cingulotomy ( ). Furthermore, electroencephalography (EEG) may be informative in identifying patients likely to respond to SCC DBS. Twelve patients enrolled in a single-institution study of SCC DBS for TRD were assessed using resting-state quantitative EEG at baseline, 4 weeks following DBS, and after 24 weeks of chronic stimulation. Interestingly, lower theta-band concordance in the frontal electrodes at baseline predicted improvement in HAMD-17 scores at 24 weeks, while the degree of improvement in HAMD-17 scores was correlated with the degree to which frontal theta concordance increased after 4 weeks of stimulation ( ). However, other studies found the opposite to be true, in that decreased frontal theta concordance was correlated with better outcomes, albeit with antidepressant therapy in patients who were not treatment resistant ( ). In general, these studies suggest that noninvasive investigations may be useful in selecting patients for various treatment measures, and ongoing work aims to develop robust and reliable brain-based measurements to match TRD patients to the intervention that is most likely to get them well. Such investigations will no doubt prove useful in subclassifying patients with MDD and untangling the heterogeneity of this disease, but at present a careful clinical exam, a thorough review of comorbid conditions, evidence of a stable environment, and a period of previous response and functionality are the principal means to select candidates for SCC DBS.

Targeting the SCC

Basics of Diffusion-Weighted Imaging

It is increasingly clear that the treatment of psychiatric diseases (from major depression to obsessive–compulsive disorder and schizophrenia) must rely on network-level approaches and therapies that can engage multiple nodes of a connected network of brain regions. In the case of TRD, the most successful approach has been to target the white matter at the intersection of four critical limbic projections: the cingulum bundle, forceps minor, the uncinate fasciculus, and projections to the basal ganglia.

Anatomical understanding of white-matter pathways in human subjects relies on diffusion-weighted imaging (DWI). This imaging modality is used to quantify the molecular motion of water in the brain, which is constrained by neuron and myelin integrity ( ). A variety of measures can be generated from DWI data, though the most commonly utilized is fractional anisotropy (FA). Anisotropy refers to the degree to which diffusion is directionally constrained. The degree of anisotropy depends on the microstructural tissue components, such as the integrity of cell membranes and the organization of fiber tracts ( ). Typically, anisotropy is high in white matter because water tends to diffuse parallel to organized fiber bundles. FA measures form the basis for more elaborate postprocessing algorithms such as fiber tracking, which uses information about the diffusion properties of individual voxels to inform the likelihood of each voxel being connected to another adjacent voxel ( Fig. 91.4 ). This property can be examined by predefining a seed region and examining likely pathways of white-matter tracts emanating from that seed. By comparison with FA values (which give information about the degree of organization and integrity of white-matter structures), fiber tracking can give insights into the structural connectivity between a defined region of interest and other brain regions. Fiber-tracking models can be divided into deterministic and probabilistic categories. Deterministic models initiate fiber trajectories based on user-defined voxels and parameters, whereas probabilistic models incorporate some uncertainty into the tracking algorithm, encoding the diffusion direction of a given voxel as a probability density function, allowing greater resistance to artifacts such as noise, movement, and distortion in the diffusion data ( ).

Schematic demonstrating the fiber-tracking algorithm. Arrows represent primary eigenvectors in each voxel. Red lines are fiber trajectories.

From Mukherjee, P., Berman, J.I., Chung, S.W., Hess, C.P., Henry, R.G., 2008. Diffusion tensor MR imaging and fiber tractography: theoretic underpinnings. AJNR Am. J. Neuroradiol. 29, 632–641.

Fiber-tracking analyses based on DWI show strong convergence with histological tracer studies, though the latter remain the gold standard for defining precise connections among brain regions with high spatial accuracy ( ). Anatomical tracing studies and DWI performed in nonhuman primates have demonstrated a wide range of possible white-matter pathways to target via DBS for the treatment of depression ( ).

Development of DWI-Based Targeting Methods for SCC DBS

The earliest cohorts of SCC DBS patients received implantation guided solely by anatomical coordinates and landmarks. Despite the robust intraoperative effects of SCC DBS and encouraging treatment effects in these patients, significant between-subject variation in outcome was noted, prompting researchers to examine sources of anatomical variability in responders and nonresponders. Johansen-Berg et al. were the first to perform a fiber-tracking study ( ) showing that the patients in whom SCC DBS was effective had their electrodes placed in locations with strong connections with the orbitofrontal cortex, fornix, mesial temporal lobe in the vicinity of the amygdala, and anterior hippocampus. These findings laid the groundwork for a series of critical technical advances that enhanced the precision and predictive power of DWI-based DBS targeting. Next, we developed patient-specific tractography activation models to help identify pathways modulated by DBS ( Fig. 91.5 ) ( ). These models have four components: anatomical and diffusion-weighted neuroimaging data for the patient of interest, probabilistic tractography calculated from the brain region surrounding the electrode, finite element models of the electrical field generated by the patient-specific DBS parameter settings, and application of the simulated electric field to multicompartment cable models of axons with trajectories defined by tractography to predict action potential generation on specific pathways. This modeling demonstrated that minute differences in electrode location had the capacity to generate significant differences in the activated pathways.

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