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Rostral cingulate gyrus: A putative target for deep brain stimulation in treatment-refractory depression
Medical Hypotheses (2006) 66, 491–494
http://intl.elsevierhealth.com/journals/mehy
Rostral cingulate gyrus: A putative target for deep brain stimulation in treatment-refractory depression Damianos E. Sakas *, Ioannis G. Panourias Unit of Functional Neurosurgery, Department of Neurosurgery, University of Athens Medical School, Evangelismos Hospital, 4, Marasli Street, 10676 Athens, Greece Received 8 July 2005; accepted 13 July 2005
Summary Surgery for intractable affective illnesses has generated considerable controversy over the last century. Deep brain stimulation (DBS) has revolutionized neurosurgical practice, especially in the field of advanced Parkinson’s disease and, more recently, in selected medical-refractory cases of obsessive–compulsive disorder. In this paper, we propose a discrete area of the rostral cingulate gyrus as a potential target for DBS in medical-resistant depressive patients. Brodmann’s area 24a has proved to be a vital link in the integration of neural circuits underlying depression, both through proposed neurobiological models and accurate neuroimaging studies. The full reversibility and adjustability of DBS offer the best chance to treat the multidimensional and life-span profile of depression, so giving hope to a great number of desperate human beings. c 2005 Elsevier Ltd. All rights reserved.
Introduction Depression is a common and heterogeneous psychiatric disorder affecting approximately 1.5% of the general population at any one time. Approximately 40–50% of patients with major depression experience recurrent episodes of disease, while conservative estimates of failure to respond to optimal antidepressant medication treatment are about 20% [1,2]. It is clear the impact of depressive illness represents significant personal, ethical, mari-
* Corresponding author. Tel.: +30 210 7201405; fax: +30 210 7249986. E-mail address: [email protected] (D.E. Sakas).
tal, professional, and social burdens, occasionally resulting in some sufferers’ suicide. Over the last fifty years, neurosurgical treatments involving either brain stimulation techniques (electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation) or ablative procedures (cingulotomy, capsulotomy, limbic leucotomy, subcaudate tractotomy) have been applied for the alleviation of treatmentrefractory affective disorders. Modern stereotactic procedures guided by elaborate imaging studies carry significantly lower intra- and postoperative risks; however, considerable issues still arise when ablative interventions are selected as therapeutic options because of the irreversible brain tissue lesion.
0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.07.036
492 The advent of deep brain stimulation (DBS) that is the direct stimulation of deep brain structures has revolutionized the practice of neurosurgery over the last ten years. Currently, the methodology is well established for the alleviation of the symptoms of Parkinson’s disease. It has investigationally been applied in epilepsy, pain, dystonia, and persistent vegetative state [3]. The reversibility and adjustability of DBS has allowed neurosurgeons to explore different targets known to be implicated in the pathophysiology of affective diseases as well. So far, the implantation of electrodes in the anterior limbs of the internal capsules or the right nucleus accumbens has provided promising results in the treatment of medically-resistant obsessive–compulsive disorder (OCD) [4,5]. In this paper, the authors suggest the rostral cingulate gyrus (Brodmann’s area 24a) as a potential target for deep brain stimulation in treatmentrefractory depression. For this hypothesis, the reports that largely clarify the particular functional and metabolic characteristics of the rostral cingulate gyrus have been taken into consideration. Additionally, the neurobiological models of the disease that have given a principal role to the above region in the integration of neurocircuits between cortical, subcortical, limbic, hypothalamic and brainstem areas of the brain, have provided a solid base for the construction of this hypothesis.
Theoretical background of hypothesis Over the last ten years, the neurobiological substrate of depression has been substantiated into a proposed model of ‘limbic-cortical dysregulation’ [6–9]. Three main parts or compartments compose the neural circuit that is involved in mood regulation: the dorsal compartment, the ventral compartment and the rostral cingulate compartment. The dorsal compartment is composed by neocortical and midline limbic elements (dorsolateral prefrontal cortex [dfr 9/46], dorsal anterior cingulate [dcg 24b], inferior parietal cortex [inf Par 40], and striatum) and is involved with the attentional and cognitive aspects of depression, such as apathy, psychomotor slowing, impaired selective and directed attention and executive function [10]. The ventral compartment is composed of paralimbic cortical, subcortical hypothalamus, insula, and subgenual cingulate [Cg 25] and brainstem regions and it is postulated to mediate the vegetative and somatic dysregulations of depression in sleep, appetite, libido, and endocrine function [11,12]. The rostral cingulate compartment differs in its cytoarchitectural characteristics and thus it is distinguished from both
Sakas and Panourias the ventral and dorsal compartments [13,14]. These anatomical and clinical distinctions suggest that the rostral anterior cingulate (in particular, BA 24a) may serve an important regulatory role in the overall network by facilitating the interaction between the dorsal and ventral compartments. Dysfunction of this area thus could have significant impact on remote brain regions regulating a variety of behaviors, including the interaction among mood, cognitive, somatic, and autonomic responses. Modern neuroimaging methods (singe photon emission computed tomography, positron emission tomography) have largely clarified the particular functional, pathophysiological, and neurochemical activities underlying the heterogeneous clinical profile of depression. Recent data advocates that brain abnormalities in depression are mostly regional, as global measures (cerebral, white and gray matter and ventricular volumes) have not been affected in the majority of patients [15]. The rostral cingulate cortex (Brodmann’s area 24a), in particular, showed increased glucose metabolic activity before treatment, in patients who eventually responded to medication in comparison with both nonresponders and nonpsychiatric control subjects [6,16]. Additionally, the metabolic activity in the above region predicted by baseline levels the magnitude of treatment response [7]. Given that in persons in full remission increased activity in this area persisted, its central role in normalization of cortical and limbic dysfunction that accompanies recovery from depression has been clearly demonstrated. The synchronized modulation of the aforementioned dysfunctional cortical-limbic pathways has already been considered as critical for the remission of the disease, regardless of the treatment modality applied (pharmacotherapy, electroconvulsive therapy or cognitive therapy) [8]. Although the exact mode of action of DBS remains practically unknown [17], remarkable improvement in mood and symptoms of anxiety and depression in patients who undergo subthalamic nucleus (STN) DBS has already been reported [18]; furthermore, intractable cases of OCD have experienced favorable response to DBS in selected brain targets [4,5]. Consequently, the bilateral implantation of deep brain electrodes in Brodmann’s area 24a might modulate appropriately the dysfunctional cortical-limbic pathways as well. The remarkable adjustability of stimulation parameters (in terms of frequency, pulse width, and duration of stimulation) in combination with unipolar or bipolar function of one or more electrode channels provide better chances to optimize the therapeutic results of the DBS intervention. Currently, stereotactic cingulotomy is performed by experienced neurosurgical units with
Rostral cingulate gyrus safety and sufficient efficacy in selected cases of OCD, or, occasionally, intractable depression [19]. Bilateral thermocoagulative lesions in the anterior cingulate gyruses interrupt cingulum bundles, directly affecting the cortico–striato–thalamocortical loops. Given that DBS modulates neuronal activity of the targeted brain regions mimicking the effect of a lesion [17], the bilateral placement of electrodes in BAs 24a might simulate the effect of a ‘cingulotomy’ procedure, interrupting, however, the cingulum bundle at a more rostral site. Based on the recent experience with DBS for movement disorders, the incidence of adverse effects ranges from <1–3% [3,17]. More importantly, the stimulation parameters can be programmed, so enhancing the treatment options over the clinical course of the disease and minimizing adverse effects. In respect of the multidimensional clinical profile and the diversity of the prevailing symptoms of the depression over its often life-span course, DBS seems to offer the best chances to alleviate the presenting affective symptoms at any time.
Testing of hypothesis The Brodmann’s area 24a can be recognized precisely both by advanced magnetic resonance imaging and neurofunctional studies. The existing experience with targeting the cingulum bundle during stereotactic cingulotomy offers confidence to safely localize the aforementioned region as well. Notably, a detailed description of cingulotomy under microelectrode recording guidance and a system for standardized reporting of cingulated lesion location has already been described [19]. Standardization of this methodology and correlation of each individual patient’s imaging with the callosal reference system is highly likely to allow precise localization of the BA 24a in an accurate and reproducible manner. Theoretically, DBS is a fully reversible methodology. Stimulation itself can be modified or discontinued in the event of side effects, rendering the procedure particular safe and testable. Importantly, the stimulation can be turned ‘on’ or ‘off’ without patient’s awareness, so providing a unique opportunity for double blinding studies. All these parameters should be taken into account when a new surgical treatment is suggested, particularly in the field of depression where the underlying pathogenetic substrate has not been clarified. From that point of view, our hypothesis on the potential role of DBS of BA 24a in the treatment of medicalrefractory depression satisfies, to the authors’
493 opinion, the criteria of an ethical, testable, reversible and potentially effective procedure.
Considerations The special concern over the use of neurosurgery for the treatment of patients with psychiatric illnesses is attributable largely to the indiscriminate and widespread application of extensive, destructive procedures, particularly frontal lobotomy, in the mid-20th century. However, modern neuroimaging techniques, stereotactic targeting by digital technology, and the DBS methodology have already provided alternative efficient options for alleviation of medical-resistant symptoms of depressive illness. The ability of DBS, in particular, to modulate neural circuits subserving psychiatric phenomenon is well established; this challenges researchers to identify new putative targets in the complex cortico–striato–thalamocortical loops, modifying depression’s pathophysiological substrate. The catalytic role of Brodmann’s area 24a in the integration of limbic-cortical pathways affected in depression has both been suggested in approved neurobiological models of the disease and demonstrated by accurate functional neuroimaging studies. In the authors’ opinion, these data justify the proposal of the above region as a putative target for DBS in treatment-refractory depression. Given the past history of the field, however, it is particularly important that research moves forward on a solid scientific and ethical line; testing of any hypothesis should be accomplished in the moral, social and scientific frame that has already been approved [20]. If DBS of Brodmann’s area 24a proves to be an effective treatment for medical-refractory cases of depression, a great number of patients who experience extreme distress and feel unable to participate in social and occupational activities would have been given hope to continue their lives.
References [1] Judd LL. The clinical course of unipolar major depressive disorders. Arch Gen Psych 1997;54:989–91. [2] Malhi GS, Bartlett JR. Depression: A role for neurosurgery? Br J Neurosurg 2000;14:415–23. [3] Greenberg BD. Update on deep brain stimulation. J ECT 2002;18:193–196. [4] Nuttin B, Cosyns P, Demeulemeester H, et al. Electrical stimulation in anterior limbs of internal capsules in patients with obsessive–compulsive disorder. Lancet 1999;354: 1526. [5] Sturm V, Lenartz D, Koulousakis A, Treuer H, Herholz K, Klein JC, et al. The nucleus accumbens: a target for deep
494
[6]
[7]
[8]
[9]
[10]
[11] [12]
Sakas and Panourias brain stimulation in obsessive–compulsive- and anxietydisorders. J Chem Neuroanat 2003;26:293–9. Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci 1997;9:471–81. Pizzagalli D, Pascual-Marqui RD, Nitshke JB, et al. Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical topography analysis. Am J Psychiatry 2001;158:405–15. Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimized treatment. Br Med Bull 2003;65:193–207. Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 2004;22:409–18. Flint AJ, Black SE, Campbell-Taylor I, et al. Abnormal speech articulation, psychomotor retardation, and subcortical dysfunction in major depression. J Psychiatr Res 1993;27:285–7. MacLean PD. The triune brain in evolution: role in paleocerebral function. New York: Plenum Press; 1990. p. 247–68. Cowan PJ. Biological markers of depression. Psychol Med 1991;21:831–6.
[13] Vogt BA, Nimchinsky EA, Vogt LJ, et al. Human cingulate cortex: surface features, flat maps, and cytoarchitecture. J Comp Neurol 1995;359:490–506. [14] Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995;118:279–306. [15] Haldane M, Frangou S. New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings. Prog Neuropsychoph Biol Res 2004;28:943–60. [16] Mayberg HS, Brannan SK, Mahurin RK, et al. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 1997;8:1057–61. [17] Greenberg BD, Rezai AR. Mechanisms and the current state of deep brain stimulation in neuropsychiatry. CNS Spectr 2003;8:522–6. [18] Woods SP, Fields JA, Troster AI. Neuropsychological sequelae of subthalamic nucleus deep brain stimulation in Parkinson’s disease: a critical review. Neuropsychol Rev 2002;12:111–6. [19] Richter EO, Davis KD, Hamani C, Hatchison WD, Dostrovsky JO, Lozano AM. Cingulotomy for psychiatric disease: microelectrode guidance, a callosal reference system for documenting lesion location, and clinical results. Neurosurgery 2004;54:622–8. [20] Nuttin B, Gybels J, Cosyns P, et al. Deep brain stimulation for psychiatric disorders. Neurosurgery 2002;51:519.
http://intl.elsevierhealth.com/journals/mehy
Rostral cingulate gyrus: A putative target for deep brain stimulation in treatment-refractory depression Damianos E. Sakas *, Ioannis G. Panourias Unit of Functional Neurosurgery, Department of Neurosurgery, University of Athens Medical School, Evangelismos Hospital, 4, Marasli Street, 10676 Athens, Greece Received 8 July 2005; accepted 13 July 2005
Summary Surgery for intractable affective illnesses has generated considerable controversy over the last century. Deep brain stimulation (DBS) has revolutionized neurosurgical practice, especially in the field of advanced Parkinson’s disease and, more recently, in selected medical-refractory cases of obsessive–compulsive disorder. In this paper, we propose a discrete area of the rostral cingulate gyrus as a potential target for DBS in medical-resistant depressive patients. Brodmann’s area 24a has proved to be a vital link in the integration of neural circuits underlying depression, both through proposed neurobiological models and accurate neuroimaging studies. The full reversibility and adjustability of DBS offer the best chance to treat the multidimensional and life-span profile of depression, so giving hope to a great number of desperate human beings. c 2005 Elsevier Ltd. All rights reserved.
Introduction Depression is a common and heterogeneous psychiatric disorder affecting approximately 1.5% of the general population at any one time. Approximately 40–50% of patients with major depression experience recurrent episodes of disease, while conservative estimates of failure to respond to optimal antidepressant medication treatment are about 20% [1,2]. It is clear the impact of depressive illness represents significant personal, ethical, mari-
* Corresponding author. Tel.: +30 210 7201405; fax: +30 210 7249986. E-mail address: [email protected] (D.E. Sakas).
tal, professional, and social burdens, occasionally resulting in some sufferers’ suicide. Over the last fifty years, neurosurgical treatments involving either brain stimulation techniques (electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation) or ablative procedures (cingulotomy, capsulotomy, limbic leucotomy, subcaudate tractotomy) have been applied for the alleviation of treatmentrefractory affective disorders. Modern stereotactic procedures guided by elaborate imaging studies carry significantly lower intra- and postoperative risks; however, considerable issues still arise when ablative interventions are selected as therapeutic options because of the irreversible brain tissue lesion.
0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.07.036
492 The advent of deep brain stimulation (DBS) that is the direct stimulation of deep brain structures has revolutionized the practice of neurosurgery over the last ten years. Currently, the methodology is well established for the alleviation of the symptoms of Parkinson’s disease. It has investigationally been applied in epilepsy, pain, dystonia, and persistent vegetative state [3]. The reversibility and adjustability of DBS has allowed neurosurgeons to explore different targets known to be implicated in the pathophysiology of affective diseases as well. So far, the implantation of electrodes in the anterior limbs of the internal capsules or the right nucleus accumbens has provided promising results in the treatment of medically-resistant obsessive–compulsive disorder (OCD) [4,5]. In this paper, the authors suggest the rostral cingulate gyrus (Brodmann’s area 24a) as a potential target for deep brain stimulation in treatmentrefractory depression. For this hypothesis, the reports that largely clarify the particular functional and metabolic characteristics of the rostral cingulate gyrus have been taken into consideration. Additionally, the neurobiological models of the disease that have given a principal role to the above region in the integration of neurocircuits between cortical, subcortical, limbic, hypothalamic and brainstem areas of the brain, have provided a solid base for the construction of this hypothesis.
Theoretical background of hypothesis Over the last ten years, the neurobiological substrate of depression has been substantiated into a proposed model of ‘limbic-cortical dysregulation’ [6–9]. Three main parts or compartments compose the neural circuit that is involved in mood regulation: the dorsal compartment, the ventral compartment and the rostral cingulate compartment. The dorsal compartment is composed by neocortical and midline limbic elements (dorsolateral prefrontal cortex [dfr 9/46], dorsal anterior cingulate [dcg 24b], inferior parietal cortex [inf Par 40], and striatum) and is involved with the attentional and cognitive aspects of depression, such as apathy, psychomotor slowing, impaired selective and directed attention and executive function [10]. The ventral compartment is composed of paralimbic cortical, subcortical hypothalamus, insula, and subgenual cingulate [Cg 25] and brainstem regions and it is postulated to mediate the vegetative and somatic dysregulations of depression in sleep, appetite, libido, and endocrine function [11,12]. The rostral cingulate compartment differs in its cytoarchitectural characteristics and thus it is distinguished from both
Sakas and Panourias the ventral and dorsal compartments [13,14]. These anatomical and clinical distinctions suggest that the rostral anterior cingulate (in particular, BA 24a) may serve an important regulatory role in the overall network by facilitating the interaction between the dorsal and ventral compartments. Dysfunction of this area thus could have significant impact on remote brain regions regulating a variety of behaviors, including the interaction among mood, cognitive, somatic, and autonomic responses. Modern neuroimaging methods (singe photon emission computed tomography, positron emission tomography) have largely clarified the particular functional, pathophysiological, and neurochemical activities underlying the heterogeneous clinical profile of depression. Recent data advocates that brain abnormalities in depression are mostly regional, as global measures (cerebral, white and gray matter and ventricular volumes) have not been affected in the majority of patients [15]. The rostral cingulate cortex (Brodmann’s area 24a), in particular, showed increased glucose metabolic activity before treatment, in patients who eventually responded to medication in comparison with both nonresponders and nonpsychiatric control subjects [6,16]. Additionally, the metabolic activity in the above region predicted by baseline levels the magnitude of treatment response [7]. Given that in persons in full remission increased activity in this area persisted, its central role in normalization of cortical and limbic dysfunction that accompanies recovery from depression has been clearly demonstrated. The synchronized modulation of the aforementioned dysfunctional cortical-limbic pathways has already been considered as critical for the remission of the disease, regardless of the treatment modality applied (pharmacotherapy, electroconvulsive therapy or cognitive therapy) [8]. Although the exact mode of action of DBS remains practically unknown [17], remarkable improvement in mood and symptoms of anxiety and depression in patients who undergo subthalamic nucleus (STN) DBS has already been reported [18]; furthermore, intractable cases of OCD have experienced favorable response to DBS in selected brain targets [4,5]. Consequently, the bilateral implantation of deep brain electrodes in Brodmann’s area 24a might modulate appropriately the dysfunctional cortical-limbic pathways as well. The remarkable adjustability of stimulation parameters (in terms of frequency, pulse width, and duration of stimulation) in combination with unipolar or bipolar function of one or more electrode channels provide better chances to optimize the therapeutic results of the DBS intervention. Currently, stereotactic cingulotomy is performed by experienced neurosurgical units with
Rostral cingulate gyrus safety and sufficient efficacy in selected cases of OCD, or, occasionally, intractable depression [19]. Bilateral thermocoagulative lesions in the anterior cingulate gyruses interrupt cingulum bundles, directly affecting the cortico–striato–thalamocortical loops. Given that DBS modulates neuronal activity of the targeted brain regions mimicking the effect of a lesion [17], the bilateral placement of electrodes in BAs 24a might simulate the effect of a ‘cingulotomy’ procedure, interrupting, however, the cingulum bundle at a more rostral site. Based on the recent experience with DBS for movement disorders, the incidence of adverse effects ranges from <1–3% [3,17]. More importantly, the stimulation parameters can be programmed, so enhancing the treatment options over the clinical course of the disease and minimizing adverse effects. In respect of the multidimensional clinical profile and the diversity of the prevailing symptoms of the depression over its often life-span course, DBS seems to offer the best chances to alleviate the presenting affective symptoms at any time.
Testing of hypothesis The Brodmann’s area 24a can be recognized precisely both by advanced magnetic resonance imaging and neurofunctional studies. The existing experience with targeting the cingulum bundle during stereotactic cingulotomy offers confidence to safely localize the aforementioned region as well. Notably, a detailed description of cingulotomy under microelectrode recording guidance and a system for standardized reporting of cingulated lesion location has already been described [19]. Standardization of this methodology and correlation of each individual patient’s imaging with the callosal reference system is highly likely to allow precise localization of the BA 24a in an accurate and reproducible manner. Theoretically, DBS is a fully reversible methodology. Stimulation itself can be modified or discontinued in the event of side effects, rendering the procedure particular safe and testable. Importantly, the stimulation can be turned ‘on’ or ‘off’ without patient’s awareness, so providing a unique opportunity for double blinding studies. All these parameters should be taken into account when a new surgical treatment is suggested, particularly in the field of depression where the underlying pathogenetic substrate has not been clarified. From that point of view, our hypothesis on the potential role of DBS of BA 24a in the treatment of medicalrefractory depression satisfies, to the authors’
493 opinion, the criteria of an ethical, testable, reversible and potentially effective procedure.
Considerations The special concern over the use of neurosurgery for the treatment of patients with psychiatric illnesses is attributable largely to the indiscriminate and widespread application of extensive, destructive procedures, particularly frontal lobotomy, in the mid-20th century. However, modern neuroimaging techniques, stereotactic targeting by digital technology, and the DBS methodology have already provided alternative efficient options for alleviation of medical-resistant symptoms of depressive illness. The ability of DBS, in particular, to modulate neural circuits subserving psychiatric phenomenon is well established; this challenges researchers to identify new putative targets in the complex cortico–striato–thalamocortical loops, modifying depression’s pathophysiological substrate. The catalytic role of Brodmann’s area 24a in the integration of limbic-cortical pathways affected in depression has both been suggested in approved neurobiological models of the disease and demonstrated by accurate functional neuroimaging studies. In the authors’ opinion, these data justify the proposal of the above region as a putative target for DBS in treatment-refractory depression. Given the past history of the field, however, it is particularly important that research moves forward on a solid scientific and ethical line; testing of any hypothesis should be accomplished in the moral, social and scientific frame that has already been approved [20]. If DBS of Brodmann’s area 24a proves to be an effective treatment for medical-refractory cases of depression, a great number of patients who experience extreme distress and feel unable to participate in social and occupational activities would have been given hope to continue their lives.
References [1] Judd LL. The clinical course of unipolar major depressive disorders. Arch Gen Psych 1997;54:989–91. [2] Malhi GS, Bartlett JR. Depression: A role for neurosurgery? Br J Neurosurg 2000;14:415–23. [3] Greenberg BD. Update on deep brain stimulation. J ECT 2002;18:193–196. [4] Nuttin B, Cosyns P, Demeulemeester H, et al. Electrical stimulation in anterior limbs of internal capsules in patients with obsessive–compulsive disorder. Lancet 1999;354: 1526. [5] Sturm V, Lenartz D, Koulousakis A, Treuer H, Herholz K, Klein JC, et al. The nucleus accumbens: a target for deep
494
[6]
[7]
[8]
[9]
[10]
[11] [12]
Sakas and Panourias brain stimulation in obsessive–compulsive- and anxietydisorders. J Chem Neuroanat 2003;26:293–9. Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci 1997;9:471–81. Pizzagalli D, Pascual-Marqui RD, Nitshke JB, et al. Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical topography analysis. Am J Psychiatry 2001;158:405–15. Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimized treatment. Br Med Bull 2003;65:193–207. Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 2004;22:409–18. Flint AJ, Black SE, Campbell-Taylor I, et al. Abnormal speech articulation, psychomotor retardation, and subcortical dysfunction in major depression. J Psychiatr Res 1993;27:285–7. MacLean PD. The triune brain in evolution: role in paleocerebral function. New York: Plenum Press; 1990. p. 247–68. Cowan PJ. Biological markers of depression. Psychol Med 1991;21:831–6.
[13] Vogt BA, Nimchinsky EA, Vogt LJ, et al. Human cingulate cortex: surface features, flat maps, and cytoarchitecture. J Comp Neurol 1995;359:490–506. [14] Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995;118:279–306. [15] Haldane M, Frangou S. New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings. Prog Neuropsychoph Biol Res 2004;28:943–60. [16] Mayberg HS, Brannan SK, Mahurin RK, et al. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 1997;8:1057–61. [17] Greenberg BD, Rezai AR. Mechanisms and the current state of deep brain stimulation in neuropsychiatry. CNS Spectr 2003;8:522–6. [18] Woods SP, Fields JA, Troster AI. Neuropsychological sequelae of subthalamic nucleus deep brain stimulation in Parkinson’s disease: a critical review. Neuropsychol Rev 2002;12:111–6. [19] Richter EO, Davis KD, Hamani C, Hatchison WD, Dostrovsky JO, Lozano AM. Cingulotomy for psychiatric disease: microelectrode guidance, a callosal reference system for documenting lesion location, and clinical results. Neurosurgery 2004;54:622–8. [20] Nuttin B, Gybels J, Cosyns P, et al. Deep brain stimulation for psychiatric disorders. Neurosurgery 2002;51:519.