Rules Ventral Prefrontal Cortical Axons Use to Reach Their Targets: Implications for Diffusion Tensor Imaging Tractography and Deep Brain Stimulation for Psychiatric Illness

Lehman, Julia; Greenberg, Benjamin D.; McIntyre, Cameron C.; Rasmussen, S.; Haber, Suzanne N.

doi:10.1523/jneurosci.0595-11.2011

Cited by 169 publications

(196 citation statements)

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“…In terms of mechanisms data published to date suggest that a DBS-induced modulation of fiber pathways might play a role in the antidepressant-like effects of stimulation in humans (62). Preclinical studies are consistent with these findings but also show that a functional target inactivation might be important.…”

Section: Discussionmentioning

confidence: 56%

“…This has been shown to influence activity in brain regions at a distance from the stimulated target, leading to neurotransmitter release and inducing plastic changes in systems and substrates thought to be involved in the mechanisms of antidepressant treatments (56,57). In a recent study, the trajectory of white matter tracts running from prefrontal/orbitofrontal cortical regions to subcortical structures has been characterized in nonhuman primates with the use of tract tracing techniques (62). A functional organization of components from medial to lateral areas in the PFC and orbitofrontal cortex has been identified in tracts such as the uncinate fascicle and the internal capsule.…”

Section: Mechanisms Involved In the Effects Of Vmpfc Stimulation In Tmentioning

confidence: 99%

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Preclinical Studies Modeling Deep Brain Stimulation for Depression

Hamani¹,

Nóbrega²

2012

Biological Psychiatry

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Deep brain stimulation (DBS) is currently being investigated for the treatment of depression. Results of early clinical trials have been very promising, but the mechanisms responsible for the effects of DBS are still unknown. This article reviews behavioral findings of stimulation applied to different brain targets in rodents, with a particular focus on the ventromedial prefrontal cortex. Mechanisms and substrates involved in the antidepressant-like effects of DBS, including the role of local tissue inactivation, the modulation of fiber pathways in the vicinity of the electrodes, as well as the importance of the serotonergic system and brain derived neurotrophic factor are discussed. KeywordsAnimal models; deep brain stimulation; depression; fiber pathways; psychiatry; radiofrequency lesions; serotonin Deep brain stimulation (DBS) has been investigated for the treatment of depression with promising clinical results (1-11). Although preclinical research using electrical stimulation to study behavior has been conducted for over 50 years, results from animal studies did not comprise the rationale for the current use of DBS in depression. Experiments i n animal models to investigate substrates and mechanisms responsible for the antidepressant-like effects of DBS were only conducted after the initial clinical trials were published (2,7,8,(10)(11)(12).This article provides an overview of current findings and some of the emerging concepts from experiments with DBS in models of depression, with a particular focus on results obtained with ventromedial prefrontal cortex (vmPFC) stimulation in rodents. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscript Choosing a Stimulation TargetThe medial surface of the frontal cortex in rodents has been subdivided into four cytoarchitectural regions: the agranular frontal cortex, anterior cingulate cortex (AC), prelimbic cortex (PL), and infralimbic cortex(IL)( Figure 1A)(13-15).Alternatively, it has also been subdivided into dorsal and ventral "systems," according to functional role as well as afferent and efferent projections (15). The dorsal system includes the frontal agranular cortex, AC, and dorsal PL and seems to be involved in the control of eye and head movements (14-16). The ventral system, comprises the IL and ventral aspects of the PL (vPL), projects mainly to the amygdala, hypothalamus, insula, and brainstem and has been suggested to play a role in autonomic control (17)(18)(19)(20). Vertes (21) proposed an alternative subdivision of the medial prefrontal cortex (PFC) in dorsal (frontal agranular cortex and AC) and ventral regions (PL and IL). To mimic the effects of subgenual cingulum (SCG) DBS in rodents, we have been applying stimulation to the vmPFC (12,(22)(23)(24)(25)(26), including IL and vPL.Overall, the limits of the vPL are hard to delineate. However, if an arbitrary line is traced dividing the PL into dorsal and ventral halves, the approximate anteroposterior, mediolateral, and dorsoventral dimensions of the vmPFC (including IL and vPL...

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Section: Discussionmentioning

confidence: 56%

Section: Mechanisms Involved In the Effects Of Vmpfc Stimulation In Tmentioning

confidence: 99%

Preclinical Studies Modeling Deep Brain Stimulation for Depression

Hamani¹,

Nóbrega²

2012

Biological Psychiatry

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“…There is a high degree of homology of fear circuits in rodents and humans, especially in the prefrontal cortex and amygdala (13,(54)(55)(56)(57). Fibers from the ventromedial prefrontal cortex (a homolog of IL) and the dorsal anterior cingulate cortex (a homolog of PL) pass through the VS and ventral capsule on their way to the amygdala and thalamus (15). Clinical DBS of the VC/VS site shows a similar dorsalventral pattern to what we observed here: stimulation ventral to the most clinically effective site can induce panic and fear (58,59).…”

Section: Discussionmentioning

confidence: 99%

“…The DBS target for OCD is the VC/VS (14), which contains fiber bundles interconnecting cortical areas implicated in fear extinction, such as the ventromedial prefrontal cortex, the dorsal anterior cingulate cortex, and the orbitofrontal cortex (OFC), with subcortical areas implicated in conditioned fear, such as the amygdala (15). Previous studies in anesthetized rats (16,17) have shown that DBS of the VS modifies the excitability of the OFC as well as prelimbic (PL) and infralimbic (IL) prefrontal regions that modulate fear via projections to the amygdala (18).…”

Section: Eep Brain Stimulation (Dbs) Is a Neurosurgical Techniquementioning

confidence: 99%

Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear

Rodríguez-Romaguera

Monte

Quirk

2012

Proc. Natl. Acad. Sci. U.S.A.

122

128

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Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces symptoms of intractable obsessive-compulsive disorder (OCD), but the mechanism of action is unknown. OCD is characterized by avoidance behaviors that fail to extinguish, and DBS could act, in part, by facilitating extinction of fear. We investigated this possibility by using auditory fear conditioning in rats, for which the circuits of fear extinction are well characterized. We found that DBS of the VS (the VC/VS homolog in rats) during extinction training reduced fear expression and strengthened extinction memory. Facilitation of extinction was observed for a specific zone of dorsomedial VS, just above the anterior commissure; stimulation of more ventrolateral sites in VS impaired extinction. DBS effects could not be obtained with pharmacological inactivation of either dorsomedial VS or ventrolateral VS, suggesting an extrastriatal mechanism. Accordingly, DBS of dorsomedial VS (but not ventrolateral VS) increased expression of a plasticity marker in the prelimbic and infralimbic prefrontal cortices, the orbitofrontal cortex, the amygdala central nucleus (lateral division), and intercalated cells, areas known to learn and express extinction. Facilitation of fear extinction suggests that, in accord with clinical observations, DBS could augment the effectiveness of cognitive behavioral therapies for OCD.prefrontal cortex | anxiety disorders | posttraumatic stress disorder | phosphorylated extracellular signal-regulated kinase | accumbens D eep brain stimulation (DBS) is a neurosurgical technique that has become the standard of care for movement disorders (1-3) and is under investigation in major depression (4-6). In DBS, chronic high-frequency stimulation of specific sites reduces symptoms in medically intractable illness. DBS of the ventral capsule and the adjacent ventral striatum (VC/VS) has been used to treat refractory obsessive-compulsive disorder (OCD) in the European Union and the United States (7-10). Little is known about how DBS acts in OCD, emphasizing the need for translational animal studies. A prominent feature observed in most OCD patients is repetitive avoidance behaviors to perceived threats (11,12). The persistent avoidance in OCD suggests a deficit in circuits that regulate fear extinction (11). Given the strong parallels between fear circuits in rodents and humans (13), well-characterized rodent models of fear conditioning could shed light on DBS mechanisms in OCD and related illnesses that feature pathological anxiety.The DBS target for OCD is the VC/VS (14), which contains fiber bundles interconnecting cortical areas implicated in fear extinction, such as the ventromedial prefrontal cortex, the dorsal anterior cingulate cortex, and the orbitofrontal cortex (OFC), with subcortical areas implicated in conditioned fear, such as the amygdala (15). Previous studies in anesthetized rats (16,17) have shown that DBS of the VS modifies the excitability of the OFC as well as prelimbic (PL) and infralimbic (IL) prefron...

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“…Moreover, neurosurgical interventions (lesions or deep brain stimulation-DBS) within the ventral internal capsule (VC), ventral striatum (VS), or dACC (treatments for intractable OCD) all act on subcomponents of the vmPFC/OFC/dACC-basal ganglia network (Greenberg et al, 2010). Indeed, DBS interventions specifically affect vmPFC, OFC, and possibly dACC connections with striatum, thalamus, and/or brainstem (Figure 1) (Lehman et al, 2011). The efficacy of VC/VS DBS (or lesions) for OCD likely requires modulating the OFC/ vmPFC/dACC-basal ganglia circuit.…”

mentioning

confidence: 99%