Deep Brain Stimulation
Deep Brain Stimulation
As in PD, our understanding of the pathophysiology of obsessive-compulsive disorder (OCD) has evolved to include abnormal oscillatory activity through corticostriatal-thalamic loops. Cortical regions of the brain implicated in OCD include the orbitofrontal cortex, dorsolateral prefrontal cortex, ventromedial prefrontal cortex, and anterior cingulate cortex, while subcortical regions include the ventral striatum, mediodorsal thalamus, amygdala, and hippocampus. Overactivity of the orbitofrontal cortex correlates with anxiety levels and likely impacts behavioral planning and reward expectation. Decreased medial orbitofrontal cortex activity and increased lateral orbitofrontal cortex activity may underlie an increased fear response and impaired positive valence processing. The anterior cingulate cortex likely plays a role in conflict monitoring and error processing, and has increased activity in OCD. Increased caudate activity, along with decreased caudate neuronal density and abnormal dopamine management, may lead to abnormal behavioral inhibition and release, similarly to how basal ganglia abnormalities impact movement. Clinical symptoms in OCD also involve fear conditioning and the association of external stimuli with emotion, suggesting involvement of the hippocampus and amygdala. Both structures have been implicated in OCD, although not in all cases.
In the section on PD, hyperdirect pathways connecting the motor cortex with the STN play an important role in the ability of aberrant oscillatory propagation between cortex and basal ganglia structures. Thus, for a similar mechanism to be relevant for OCD, one would expect hyperdirect cortico-STN pathways to exist, connecting the cognitive and motivational cortical regions discussed above with the STN. Haynes and Haber recently illustrated the existence of a set of such prefrontal-STN hyperdirect connections in macaque monkeys. Interestingly, projections from functionally diverse regions of cortex were found to converge on overlapping regions of the STN. This work, along with others, also further helps to delineate the "associative-limbic" STN as the ventromedial STN, and includes the adjacent lateral hippocampus in the definition of the "limbic" STN.
With the increasing use of DBS for OCD, LFP and single-neuron recordings are now beginning to shed light on abnormal oscillatory activity in this circuit. Early single-unit recording data in the caudate nucleus suggested that abnormally high frequency and increasingly variable interspike intervals occur during obsessions. High-frequency burst firing, associated with motor loop dysfunction when occurring in the sensorimotor STN in patients with PD, has also been reported in the ventromedial STN of patients with OCD. Moreover, low-frequency band (1–8 Hz) oscillatory and burst activity in the ventromedial STN correlates with OCD symptom severity and clinical improvement after STN stimulation. A single-neuron recording study of ventromedial STN activity during a cognitive decision-making task in which some trials require repetitive checking showed that ventromedial STN neurons were more active during checking behavior. The authors concluded that in addition to playing a role in the integration of multiple streams of information, ventromedial STN neurons are also involved in repetitive doubt-related thinking. Task-based, single-cell recordings have also helped to clarify the role of neurons in the dorsal anterior cingulate cortex. These neurons were observed to encode current and recent cognitive load, playing an important role in determining how much cognitive control is required in the task at hand.
Most recently, optogenetics has been used to generate and suppress compulsive-like behaviors in a mouse model (Fig. 2). Multiple days of repeated hyperactivation of the orbitofrontal cortex neurons projecting to the ventromedial striatum was found to cause progressively increasing ventromedial striatum light-evoked firing in originally normal mice. Moreover, this increasing ventromedial striatum firing occurred in parallel with a temporally linked increase in grooming activity in the mice, an OCD-like phenotype. The effects became self-sustained without orbitofrontal cortex–ventromedial striatum hyperactivation and were reversible with fluoxetine (Fig. 2A). In a different experiment, this time in a genetic mouse model of OCD, behavioral response inhibition was associated with defective downregulation in striatal neuron projections. The authors were then able to improve behavior and correct abnormal microcircuit pathology with optogenetic stimulation of the lateral orbitofrontal cortex and its striatal terminals (Fig. 2B).
(Enlarge Image)
Figure 2.
Optogenetic stimulation of unique orbitofrontal cortex cell types creates and inhibits OCD phenotypes in mice. A: Illustration of the experiment of Ahmari and colleagues. In normal mice, repeated light stimulation of optogenetically modified orbitofrontal cortex (OFC) glutamatergic axons projecting onto the ventromedial striatum (VMS) leads to increased grooming behavior that persists after termination of light stimulation. B: Illustration of the experiment of Burguière and colleagues. In a genetic mouse model of OCD, increased activity of striatal medium spiny neurons (MSNs) was correlated with OCD-like behavior. Light stimulation of lateral orbitofrontal cortex axons that project onto fast-spiking striatal interneurons (FSIs) in the centromedial striatum led to increased FSI activity. Increased FSI activity led to increased inhibition of MSNs in the striatum, and OCD-like behavior was instantly eliminated.
Since 2009, DBS has been an accepted treatment for refractory OCD under an FDA Humanitarian Device Exemption. Current targets in practice and under investigation include the ventral capsule/ventral striatum, anterior limb of the internal capsule, STN, ventral caudate nucleus, nucleus accumbens, and inferior thalamic peduncle (reviewed by Mian et al., 2010). The Yale-Brown Obsessive-Compulsive Scale (YBOCS) score is commonly used to track patient outcomes in clinical trials. Data from lesional capsulotomy treatment for OCD served as initial motivation for using the ventral capsule/ventral striatum and anterior limb of the internal capsule as targets for DBS. A review of 4 centers performing anterior limb of the internal capsule and ventral capsule/ventral striatum DBS demonstrated clinical improvement (> 35% reduction in YBOCS score) in more than two-thirds of patients. Moreover, there was an improvement in results depending on location of the implantation, allowing the authors to conclude that the optimal location for ventral capsule/ventral striatum stimulation is at the junction of the anterior commissure, anterior capsule, and posterior ventral striatum. Recently, a study in 16 patients with OCD after at least 1 year of nucleus accumbens stimulation showed a 50% increase in symptoms after turning patients' stimulators off. They also used functional MRI, resting state functional MRI, and electroencephalography to suggest that nucleus accumbens DBS reinstates normal nucleus accumbens function and decreases the overactive frontostriatal network connectivity characteristic of OCD. A report of inferior thalamic peduncle stimulation in 6 patients with OCD showed a 51% mean decrease in YBOCS score after 12 months. While efficacy has been shown in numerous stimulation targets, randomized controlled clinical trials are still needed to prove efficacy and determine optimal targets.
DBS in OCD
Mechanistic Understanding
As in PD, our understanding of the pathophysiology of obsessive-compulsive disorder (OCD) has evolved to include abnormal oscillatory activity through corticostriatal-thalamic loops. Cortical regions of the brain implicated in OCD include the orbitofrontal cortex, dorsolateral prefrontal cortex, ventromedial prefrontal cortex, and anterior cingulate cortex, while subcortical regions include the ventral striatum, mediodorsal thalamus, amygdala, and hippocampus. Overactivity of the orbitofrontal cortex correlates with anxiety levels and likely impacts behavioral planning and reward expectation. Decreased medial orbitofrontal cortex activity and increased lateral orbitofrontal cortex activity may underlie an increased fear response and impaired positive valence processing. The anterior cingulate cortex likely plays a role in conflict monitoring and error processing, and has increased activity in OCD. Increased caudate activity, along with decreased caudate neuronal density and abnormal dopamine management, may lead to abnormal behavioral inhibition and release, similarly to how basal ganglia abnormalities impact movement. Clinical symptoms in OCD also involve fear conditioning and the association of external stimuli with emotion, suggesting involvement of the hippocampus and amygdala. Both structures have been implicated in OCD, although not in all cases.
In the section on PD, hyperdirect pathways connecting the motor cortex with the STN play an important role in the ability of aberrant oscillatory propagation between cortex and basal ganglia structures. Thus, for a similar mechanism to be relevant for OCD, one would expect hyperdirect cortico-STN pathways to exist, connecting the cognitive and motivational cortical regions discussed above with the STN. Haynes and Haber recently illustrated the existence of a set of such prefrontal-STN hyperdirect connections in macaque monkeys. Interestingly, projections from functionally diverse regions of cortex were found to converge on overlapping regions of the STN. This work, along with others, also further helps to delineate the "associative-limbic" STN as the ventromedial STN, and includes the adjacent lateral hippocampus in the definition of the "limbic" STN.
With the increasing use of DBS for OCD, LFP and single-neuron recordings are now beginning to shed light on abnormal oscillatory activity in this circuit. Early single-unit recording data in the caudate nucleus suggested that abnormally high frequency and increasingly variable interspike intervals occur during obsessions. High-frequency burst firing, associated with motor loop dysfunction when occurring in the sensorimotor STN in patients with PD, has also been reported in the ventromedial STN of patients with OCD. Moreover, low-frequency band (1–8 Hz) oscillatory and burst activity in the ventromedial STN correlates with OCD symptom severity and clinical improvement after STN stimulation. A single-neuron recording study of ventromedial STN activity during a cognitive decision-making task in which some trials require repetitive checking showed that ventromedial STN neurons were more active during checking behavior. The authors concluded that in addition to playing a role in the integration of multiple streams of information, ventromedial STN neurons are also involved in repetitive doubt-related thinking. Task-based, single-cell recordings have also helped to clarify the role of neurons in the dorsal anterior cingulate cortex. These neurons were observed to encode current and recent cognitive load, playing an important role in determining how much cognitive control is required in the task at hand.
Most recently, optogenetics has been used to generate and suppress compulsive-like behaviors in a mouse model (Fig. 2). Multiple days of repeated hyperactivation of the orbitofrontal cortex neurons projecting to the ventromedial striatum was found to cause progressively increasing ventromedial striatum light-evoked firing in originally normal mice. Moreover, this increasing ventromedial striatum firing occurred in parallel with a temporally linked increase in grooming activity in the mice, an OCD-like phenotype. The effects became self-sustained without orbitofrontal cortex–ventromedial striatum hyperactivation and were reversible with fluoxetine (Fig. 2A). In a different experiment, this time in a genetic mouse model of OCD, behavioral response inhibition was associated with defective downregulation in striatal neuron projections. The authors were then able to improve behavior and correct abnormal microcircuit pathology with optogenetic stimulation of the lateral orbitofrontal cortex and its striatal terminals (Fig. 2B).
(Enlarge Image)
Figure 2.
Optogenetic stimulation of unique orbitofrontal cortex cell types creates and inhibits OCD phenotypes in mice. A: Illustration of the experiment of Ahmari and colleagues. In normal mice, repeated light stimulation of optogenetically modified orbitofrontal cortex (OFC) glutamatergic axons projecting onto the ventromedial striatum (VMS) leads to increased grooming behavior that persists after termination of light stimulation. B: Illustration of the experiment of Burguière and colleagues. In a genetic mouse model of OCD, increased activity of striatal medium spiny neurons (MSNs) was correlated with OCD-like behavior. Light stimulation of lateral orbitofrontal cortex axons that project onto fast-spiking striatal interneurons (FSIs) in the centromedial striatum led to increased FSI activity. Increased FSI activity led to increased inhibition of MSNs in the striatum, and OCD-like behavior was instantly eliminated.
Current Practice
Since 2009, DBS has been an accepted treatment for refractory OCD under an FDA Humanitarian Device Exemption. Current targets in practice and under investigation include the ventral capsule/ventral striatum, anterior limb of the internal capsule, STN, ventral caudate nucleus, nucleus accumbens, and inferior thalamic peduncle (reviewed by Mian et al., 2010). The Yale-Brown Obsessive-Compulsive Scale (YBOCS) score is commonly used to track patient outcomes in clinical trials. Data from lesional capsulotomy treatment for OCD served as initial motivation for using the ventral capsule/ventral striatum and anterior limb of the internal capsule as targets for DBS. A review of 4 centers performing anterior limb of the internal capsule and ventral capsule/ventral striatum DBS demonstrated clinical improvement (> 35% reduction in YBOCS score) in more than two-thirds of patients. Moreover, there was an improvement in results depending on location of the implantation, allowing the authors to conclude that the optimal location for ventral capsule/ventral striatum stimulation is at the junction of the anterior commissure, anterior capsule, and posterior ventral striatum. Recently, a study in 16 patients with OCD after at least 1 year of nucleus accumbens stimulation showed a 50% increase in symptoms after turning patients' stimulators off. They also used functional MRI, resting state functional MRI, and electroencephalography to suggest that nucleus accumbens DBS reinstates normal nucleus accumbens function and decreases the overactive frontostriatal network connectivity characteristic of OCD. A report of inferior thalamic peduncle stimulation in 6 patients with OCD showed a 51% mean decrease in YBOCS score after 12 months. While efficacy has been shown in numerous stimulation targets, randomized controlled clinical trials are still needed to prove efficacy and determine optimal targets.
Source...