Deep brain stimulation of the amygdala for treatment-resistant combat post-traumatic stress disorder: Long-term results.

Deep brain stimulation (DBS) holds promise for neuropsychiatric conditions where imbalance in network activity contributes to symptoms. Treatment-resistant Combat post-traumatic stress disorder (TR-PTSD) is a highly morbid condition and 50% of PTSD sufferers fail to recover despite psychotherapy or pharmacotherapy. Reminder-triggered symptoms may arise from inadequate top-down ventromedial prefrontal cortex (vmPFC) control of amygdala reactivity. Here, we report long-term data on two TR-PTSD participants from an investigation utilizing high-frequency amygdala DBS. The two combat veterans were implanted bilaterally with quadripolar electrodes targeting the basolateral amygdala. Following a randomized staggered onset, patients received stimulation with adjustments based on PTSD symptom severity for four years while psychiatric and neuropsychiatric symptoms, neuropsychological performance, and electroencephalography were systematically monitored. Evaluation of vmPFC-Amygdala network engagement was assessed with 18FDG positron emission tomography (PET). CAPS-IV scores varied over time, but improved 55% from 119 at baseline to 53 at 4-year study endpoint in participant 1; and 44%, from 68 to 38 in participant 2. Thereafter, during 5 and 1.5 years of subsequent clinical care respectively, long-term bilateral amygdala DBS was associated with additional, clinically significant symptomatic and functional improvement. There were no serious stimulation-related adverse psychiatric, neuropsychiatric, neuropsychological, neurological, or neurosurgical effects. In one subject, symptomatic improvement was associated with an intensity-dependent reduction in amygdala theta frequency power. In our two participants, FDG-PET findings were inconclusive regarding the hypothesized mechanism of suppression of amygdala hyperactivity. Our findings encourage further research to confirm and extend our preliminary observations.

A pilot study of closed-loop neuromodulation for treatment-resistant post-traumatic stress disorder.

The neurophysiological mechanisms in the human amygdala that underlie post-traumatic stress disorder (PTSD) remain poorly understood. In a first-of-its-kind pilot study, we recorded intracranial electroencephalographic data longitudinally (over one year) in two male individuals with amygdala electrodes implanted for the management of treatment-resistant PTSD (TR-PTSD) under clinical trial NCT04152993. To determine electrophysiological signatures related to emotionally aversive and clinically relevant states (trial primary endpoint), we characterized neural activity during unpleasant portions of three separate paradigms (negative emotional image viewing, listening to recordings of participant-specific trauma-related memories, and at-home-periods of symptom exacerbation). We found selective increases in amygdala theta (5-9 Hz) bandpower across all three negative experiences. Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms (trial secondary endpoint) following one year of treatment as well as reductions in aversive-related amygdala theta activity. Altogether, our findings provide early evidence that elevated amygdala theta activity across a range of negative-related behavioral states may be a promising target for future closed-loop neuromodulation therapies in PTSD.

Acute Effects and the Dreamy State Evoked by Deep Brain Electrical Stimulation of the Amygdala: Associations of the Amygdala in Human Dreaming, Consciousness, Emotions, and Creativity.

Accurate localization of complex human experiences such as emotions, dreaming, creativity, and consciousness to specific cerebral structures or neural networks has remained elusive despite technological advances. We report the use of acute deep brain stimulation (DBS) to evoke behavioral and emotional effects by applying electrical stimulation (ES) at various voltage strengths to the basolateral and central subnuclei of the amygdala in addition to the head of hippocampus (HC) for two subjects with medically refractory post-traumatic stress disorder (PTSD). Our results suggest that the amygdala could be a node in a neural network responsible for the generation of complex vivid mental imagery and integrated sensory experiences similar to John Hughlings Jackson's "dreamy state" and "double consciousness," which have been classically associated with temporal lobe epilepsy during uncinate seizures. That we were able to elicit similar vivid, dynamic, complex, bizarre, and original mental imagery with ES in non-epileptic subjects suggests that Jackson's seizure related "dreamy state" and "double consciousness" may arise from heightened innate brain mechanisms with the amygdala acting as a node in the neural network responsible for physiologic dreaming and creative functions. Furthermore, our subjects experienced different emotions with different stimulation strengths at various electrode contacts. Our results suggest that higher voltage stimulation of the amygdala and HC at 4-5 V leads to predominantly negative responses and 2-4 V stimulation showed inversely coupled positive and negative responses of the amygdala in either hemisphere which may imply hemispheric dominance of emotional valences without relation to handedness. Due to the unique and complex responses dependent on location and strength of stimulation, we advise that all patients receiving DBS of the amygdala undergo acute stimulation mapping in a monitored setting before selecting therapeutic parameters for chronic stimulation.

Case Series: Deep Brain Stimulation for Facial Pain.

BACKGROUND: Deep brain stimulation (DBS) has been used for chronic pain for decades, but its use is limited due to a lack of reliable data about its efficacy for specific indications. OBJECTIVE: To report on 9 patients who underwent DBS for facial pain, with a focus on differences in outcomes between distinct etiologies. METHODS: We retrospectively reviewed 9 patients with facial pain who were treated with DBS of the ventral posteromedial nucleus of the thalamus and periventricular gray. We report on characteristics including facial pain etiology, complications, changes in pain scores using the visual analog scale (VAS), and willingness to undergo DBS again. RESULTS: Nine patients underwent DBS for either poststroke, post-traumatic, postherpetic, or atypical facial pain. Eight patients (89%) were permanently implanted. Seven patients had sufficient follow-up (mean 40.3 mo). Of these 7 patients, average VAS scores decreased from 9.4 to 6.1 after DBS. The average decrease in VAS was 55% for post-traumatic facial pain (2 patients), 45% for poststroke (2 patients), 15% for postherpetic neuralgia (2 patients), and 0% for atypical facial pain (1 patient). Three of the 8 implanted patients (38%) had complications which required removal of hardware. Only 2 of 7 (29%) patients met classical criteria for responders (50% decrease in pain scores). However, among 4 patients who were asked about willingness to undergo DBS again, all expressed that they would repeat the procedure. CONCLUSION: There is a trend towards improvement in pain scores following DBS for facial pain, most prominently with post-traumatic pain.

Modulation of food intake following deep brain stimulation of the ventromedial hypothalamus in the vervet monkey. Laboratory investigation.

OBJECT: Deep brain stimulation (DBS) has become an effective therapy for an increasing number of brain disorders. Recently demonstrated DBS of the posterior hypothalamus as a safe treatment for chronic intractable cluster headaches has drawn attention to this target, which is involved in the regulation of diverse autonomic functions and feeding behavior through complex integrative mechanisms. In this study, the authors assessed the feasibility of ventromedial hypothalamus (VMH) DBS in freely moving vervet monkeys to modulate food intake as a model for the potential treatment of eating disorders. METHODS: Deep brain stimulation electrodes were bilaterally implanted into the VMH of 2 adult male vervet monkeys by using the stereotactic techniques utilized in DBS in humans. Stimulators were implanted subcutaneously on the upper back, allowing ready access to program stimulation parameters while the animal remained conscious and freely moving. In anesthetized animals, intraoperatively and 6-10 weeks postsurgery, VMH DBS parameters were selected according to minimal cardiovascular and autonomic nervous system responses. Thereafter, conscious animals were subjected to 2 cycles of VMH DBS for periods of 8 and 3 days, and food intake and behavior were monitored. Animals were then killed for histological verification of probe placement. RESULTS: During VMH DBS, total food consumption increased. The 3-month bilateral implant of electrodes and subsequent periods of high-frequency VMH stimulation did not result in significant adverse behavioral effects. CONCLUSIONS: This is the first study in which techniques of hypothalamic DBS in humans have been applied in freely moving nonhuman primates. Future studies can now be conducted to determine whether VMH DBS can change hypothalamic responsivity to endocrine signals associated with adiposity for long-term modulation of food intake.

Neuromodulation for Treatment-Refractory PTSD.

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor and is now reducing PTSD symptoms in the first patient enrolled in an early-phase safety trial.

VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms.

Currently available therapeutic interventions for treatment-resistant depression, including switch, combination, and augmentation strategies, are less than ideal. Observations of mood elevation during vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy suggested a role for VNS therapy in refractory major depression and prompted clinical investigation of this neurostimulation modality. The VNS Therapy System has been available for treatment of pharmacoresistant epilepsy since 1997 and was approved by the US Food and Drug Administration for treatment-resistant depression in July, 2005. The physiology of the vagus nerve, mechanics of the VNS Therapy System, and efficacy and safety in pharmacoresistant epilepsy are reviewed. Promising results of VNS therapy for treatment-resistant depression have been forthcoming from both acute and long-term studies, evidenced in part by progressive improvements in depression rating scale scores during the 1st year of treatment with maintenance of response thereafter. VNS therapy is well tolerated in patients with either pharmacoresistant epilepsy or treatment-resistant depression. As in epilepsy, the mechanisms of VNS therapy of treatment-resistant depression are incompletely understood. However, evidence from neuroimaging and other studies suggests that VNS therapy acts via innervation of the nucleus tractus solitarius, with secondary projections to limbic and cortical structures that are involved in mood regulation, including brainstem regions that contain serotonergic (raphe nucleus) and noradrenergic (locus ceruleus) perikarya that project to the forebrain. Mechanisms that mediate the beneficial effects of VNS therapy for treatment-resistant depression remain obscure. Suggestions for future research directions are described.

Deep Brain Stimulation of the Basolateral Amygdala: Targeting Technique and Electrodiagnostic Findings.

The amygdala plays a critical role in emotion regulation. It could prove to be an effective neuromodulation target in the treatment of psychiatric conditions characterized by failure of extinction. We aim to describe our targeting technique, and intra-operative and post-operative electrodiagnostic findings associated with the placement of deep brain stimulation (DBS) electrodes in the amygdala. We used a transfrontal approach to implant DBS electrodes in the basolateral nucleus of the amygdala (BLn) of a patient suffering from severe post-traumatic stress disorder. We used microelectrode recording (MER) and awake intra-operative neurostimulation to assist with the placement. Post-operatively, the patient underwent monthly surveillance electroencephalograms (EEG). MER predicted the trajectory of the electrode through the amygdala. The right BLn showed a higher spike frequency than the left BLn. Intra-operative neurostimulation of the BLn elicited pleasant memories. The monthly EEG showed the presence of more sleep patterns over time with DBS. BLn DBS electrodes can be placed using a transfrontal approach. MER can predict the trajectory of the electrode in the amygdala and it may reflect the BLn neuronal activity underlying post-traumatic stress disorder PTSD. The EEG findings may underscore the reduction in anxiety.

Bilateral neurostimulation systems used for deep brain stimulation: in vitro study of MRI-related heating at 1.5 T and implications for clinical imaging of the brain.

Deep brain stimulation (DBS) is used increasingly in the field of movement disorders. The implanted electrodes create not only a prior risk to patient safety during MRI, but also a unique opportunity in the collection of functional MRI data conditioned by direct neural stimulation. We evaluated MRI-related heating for bilateral neurostimulation systems used for DBS with an emphasis on assessing clinically relevant imaging parameters. Magnetic resonance imaging was performed using transmit body radiofrequency (RF) coil and receive-only head RF coil at various specific absorption rates (SARs) of RF power. In vitro testing was performed using a gel-filled phantom with temperatures recorded at the electrode tips. Each DBS electrode was positioned with a single extension loop around each pulse generator and a single loop at the "head" end of the phantom. Various pulse sequences were used for MRI including fast spin-echo, echo-planar imaging, magnetization transfer contrast and gradient-echo techniques. The MRI sequences had calculated whole-body averaged SARs and local head SARs ranging from 0.1 to 1.6 W/kg and 0.1 to 3.2 W/kg, respectively. Temperature elevations of less than 1.0 degrees C were found with the fast spin-echo, magnetization transfer contrast, gradient-echo and echo-planar clinical imaging sequences. Using the highest SAR levels, whole-body averaged, 1.6 W/kg, local exposed-body, 3.2 W/kg, and local head, 2.9 W/kg, the temperature increase was 2.1 degrees C. These results showed that temperature elevations associated with clinical sequences were within an acceptable physiologically safe range for the MR conditions used in this evaluation, especially for the use of relatively low SAR levels. Notably, these findings are highly specific to the neurostimulation systems, device positioning technique, MR system and imaging conditions used in this investigation.

Vagus nerve stimulation (VNS) is effective in a rat model of antidepressant action.

Depression is a common but debilitating illness that afflicts a large population and costs the US economy a staggering $40 billion dollars per year. Clinical studies have demonstrated that vagus nerve stimulation (VNS) is an effective treatment for medication-resistant depression. Understanding VNS's antidepressant mechanisms is key to improving the therapy and selecting the best surgical candidates, and demonstration that VNS is effective in a validated test of antidepressant activity allows us to elucidate these mechanisms in a cost-effective manner. In the present study, Wistar Kyoto rats were implanted with a cuff electrode on the left cervical vagus nerve. The next day, they were placed into a water-filled Plexiglas cylinder for 15 min. After this forced-swim session, one of three treatment conditions were administered over 4 consecutive days: 30 min per day of continuous VNS, 10 mg/kg of desipramine twice per day, or three daily electroconvulsive shocks (ECS). Yoked controls underwent sham procedures, but received no treatment. On the fourth day, the rats were given a 5-min, videotaped swim test. A blinded observer used the videotape to calculate the percentage of time that the rats were immobile (an index of depression) during the swim test. VNS significantly reduced immobility time as compared to unstimulated controls, indicating good antidepressant efficacy. This reduction did not differ statistically from that obtained from rats treated with either desipramine or ECS, two standard antidepressant treatments. These results indicate that VNS is an effective antidepressant in the forced-swim test, allowing us to now investigate possible therapeutic mechanisms.

Vagus nerve stimulation inhibits harmaline-induced tremor.

Excessive olivo-cerebellar burst-firing occurs during harmaline-induced tremor. This system receives rich sensory inputs, including visceral. We hypothesized that electrical vagus nerve stimulation (VNS) would suppress harmaline tremor, as measured with digitized motion power in the rat. Cervical vagus nerve stimulation suppressed power in the 8-12-Hz tremor range by 40%, whereas sham stimulation was ineffective. This study raises the possibility that activation of various sensory modalities, as well as visceral, may reduce tremor.

Right-sided vagus nerve stimulation reduces generalized seizure severity in rats as effectively as left-sided.

As currently utilized, vagus nerve stimulation (VNS) is applied to the cervical trunk of the left vagus nerve to suppress seizures clinically. Demonstration that VNS can also reduce seizure severity when electrodes are placed on the right cervical vagus nerve in rats would provide empirical evidence that the antiepileptic effects of VNS are not an exclusive property of the left vagus nerve. Rats were implanted with a custom cuff electrode on either the left or right cervical vagus nerve. Two days later, continuous VNS was begun in half the rats with left-sided and half with right-sided electrodes. The remaining rats were connected to the stimulator, but did not receive VNS. After 30s, pentylenetetrazole (PTZ) was administered systemically and seizures were rated by a blinded observer. The PTZ test was repeated two days later, with VNS administered to the previously unstimulated rats, while the others received no stimulation. VNS significantly reduced the severity of PTZ-induced seizures in rats regardless of the side of stimulation as compared to their no-VNS (control condition) seizure severity. No significant differences in efficacy existed based on the side of stimulation. These results indicate that right-sided VNS in rats is just as effective as left-sided VNS, suggesting that fibers necessary for seizure suppression are not unique to the left vagus nerve.

Eyelid apraxia associated with deep brain stimulation of the periaqueductal gray area.

We report a patient with eyelid apraxia following deep brain stimulation of the periaqueductal gray area. Based on the position of our electrode, we argue that the phenomenon is linked to inhibition of the nearby central caudal nucleus of the oculomotor nucleus by high frequency stimulation.

Deep brain stimulation of the basolateral amygdala for treatment-refractory combat post-traumatic stress disorder (PTSD): study protocol for a pilot randomized controlled trial with blinded, staggered onset of stimulation.

BACKGROUND: Combat post-traumatic stress disorder (PTSD) involves significant suffering, impairments in social and occupational functioning, substance use and medical comorbidity, and increased mortality from suicide and other causes. Many veterans continue to suffer despite current treatments. Deep brain stimulation (DBS) has shown promise in refractory movement disorders, depression and obsessive-compulsive disorder, with deep brain targets chosen by integration of clinical and neuroimaging literature. The basolateral amygdala (BLn) is an optimal target for high-frequency DBS in PTSD based on neurocircuitry findings from a variety of perspectives. DBS of the BLn was validated in a rat model of PTSD by our group, and limited data from humans support the potential safety and effectiveness of BLn DBS. METHODS/DESIGN: We describe the protocol design for a first-ever Phase I pilot study of bilateral BLn high-frequency DBS for six severely ill, functionally impaired combat veterans with PTSD refractory to conventional treatments. After implantation, patients are monitored for a month with stimulators off. An electroencephalographic (EEG) telemetry session will test safety of stimulation before randomization to staggered-onset, double-blind sham versus active stimulation for two months. Thereafter, patients will undergo an open-label stimulation for a total of 24 months. Primary efficacy outcome is a 30% decrease in the Clinician Administered PTSD Scale (CAPS) total score. Safety outcomes include extensive assessments of psychiatric and neurologic symptoms, psychosocial function, amygdala-specific and general neuropsychological functions, and EEG changes. The protocol requires the veteran to have a cohabiting significant other who is willing to assist in monitoring safety and effect on social functioning. At baseline and after approximately one year of stimulation, trauma script-provoked 18FDG PET metabolic changes in limbic circuitry will also be evaluated. DISCUSSION: While the rationale for studying DBS for PTSD is ethically and scientifically justified, the importance of the amygdaloid complex and its connections for a myriad of emotional, perceptual, behavioral, and vegetative functions requires a complex trial design in terms of outcome measures. Knowledge generated from this pilot trial can be used to design future studies to determine the potential of DBS to benefit both veterans and nonveterans suffering from treatment-refractory PTSD. TRIAL REGISTRATION: PCC121657, 19 March 2014.

Neurostimulation for drug-resistant epilepsy.

PURPOSE OF REVIEW: The purpose of this review is to provide an evidence-based update on the neurostimulation options available for patients with drug-resistant epilepsy in the United States and in European countries. RECENT FINDINGS: The field of neurostimulation for epilepsy has grown dramatically since 1997, when vagus nerve stimulation became the first device to be approved for epilepsy by the US Food and Drug Administration (FDA). New data from recently completed randomized controlled trials are available for deep brain stimulation of the anterior thalamus, responsive neurostimulation, and trigeminal nerve stimulation. Although vagus nerve stimulation is the only device currently approved in the United States, deep brain stimulation and responsive neurostimulation devices are awaiting FDA approval. Deep brain stimulation, trigeminal nerve stimulation, and transcutaneous vagus nerve stimulation are now approved for epilepsy in the European Union. In this article, the mechanisms of action, safety, and efficacy of new neurostimulation devices are reviewed, and the key advantages and disadvantages of each are discussed. SUMMARY: The exponential growth of the field of neuromodulation for epilepsy is an exciting development; these new devices provide physicians with new options for patients with drug-resistant epilepsy.

Calcium antagonists: a ready prescription for treating infectious diseases?

Emergence of new and medically resistant pathogenic microbes continues to escalate toward worldwide public health, wild habitat, and commercial crop and livestock catastrophes. Attempts at solving this problem with sophisticated modern biotechnologies, such as smart vaccines and microbicidal and microbistatic drugs that precisely target parasitic bacteria, fungi, and protozoa, remain promising without major clinical and industrial successes. However, discovery of a more immediate, broad spectrum prophylaxis beyond conventional epidemiological approaches might take no longer than the time required to fill a prescription at your neighborhood pharmacy. Findings from a growing body of research suggest calcium antagonists, long approved and marketed for various human cardiovascular and neurological indications, may produce safe, efficacious antimicrobial effects. As a general category of drugs, calcium antagonists include compounds that disrupt passage of Ca(2+) molecules across cell membranes and walls, sequestration and mobilization of free intracellular Ca(2+), and downstream binding proteins and sensors of Ca(2+)-dependent regulatory pathways important for proper cell function. Administration of calcium antagonists alone at current therapeutically relevant doses and schedules, or with synergistic compounds and additional antimicrobial medications, figures to enhance host immunoprotection by directly altering pathogen infection sequences, life cycles, homeostasis, antibiotic tolerances, and numerous other infective, survival, and reproductive processes. Short of being miracle drugs, calcium antagonists are welcome old drugs with new tricks capable of controlling some of the most virulent and pervasive global infectious diseases of plants, animals, and humans, including Chagas' disease, malaria, and tuberculosis.

Amygdala deep brain stimulation is superior to paroxetine treatment in a rat model of posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a very debilitating disease refractory to current treatment with selective serotonin reuptake inhibitors (SSRIs) in up to 30 percent of patients, illustrating the need for new treatments of PTSD. Neuroimaging studies have shown increased activity of the amygdala of patients with PTSD. OBJECTIVE/HYPOTHESIS: To investigate amygdala deep brain stimulation (DBS) as a possible novel treatment for PTSD and compare it to current treatment with a commonly used SSRI, paroxetine, in a rat PTSD model. METHODS: A PTSD model was created by subjecting rats to inescapable foot shocks in the presence of a conspicuous ball. Response to treatment was measured as a decreased burying behavior when presented with the same ball 1 and 2 weeks after the shocks. Rats were treated with either daily intraperitoneal paroxetine injections or amygdala DBS via an electrode implanted 1 week prior to shocks. Generalized anxiety was assessed using an elevated plus maze. RESULTS: Animals treated with amygdala DBS showed less ball burying at 2 weeks relative to the animals treated with paroxetine. The animals treated with paroxetine, however, had a lower general anxiety level compared to the DBS-treated group. CONCLUSIONS: In this PTSD model, paroxetine was found to decrease the measured general anxiety level of rats that underwent the PTSD protocol, but did not counteract shock-induced hyper-vigilance toward the trauma-associated object (ball). Amygdala DBS, however, did decrease shock-induced hyper-vigilance as measured by a lower burying time, but had no effect on general anxiety assessed in the elevated plus maze. By attenuating amygdala function, DBS may act to treat the cause of PTSD, hyperactive amygdala function, and may be a promising novel alternative in cases of PTSD refractory to current pharmacological treatments.

Vagus nerve stimulation for epilepsy: A review of the peripheral mechanisms.

Vagus nerve stimulation (VNS) is a unique epilepsy treatment in that a peripheral intervention is used to treat a disease that is entirely related to pathological events occurring within the brain. To understand how stimulation of the vagus nerve can be used to stop seizures, an understanding of the peripheral anatomy and physiology of the vagus nerve is essential. The peripheral aspects of the vagus nerve are discussed in this review, with an explanation of which fibers and branches are involved in producing these antiepileptic effects, along with speculation about the potential for improving the therapy.

Vagus nerve stimulation for epilepsy: A review of central mechanisms.

In a previous paper, the anatomy and physiology of the vagus nerve was discussed in an attempt to explain which vagus nerve fibers and branches are affected by clinically relevant electrical stimulation. This companion paper presents some of vagus nerve stimulation's putative central nervous system mechanisms of action by summarizing known anatomical projections of vagal afferents and their effects on brain biogenic amine pathways and seizure expression.