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.

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.

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.

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.

Treatment of post-traumatic epilepsy.

OPINION STATEMENT: Post-traumatic epilepsy (PTE) due to traumatic brain injury is a diagnosis with multifactorial causes, diverse clinical presentations, and an evolving concept of management. Due to sports injuries, work-related injuries, vehicular accidents, and wartime combat, there is rising demand to understand the epidemiology, pathophysiology, diagnosis, prognosis, and treatment of PTE. PTE could occur at any time after injury and up to decades post-injury. The frontal and temporal lobes are the most commonly affected regions, and the resulting epilepsy syndrome is typically localization related. PTE should be actively considered as a diagnosis in any patient with a history of head trauma and episodic neurologic compromise regardless of how temporally remote the trauma occurred. The standard work-up includes a thorough history, neurological examination, neuroimaging, and electroencephalogram. Psychogenic nonepileptic seizures have a high comorbidity with seizures and need to be carefully excluded. PTE can spontaneously remit. For patients who do not go into remission, treatment for confirmed PTE includes antiepileptics, vagal nerve stimulator, and, when appropriate, surgical resection of an epileptogenic lesion. Lifestyle modification and counseling are critical for patients with PTE and should be routinely included in clinical management. The published evidence on the efficacy of various treatment modalities specific to PTE consists largely of retrospective studies and case reports. Despite a unique pathogenesis, the majority of current care parameters for PTE parallel those of standard care for localization-related epilepsy. The potential and need for rigorous clinical research in PTE continue to be in great demand.

Alternative cerebral generators and circuitry pathways in alpha coma revealed by independent component analysis.

OBJECTIVE: This study investigates the generators of alpha coma activity and the probable cerebral pathways involved in alpha coma patients. METHODS: This study uses independent component analysis (ICA) and dipole fitting algorithm to locate the cerebral generators in alpha coma and normal alpha rhythms. RESULTS: Distinct distributions of the source generators for alpha activity were noted in alpha coma. They were localized to the anterior neocortical and subcortical regions, which includes caudate nucleus, midbrain and hypothalamus. In addition, the two patients who survive long term have five independent components identified vs. the other five patients who demised only had one or two independent components. CONCLUSIONS: The findings showed that alpha activity could be generated using alternative generators and pathways. This is probably due to the disinhibition of the normally inhibited pathways in coma. The presence of less independent components is probably a marker of less preserved brain tissue and predicts worse outcome. SIGNIFICANCE: This is the first known human study using the ICA method to localize the cerebral generators in alpha coma. It might provide a new dimension of interpreting clinical EEGs in patients with alpha coma. It also might have significant application in predicting the clinical outcomes.

Posttraumatic epilepsy and treatment.

Posttraumatic epilepsy (PTE) is a major long-term complication of traumatic brain injury (TBI). PTE usually develops within 5 years of head injury. The risk for developing PTE varies with TBI type. Both Korean and Vietnam war veterans with penetrating TBI had a 53% risk of developing PTE. The risk of developing PTE is between 10% and 25% in combat-associated closed-head trauma with positive brain imaging and about 5% in moderately severe closed-head injury without imaging finding. We do not know the risk of PTE among Operation Iraqi Freedom/Operation Enduring Freedom veterans with minimal TBI because of blast exposure.Partial seizures may manifest with subtle behavioral alterations that can be mistaken for manifestations of posttraumatic stress disorder and improperly treated. Accidents and medical complications commonly occur during seizures. Sudden unexpected death in epilepsy is most frequent among 20- to 40-year-olds. Seizures increase the likelihood of refractory seizures years after TBI. Seizures are also a social stigma that compromise veterans' reintegration into society. People with uncontrolled epilepsy are not allowed to drive and have difficulty obtaining or maintaining employment. Optimal seizure control is essential to the physical and emotional health of veterans with TBI and to their ability to lead productive lives.

Mechanistic and pharmacologic aspects of status epilepticus and its treatment with new antiepileptic drugs.

We review recent advances in our understanding and treatment of status epilepticus (SE). Repeated seizures cause an internalization of gamma-aminobutyric acid (GABA)(A) receptors, together with a movement of N-methyl-d-aspartate (NMDA) receptors to the synapse. As a result, the response of experimental SE to treatment with GABAergic drugs (but not with NMDA antagonists) fades with increasing seizure duration. Prehospital treatment, which acts before these changes are established, is finding increased acceptance, and solid evidence of its efficacy is available, particularly in children. Rational polypharmacy aims at multiple receptors or ion channels to increase inhibition and simultaneously reduce excitation. Combining GABA(A) agonists with NMDA antagonists and with agents acting at other sites is successful in treating experimental SE, and in reducing SE-induced brain damage and epileptogenesis. The relevance of these experimental data to clinical SE is actively debated. Valproate and levetiracetam have recently become available for intravenous use, and the use of ketamine and of other agents (topiramate, felbamate, etc.) have seen renewed interest. A rapidly increasing but largely anecdotal body of literature reports success in seizure control at the price of relatively few complications with the clinical use of those agents in refractory SE.

Status epilepticus: pathophysiology and management in adults.

As in Clark and Prout's classic work, we identify three phases of generalised convulsive status epilepticus, which we call impending, established, and subtle. We review physiological and subcellular changes that might play a part in the transition from single seizures to status epilepticus and in the development of time-dependent pharmacoresistance. We review the principles underlying the treatment of status epilepticus and suggest that prehospital treatment is beneficial, that therapeutic drugs should be used in rapid sequence according to a defined protocol, and that refractory status epilepticus should be treated with general anaesthesia. We comment on our preference for drugs with a short elimination half-life and discuss some therapeutic choices.

Functional signal- and paradigm-dependent linear relationships between synaptic activity and hemodynamic responses in rat somatosensory cortex.

Linear relationships between synaptic activity and hemodynamic responses are critically dependent on functional signal etiology and paradigm. To investigate these relationships, we simultaneously measured local field potentials (FPs) and optical intrinsic signals in rat somatosensory cortex while delivering a small number of electrical pulses to the hindpaw with varied stimulus intensity, number, and interstimulus interval. We used 570 and 610 nm optical signals to estimate cerebral blood volume (CBV) and oxygenation, respectively. The spatiotemporal evolution patterns and trial-by-trial correlation analyses revealed that CBV-related optical signals have higher fidelity to summed evoked FPs (SigmaFPs) than oxygenation-derived signals. CBV-related signals even correlated with minute SigmaFP fluctuations within trials of the same stimulus condition. Furthermore, hemodynamic signals (CBV and late oxygenation signals) increased linearly with SigmaFP while varying stimulus number, but they exhibited a threshold and steeper gradient while varying stimulus intensity, suggesting insufficiency of the homogeneity property of linear systems and the importance of spatiotemporal coherence of neuronal population activity in hemodynamic response formation. These stimulus paradigm-dependent linear and nonlinear relationships demonstrate that simple subtraction-based analyses of hemodynamic signals produced by complex stimulus paradigms may not reflect a difference in SigmaFPs between paradigms. Functional signal- and paradigm-dependent linearity have potentially profound implications for the interpretation of perfusion-based functional signals.

Multiwavelength optical intrinsic signal imaging of cortical spreading depression.

Cortical spreading depression (CSD) is an important disease model for migraine and cerebral ischemia. In this study, we exploit the high temporal and spatial resolution of optical imaging to characterize perfusion-dependent and -independent changes in response to CSD and to investigate the etiology of reflectance changes during CSD. In this experiment, we characterized the optical response to CSD at wavelengths that emphasize perfusion-related changes (610 and 550 nm), and we compared these results with 850 nm and blood volume data. Blood volume changes during CSD were recorded using an intravascular fluorescent dye, Texas Red dextran. We observed triphasic optical signals at 850 and 550 nm characterized by spreading waves of increased, decreased, then increased reflectance (Fig. 1) which expanded at a rate of approximately 3-5 mm/min. The signal at 610 nm had a similar initial phase, but the phase 2 response was slightly more complex, with a parenchymal decrease in reflectance but a vascular increase in reflectance. Reflectance values decreased in phase three. Blood volume signals were delayed relative to the optical intrinsic signals and corresponded temporally to phases 2 and 3. This is the first study to characterize optical imaging of intrinsic signal responses to CSD, in vivo, at multiple wavelengths. The data presented here suggest that changes in light scattering precede perfusion responses, the blood volume increase (phase 2) is accompanied by a reduction in deoxyhemoglobin, and the blood volume decrease (phase 3) is accompanied by an increase in deoxyhemoglobin. Previous studies have suggested the oligemia of spreading depression was a result of decreased metabolic demand. This study suggests that during the oligemic period there is a greater reduction in oxygen delivery than in demand.