Prefrontal Cortical Stimulation Research Articles

The Effect of Multi-Session Prefrontal Cortical Stimulation on Aggression: A Randomized, Double-Blind, Parallel-Group Trial.

Findings from brain imaging studies investigating the neural underpinnings of antisocial behavior have implicated the prefrontal cortex in the regulation of aggressive reactions. However, relatively few studies have examined the role of the prefrontal cortex on aggression in an experimental way. This study examines whether upregulating the prefrontal cortex using repeated transcranial direct current stimulation (tDCS) reduces aggressive behavior. In a double-blind, parallel-group, randomized controlled trial, 88 healthy adults (42 males, 46 females) were assigned to one session of anodal tDCS over the ventromedial prefrontal cortex (n = 47) or sham stimulation (n = 41) per day for three consecutive days and assessed using a behavioral measure of aggression. Levels of aggressive responses post-intervention did not significantly differ between the active and sham stimulation groups. However, a significant interaction effect between the stimulation group and gender was observed, whereby males, but not females, exhibited reduced aggression after prefrontal stimulation. To the authors' knowledge, this is the first study to examine the effect of multi-session prefrontal tDCS on aggressive behavior in healthy adults. Results highlight that there are differences in responsivity to tDCS in modifying aggressive behavior.

The effect of repeated prefrontal cortical stimulation on aggression: A randomized controlled trial

The effect of repeated prefrontal cortical stimulation on aggression: A randomized controlled trial

Effects of prefrontal cortical stimulation on aggressive and antisocial behavior: A double-blind, stratified, randomized, sham-controlled, parallel-group trial

This study examines the influence of high-definition transcranial direct current stimulation (HD-tDCS) of the prefrontal cortex (PFC) on aggressive behavior and antisocial intentions, and provides an updated meta-analysis of prior studies. In this double-blind, stratified, randomized, sham-controlled, parallel-group trial, 94 participants received sham or 20 min of 2 mA anodal stimulation of the PFC using HD-tDCS. The Voodoo Doll Task and hypothetical vignettes were used to measure aggressive behavior and antisocial intentions, respectively. There were no significant group differences in aggressive behavior or antisocial intentions after stimulation. To the authors’ knowledge, this is the first study to examine HD-tDCS in reducing aggressive and antisocial behavior. The null effects on aggressive behavior align with an updated meta-analysis of prior studies (d = − 0.028, 95% CI [− 1.14, 1.08]). Future studies employing repeated tDCS sessions on significantly antisocial populations could further help assess the utility of tDCS for reducing antisociality.

Prefrontal Cortical Stimulation in Tourette Disorder: Proof‐of‐concept Clinical and Neuroimaging Study

The benefits of neurosurgery in Tourette Syndrome (TS) are still incompletely understood. Prefrontal cortical electrical stimulation offers a less invasive alternative to deep brain stimulation. To perform a pilot assessment on safety and efficacy of prefrontal cortical bilateral electrical stimulation in TS using clinical and brain metabolic assessments. Four adult TS patients underwent tic assessment using the Yale Global Tic Severity Scale and the Rush Video Rating Scale at baseline and 1, 3, 6, and 12-months after implant; whereas FDG-PET scans were acquired at baseline and after 6 and 12 months. Tic clinical scores were improved at 6 months after implant, meanwhile they showed a tendency to re-emerge at the 12-month follow-up. There was a correlation between FDG-PET and tics, mainly consisting in a reduction of baseline brain hypermetabolism, which paralleled tic score reduction. Epidural stimulation in TS is safe and yields a modulation of tics, paralleled by FDG-PET metabolic modulation.

EP 23. Bilateral epidural prefrontal cortical stimulation (EpCS) over fronto-polar and mid-frontal gyrus accesses mood regulation networks: Evidence from diffusion tensor imaging

Introduction The functional neuroanatomy of depression involves the prefrontal, cingulate and insular cortices, the amygdala, the nucleus accumbens and the hippocampus. The anterior and lateral prefrontal cortices are different in their cognitive and emotional integration roles and their modulation of sub-cortical regions. Both offer a distinct opportunity for targeted antidepressant treatments. Epidural prefrontal cortical stimulation (EpCS) is a unique therapeutic approach. It is more direct than transcranial magnetic stimulation (TMS) or vagus nerve stimulation (VNS), safer than deep brain stimulation (DBS) and, when applied chronically can reduce negative emotional arousal, increases stress tolerance and possibly lead to fewer relapses than observed with antidepressant pharmacotherapy Question Document the direct anatomical connections accessed with bilateral EpCS over fronto-polar and mid-frontal gyrus using diffusion tensor imaging (DTI). Methods Five patients treatment-resistant depression were implanted with bilateral EpCS leads over fronto-polar and mid-frontal gyrus. Patients underwent structural imaging (high resolution T1-weighted (T1w) MRI image and a DTI with 32 gradient directions) before surgery and a CT scan post-implantation. Image analysis was performed using the FMRIB Software Library. BA25, BA10 and BA46 areas, and Amygdala were extracted from the Broadmann area template to serve as guides for tractography. Similarly, individual EpCS paddles identified on CT scan were also transformed. First, an affine (12 parameter model) registration was applied to register Broadmann template onto T1w images and then T1w onto DTI data. Transformations were then applied to the guides. Second, a binary mask of the brain was extracted and applied to all images after correction for eddy currents. BedpostX was then run on the preprocessed data to generate the basis for probabilistic tractography using ProbtrackX. Estimation of tracts was done probabilistically, using a dual-fiber model with 5000 tract-following samples at each voxel. All tractography was done in each subject’s native space. Eight tractography combinations (left & right) were performed: BA10/BA46 as seeds for tractography and Amygdala/BA25 as waypoints masks. Similar approached was applied with EpCS actual lead masks. The resulting fibers were then thresholded at 0.01 (99% likelihood of connectivity) and then binarized, and transferred into MNI152 standard space for cross-subject analysis using a non-linear registration. To generate population-based probability fibers, all subjects’ individual fibers were added up and used as a basis for calculation of a mean image. Finally, the resulting mean fiber was thresholded to show voxels common to 80% or more of the subjects. Results All patients showed robust connections of different pathways in both left and right hemispheres. The resulting pathways connected to each seed combination are shown in Fig. 1 . Electrodes implanted over both BA10 and BA46 areas resulted in direct activation of axons that primarily project from BA10 or BA46 to BA25 and Amygdala, and extend to the cingulum bundle and to the middle occipital gyrus. Conclusion This is the first demonstration of EpCS direct anatomical access to the medial and lateral mood regulation networks. Encouraging clinical data have been reported elsewhere with 3 patients out of 5 showing remission at 7 months (Nahas et al., 2010) and at 5 years (Williams et al., under review). Bilateral anterior and lateral EpCS promises to be an innovative new treatment for a highly morbid disease through adaptive cortical governance of limbic structures but larger studies are needed.

Five-Year Follow-Up of Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression.

Epidural prefrontal cortical stimulation (EpCS) represents a novel therapeutic approach with many unique benefits that can be used for treatment-resistant depression (TRD). To examine the long-term safety and efficacy of EpCS of the frontopolar cortex (FPC) and dorsolateral prefrontal cortex (DLPFC) for treatment of TRD. Adults (N = 5) who were 21-80 years old with severe TRD [failure to respond to adequate courses of at least 4 antidepressant medications, psychotherapy and ≥20 on the Hamilton Rating Scale for Depression (HRSD24)] were recruited. Participants were implanted with bilateral EpCS over the FPC and DLPFC and received constant, chronic stimulation throughout the five years with Medtronic IPGs. They were followed for 5 years (2/1/2008-10/14/2013). Efficacy of EpCS was assessed with the HRSD24 in an open-label design as the primary outcome measure at five years. All 5 patients continued to tolerate the therapy. The mean improvements from pre-implant baseline on the HRSD24 were [7 months] 54.9% (±37.7), [1 year] 41.2% (±36.6), [2 years] 53.8% (±21.7), and [5 years] 45% (±47). Three of 5 (60%) subjects continued to be in remission at 5 years. There were 5 serious adverse events: 1 electrode 'paddle' infection and 4 device malfunctions, all resulting in suicidal ideation and/or hospitalization. These results suggest that chronic bilateral EpCS over the FPC and DLPFC is a promising and potentially durable new technology for treating TRD, both acutely and over 5 years.

Five-Year Follow-up of Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression

Treatment-resistant depression (TRD) is a severely disabling disorder with no proven treatment options once standard therapies (medication, psychotherapy, TMS, VNS, ECT) have failed. The fronto-polar (FP) and midlateral (ML) prefrontal cortices play distinct, yet complementary roles in the integration of emotional and cognitive experiences. Stimulation at both cortical areas provides a distinct opportunity for targeted antidepressant treatment. This five-year follow-up provides further evidence of the safety and therapeutic benefits of chronic epidural prefrontal cortical stimulation (EpCS) in TRD patients.

Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression

Treatment-resistant depression presents a serious challenge to both patients and clinicians. The anterior and midlateral prefrontal cortices play complementary roles in integrating emotional and cognitive experiences and in modulating subcortical regions. Both regions offer a distinct opportunity for targeted antidepressant treatments. We chose to pilot the safety and therapeutic benefits of chronic and intermittent epidural prefrontal cortical stimulation (EpCS) in patients with treatment-resistant depression. We enrolled five adults with an average of 5.8 failed antidepressant treatments in their current depressive episode. All subjects underwent comprehensive clinical assessments, detailed neuropsychological testing, and presurgical magnetic resonance imaging. Four cortical stimulation paddle leads were stereotactically placed bilaterally over the anterior frontal poles and midlateral prefrontal cortex. We also acquired a postsurgical computed tomography scan and repeatedly assessed clinical outcomes over time of EpCS as an adjunctive treatment to constant medications. All patients tolerated the therapy. At 7-month follow-up, the average improvement from preimplant baseline on the Hamilton Rating Scale for Depression and the Inventory of Depressive Symptoms-Self-Report were 54.9% (+/- 37.7) and 60.1% (+/- 34.1), respectively. Three implanted subjects reached remission. One patient's left hemisphere leads were explanted 12 weeks postsurgery because of a scalp infection. Bilateral EpCS over anterior and midlateral frontal cortex is a promising new technology for treatment-resistant depression. Future double-blind studies are warranted.

Reproducibility of TMS—Evoked EEG responses

Navigated transcranial magnetic stimulation combined with electroencephalography (nTMS-EEG), allows noninvasive studies of cortical excitability and connectivity in humans. We investigated the reproducibility of nTMS-EEG in seven healthy subjects by repeating left motor and prefrontal cortical stimulation with a 1-week interval. TMS was applied at three intensities: 90, 100, and 110% of subjects' motor threshold (MT). The TMS-compatible neuronavigation system guaranteed precise repositioning of the stimulation coil. The responses were recorded by a 60-channel whole head TMS-compatible EEG amplifier. A high overall reproducibility (r > 0.80) was evident in nTMS-EEG responses over both hemispheres for both motor and prefrontal cortical stimulation. The results suggest that nTMS-EEG is a reliable tool for studies investigating cortical excitability changes in the test-retest designs.

Cellular Mechanisms of Infralimbic and Prelimbic Prefrontal Cortical Inhibition and Dopaminergic Modulation of Basolateral Amygdala NeuronsIn Vivo

The basolateral amygdala (BLA) is believed to be involved in schizophrenia, depression, and other disorders that display affective components. The neuronal activity of the BLA, and BLA-mediated affective behaviors, are driven by sensory stimuli transmitted in part from sensory association cortical regions. These same behaviors may be regulated by prefrontal cortical (PFC) inputs to the BLA. However, it is unclear how two sets of glutamatergic inputs to the BLA can impose opposing actions on BLA-mediated behaviors; specifically, it is unclear how PFC inputs exert inhibitory actions over BLA projection neurons. Dopamine (DA) receptor activation enhances BLA-mediated behaviors. Although we have demonstrated that DA suppresses medial PFC inputs to the BLA and enhances sensory cortical inputs, the precise cellular mechanisms for its actions are unknown. In this study we use in vivo intracellular recordings to determine the means by which glutamatergic inputs from the PFC inhibit BLA projection neurons, contrast that with glutamatergic inputs from the association sensory cortex (Te3) that drive BLA projection neurons, and examine the effects of DA receptor activation on neuronal excitability, spontaneous postsynaptic potentials (PSPs), and PFC-evoked PSPs. We found that PFC stimulation inhibits BLA projection neurons by three mechanisms: chloride-mediated hyperpolarization, a persistent decrease in neuronal input resistance, and shunting of PSPs; all effects are possibly attributable to recruitment of inhibitory interneurons. DA receptor activation enhanced neuronal input resistance by a postsynaptic mechanism (via DA D2 receptors), suppressed spontaneously occurring and PFC-evoked PSPs (via DA D1 receptors), and enhanced Te3-evoked PSPs.

The cerebral cortex and parafascicular thalamic nucleus facilitate in vivo acetylcholine release in the rat striatum through distinct glutamate receptor subtypes.

Electrical stimulation (ten pulses of 0.5 ms, 10 V applied over 10 s at 10 Hz, 140 microA) delivered bilaterally to the prefrontal cortex or the parafascicular thalamic nucleus of freely moving rats facilitated acetylcholine release in dorsal striata, assessed by trans-striatal microdialysis. The facilitatory effects were blocked by coperfusion with 5 microM tetrodotoxin, suggesting that the release was of neuronal origin. The response of the striatal cholinergic neurons to prefrontal cortical stimulation was short-lived and required a longer period of stimulation (20 min) that the response to thalamic stimulation (4 min) to reach maximal effect. The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate glutamatergic receptor antagonist 6,7-dinitroquinoxaline-2,3-dione [DNQX; 12 nmol per side, intracerebroventricularly (i.c.v.)] and the AMPA antagonist 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (NBQX; 12 nmol per side, i.c.v. or 12.8 microM infused into the striatum), but not the NMDA-type receptor antagonist MK-801 (0.2 mg/kg, i.p.), abolished the facilitatory effect on striatal acetylcholine release evoked by stimulation of the prefrontal cortex. By contrast, DNQX or NBQX did not prevent the increase in striatal acetylcholine release evoked by parafascicular nucleus stimulation, but MK-801, in accordance with previous results, did so. MK-801 by itself lowered striatal acetylcholine output while DNQX and NBQX did not. The results provide in vivo evidence that the cerebral cortex facilitates cholinergic activity in the dorsal striatum apparently through the non-tonic activation of AMPA-type glutamatergic receptors while the parafascicular nucleus does this through tonic activation of NMDA receptors. Both glutamate receptor types are probably located in the striatum. The overall results suggest that the two pathways operate independently to regulate striatal cholinergic activity through distinct mechanisms.

The course of neural projection from the prefrontal cortex to the nucleus accumbens in the rat

Corticostriatal neurons linking the prefrontal cortex and the nucleus accumbens connect the terminal fields of the ascending mesotelencephalic dopamine neurons and may potentially mediate cortical dopaminergic modulation of subcortical dopamine transmission. In our attempt to develop a brain slice preparation that maximally preserves this prefrontal–accumbens pathway for in vitro electrophysiological studies, knowledge of the complete course of its projection is critical.Microinjection of biotin–dextran amine as an anterograde tracer into the prefrontal cortex revealed the following in the coronal, sagittal and oblique planes of rat brain. (1) Axonal fibers from the rostral prelimbic cortex projected at an angle of ≈60° to the horizontal plane through the infralimbic region and mainly entered the rostromedial accumbens. Some also chose a ventral route to enter the “core” of the accumbens. (2) From the central–ventral prelimbic regions, axons spread out diffusely and descended to the dorsal accumbens. They then entered throughout the rostral–caudal “shell” of the nucleus accumbens. (3) From the caudal prelimbic region of the prefrontal cortex, axonal fibers descended ≈10° to the coronal plane and entered the dorsal nucleus accumbens and the caudate nucleus. The denser caudate-projecting fibers gave rise to collaterals that entered the accumbens “core”. These results suggest that brain slices that preserve the rostral prelimbic–medial accumbens pathway can be obtained by an oblique (≈60°) cut, whereas preservation of the caudal prefrontal–accumbens neurons necessitates a 10° cut.Finally, in whole-cell patch-clamp recordings of accumbens neurons in such slices, orthodromically evoked excitatory postsynaptic potentials to deep layer prefrontal cortical stimulation were observed, thus confirming the functional preservation of portions of this prefrontal cortex–nucleus accumbens pathway.

Physiological properties of rat ventral pallidal neurons recorded intracellularly in vivo

1. The physiology of ventral pallidal (VP) cells was investigated using in vivo intracellular recording and staining techniques in adult rats. Based on electrophysiological criteria, three different types of cells were found: type A cells, which fired phasic spikes that did not exhibit a substantial afterhyperpolarization (AHP), type B cells, which exhibited a slow ramplike depolarization that preceded the short-duration action potential; the spike was followed by a prominent AHP, and type C cells, which were the only cells that fired spikes in couplets or bursts, with the spikes in a burst exhibiting a progressive increase in duration and a decrease in amplitude. These cells also exhibited a rebound low threshold spikelike event. Furthermore, 18% of the VP cells recorded exhibited a slow subthreshold oscillation of the membrane potential (< 1 Hz). 2. The response of VP cells to stimulation of fibers arising from the prefrontal cortex, nucleus accumbens, and mediodorsal thalamic nucleus (MD) was examined. In contrast to our initial predictions, all cells responded to nucleus accumbens stimulation with excitation. Type A and B cells responded to nucleus accumbens stimulation with excitation and to MD stimulation with antidromic-like responses, orthodromic excitation, or evoked inhibitory postsynaptic potentials. Only type A cells responded to prefrontal cortical stimulation. Type C cells only responded to stimulation of the nucleus accumbens, which resulted in evoked excitatory postsynaptic potentials. 3. The cells in the VP therefore can be segregated into three physiologically defined groups according to action potential discharge patterns and their response to afferent fiber stimulation.

Thalamic incremental responses to prefrontal cortical stimulation in the cat

Thalamic incremental responses to prefrontal cortical stimulation in the cat