Epilepsy is a network disorder and each type of seizure involves distinct cortical and subcortical network, differently implicated in the control and propagation of the ictal activity. The role of the basal ganglia has been revealed in several cases of focal and generalized seizures. Here, we review the data that show the implication of the basal ganglia in absence, temporal lobe, and neocortical seizures in animal models (rodent, cat, and non-human primate) and in human. Based on these results and the advancement of deep brain stimulation for Parkinson’s disease, basal ganglia neuromodulation has been tested with some success that can be equally seen as promising or disappointing. The effect of deep brain stimulation can be considered promising with a 76% in seizure reduction in temporal lobe epilepsy patients, but also disappointing, since only few patients have become seizure free and the antiepileptic effects have been highly variable among patients. This variability could probably be explained by the heterogeneity among the patients included in these clinical studies. To illustrate the importance of specific network identification, electrophysiological activity of the putamen and caudate nucleus has been recorded during penicillin-induced pre-frontal and motor seizures in one monkey. While an increase of the firing rate was found in putamen and caudate nucleus during pre-frontal seizures, only the activity of the putamen cells was increased during motor seizures. These preliminary results demonstrate the implication of the basal ganglia in two types of neocortical seizures and the necessity of studying the network to identify the important nodes implicated in the propagation and control of each type of seizure.
Optogenetics, a technique that utilizes light-sensitive ion channels or pumps to activate or inhibit neurons, has allowed scientists unprecedented precision and control for manipulating neuronal activity. With the clinical need to develop more precise and effective therapies for patients with drug-resistant epilepsy, these tools have recently been explored as a novel treatment for halting seizure activity in various animal models. In this review, we provide a detailed and current summary of these optogenetic approaches and provide a perspective on their future clinical application as a potential neuromodulatory therapy.
Parkinson's disease is a neurodegenerative disorder that has received considerable attention in allopathic medicine over the past decades. However, it is clear that, to date, pharmacological and surgical interventions do not fully address symptoms of PD and patients' quality of life. As both an alternative therapy and as an adjuvant to conventional approaches, several types of rhythmic movement (e.g., movement strategies, dance, tandem biking, and Tai Chi) have shown improvements to motor symptoms, lower limb control, and postural stability in people with PD (1-6). However, while these programs are increasing in number, still little is known about the neural mechanisms underlying motor improvements attained with such interventions. Studying limb motor control under task-specific contexts can help determine the mechanisms of rehabilitation effectiveness. Both internally guided (IG) and externally guided (EG) movement strategies have evidence to support their use in rehabilitative programs. However, there appears to be a degree of differentiation in the neural substrates involved in IG vs. EG designs. Because of the potential task-specific benefits of rhythmic training within a rehabilitative context, this report will consider the use of IG and EG movement strategies, and observations produced by functional magnetic resonance imaging and other imaging techniques. This review will present findings from lower limb imaging studies, under IG and EG conditions for populations with and without movement disorders. We will discuss how these studies might inform movement disorders rehabilitation (in the form of rhythmic, music-based movement training) and highlight research gaps. We believe better understanding of lower limb neural activity with respect to PD impairment during rhythmic IG and EG movement will facilitate the development of novel and effective therapeutic approaches to mobility limitations and postural instability.
BACKGROUND. Awake neurosurgery requires patients to converse and respond to visual or verbal prompts to identify and protect brain tissue supporting essential functions such as language, primary sensory modalities, and motor function. These procedures can be poorly tolerated because of patient anxiety, yet acute anxiolytic medications typically cause sedation and impair cortical function.
METHODS. In this study, direct electrical stimulation of the left dorsal anterior cingulum bundle was discovered to reliably evoke positive affect and anxiolysis without sedation in a patient with epilepsy undergoing research testing during standard inpatient intracranial electrode monitoring. These effects were quantified using subjective and objective behavioral measures, and stimulation was found to evoke robust changes in local and distant neural activity.
RESULTS. The index patient ultimately required an awake craniotomy procedure to confirm safe resection margins in the treatment of her epilepsy. During the procedure, cingulum bundle stimulation enhanced positive affect and reduced the patient’s anxiety to the point that intravenous anesthetic/anxiolytic medications were discontinued and cognitive testing was completed. Behavioral responses were subsequently replicated in 2 patients with anatomically similar electrode placements localized to an approximately 1-cm span along the anterior dorsal cingulum bundle above genu of the corpus callosum. CONCLUSIONS. The current study demonstrates a robust anxiolytic response to cingulum bundle stimulation in 3 patients with epilepsy.
Ablation or deep brain stimulation in the internal segment of the globus pallidus (GPi) is an effective therapy for the treatment of Parkinson's disease (PD). Yet many patients receive only partial benefit, including varying levels of improvement across different body regions, which may relate to a differential effect of GPi surgery on the different body regions. Unfortunately, our understanding of the somatotopic organization of human GPi is based on a small number of studies with limited sample sizes, including several based upon only a single recording track or plane. To fully address the three-dimensional somatotopic organization of GPi, we examined the receptive field properties of pallidal neurons in a large cohort of patients undergoing stereotactic surgery. The response of neurons to active and passive movements of the limbs and orofacial structures was determined, using a minimum of three tracks across at least two medial-lateral planes. Neurons (3183) were evaluated from 299 patients, of which 1972 (62%) were modulated by sensorimotor manipulation. Of these, 1767 responded to a single, contralateral body region, with the remaining 205 responding to multiple and/or ipsilateral body regions. Leg-related neurons were found dorsal, medial and anterior to arm-related neurons, while arm-related neurons were dorsal and lateral to orofacial-related neurons. This study provides a more detailed map of individual body regions as well as specific joints within each region and provides a potential explanation for the differential effect of lesions or DBS of the GPi on different body parts in patients undergoing surgical treatment of movement disorders.
Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson’s disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum (GPi) in two parkinsonian rhesus monkeys with stable levodopa-induced dyskinesias (LIDs). Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6–8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish. The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.
Poor functional recovery found after peripheral nerve injury has been attributed to the misdirection of regenerating axons to reinnervate functionally inappropriate muscles. We applied brief electrical stimulation (ES) to the common fibular (CF) but not the tibial (Tib) nerve just prior to transection and repair of the entire rat sciatic nerve, to attempt to influence the misdirection of its regenerating axons. The specificity with which regenerating axons reinnervated appropriate targets was evaluated physiologically using compound muscle action potentials (M responses) evoked from stimulation of the two nerve branches above the injury site. Functional recovery was assayed using the timing of electromyography (EMG) activity recorded from the tibialis anterior (TA) and soleus (Sol) muscles during treadmill locomotion and kinematic analysis of hindlimb locomotor movements. Selective ES of the CF nerve resulted in restored M-responses at earlier times than in unstimulated controls in both TA and Sol muscles. Stimulated CF axons reinnervated inappropriate targets to a greater extent than unstimulated Tib axons. During locomotion, functional antagonist muscles, TA and Sol, were coactivated both in stimulated rats and in unstimulated but injured rats. Hindlimb kinematics in stimulated rats were comparable to untreated rats, but significantly different from intact controls. Selective ES promotes enhanced axon regeneration but does so with decreased fidelity of muscle reinnervation. Functional recovery is neither improved nor degraded, suggesting that compensatory changes in the outputs of the spinal circuits driving locomotion may occur irrespective of the extent of misdirection of regenerating axons in the periphery.
by
Michal T. Berry;
Brent M. Kremen;
Vaclav Miller;
Laura Miller Khadjevand;
Fatemeh Ezzyat;
Youssef Stein;
Joel Wanda;
Paul Sperling;
Michael R. Gorniak;
Richard Davis;
Kathryn Jobst;
Barbara Gross;
Michal T. Kucewicz;
Bradley Lega;
S. Matt Stead;
Daniel S. Rizzuto;
Michael J. Kahana;
Gregory A. Worrell
Direct electrical stimulation of the brain has emerged as a powerful treatment for multiple neurological diseases, and as a potential technique to enhance human cognition. Despite its application in a range of brain disorders, it remains unclear how stimulation of discrete brain areas affects memory performance and the underlying electrophysiological activities. Here, we investigated the effect of direct electrical stimulation in four brain regions known to support declarative memory: hippocampus (HP), parahippocampal region (PH) neocortex, prefrontal cortex (PF), and lateral temporal cortex (TC). Intracranial EEG recordings with stimulation were collected from 22 patients during performance of verbal memory tasks. We found that high γ (62-118 Hz) activity induced by word presentation was modulated by electrical stimulation. This modulatory effect was greatest for trials with “poor” memory encoding. The high γ modulation correlated with the behavioral effect of stimulation in a given brain region: it was negative, i.e., the induced high γ activity was decreased, in the regions where stimulation decreased memory performance, and positive in the lateral TC where memory enhancement was observed. Our results suggest that the effect of electrical stimulation on high γ activity induced by word presentation may be a useful biomarker for mapping memory networks and guiding therapeutic brain stimulation.
by
Youssef Ezzyat;
Paul A. Wanda;
Deborah F. Levy;
Allison Kadel;
Ada Aka;
Isaac Pedisich;
Micheal R. Sperling;
Ashwini D. Sharan;
Bradley C. Lega;
Alexis Burks;
Robert Gross;
Cory S. Inman;
Barbara C. Jobst;
Mark A. Gorenstein;
Kathryn A. Davis;
Gregory A. Worrell;
Michal T. Kucewicz;
Joel M. Stein;
Richard Gorniak;
Sandhitsu R. Das;
Daniel S. Rizzuto;
Michael J. Kahana
Memory failures are frustrating and often the result of ineffective encoding. One approach to improving memory outcomes is through direct modulation of brain activity with electrical stimulation. Previous efforts, however, have reported inconsistent effects when using open-loop stimulation and often target the hippocampus and medial temporal lobes. Here we use a closed-loop system to monitor and decode neural activity from direct brain recordings in humans. We apply targeted stimulation to lateral temporal cortex and report that this stimulation rescues periods of poor memory encoding. This system also improves later recall, revealing that the lateral temporal cortex is a reliable target for memory enhancement. Taken together, our results suggest that such systems may provide a therapeutic approach for treating memory dysfunction.
An essential component of goal-directed decision-making is the ability to maintain flexible responding based on the value of a given reward, or “reinforcer.” The medial orbitofrontal cortex (mOFC), a subregion of the ventromedial prefrontal cortex, is uniquely positioned to regulate this process. We trained mice to nose poke for food reinforcers and then stimulated this region using CaMKII-driven Gs-coupled designer receptors exclusively activated by designer drugs (DREADDs). In other mice, we silenced the neuroplasticity-associated neurotrophin brain-derived neurotrophic factor (BDNF). Activation of Gs-DREADDs increased behavioral sensitivity to reinforcer devaluation, whereas Bdnf knockdown blocked sensitivity. These changes were accompanied by modifications in breakpoint ratios in a progressive ratio task, and they were recapitulated in Bdnf+/− mice. Replacement of BDNF selectively in the mOFC in Bdnf+/− mice rescued behavioral deficiencies, as well as phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2). Thus, BDNF expression in the mOFC is both necessary and sufficient for the expression of typical effort allocation relative to an anticipated reinforcer. Additional experiments indicated that expression of the immediate-early gene c-fos was aberrantly elevated in the Bdnf+/− dorsal striatum, and BDNF replacement in the mOFC normalized expression. Also, systemic administration of an MAP kinase kinase inhibitor increased breakpoint ratios, whereas the addition of discrete cues bridging the response–outcome contingency rescued breakpoints in Bdnf+/− mice. We argue that BDNF–ERK1/2 in the mOFC is a key regulator of “online” goal-directed action selection. SIGNIFICANCE STATEMENT Goal-directed response selection often involves predicting the consequences of one's actions and the value of potential payoffs. Lesions or chemogenetic inactivation of the medial orbitofrontal cortex (mOFC) in rats induces failures in retrieving outcome identity memories (Bradfield et al., 2015), suggesting that the healthy mOFC serves to access outcome value information when it is not immediately observable and thereby guide goal-directed decision-making. Our findings suggest that the mOFC also bidirectionally regulates effort allocation for a given reward and that expression of the neurotrophin BDNF in the mOFC is both necessary and sufficient for mice to sustain stable representations of reinforcer value.