Evolution of optogenetic microdevices

Implementation of optogenetic techniques is a recent addition to the neuroscientists\u27 preclinical research arsenal, helping to expose the intricate connectivity of the brain and allowing for on-demand direct modulation of specific neural pathways. Developing an optogenetic system requires thorough investigation of the optogenetic technique and of previously fabricated devices, which this review accommodates. Many experiments utilize bench-top systems that are bulky, expensive, and necessitate tethering to the animal. However, these bench-top systems can make use of power-demanding technologies, such as concurrent electrical recording. Newer portable microdevices and implantable systems carried by freely moving animals are being fabricated that take advantage of wireless energy harvesting to power a system and allow for natural movements that are vital for behavioral testing and analysis. An investigation of the evolution of tethered, portable, and implantable optogenetic microdevices is presented, and an analysis of benefits and detriments of each system, including optical power output, device dimensions, electrode width, and weight is given. Opsins, light sources, and optical fiber coupling are also discussed to optimize device parameters and maximize efficiency from the light source to the fiber, respectively. These attributes are important considerations when designing and developing improved optogenetic microdevices

The role of ventrolateral prefrontal cortex in performance of spatial self-ordered response sequences in the marmoset

The ventrolateral prefrontal cortex (vlPFC) in primates plays an important role in cognitive control and working memory, but as argued in the Introduction its contribution to those aspects of goal-directed behaviour such as planning and executing spatial response sequences requires further analysis, using more refined methods than have been employed hitherto. These studies investigated the role of vlPFC in performance of self-ordered response sequences using intra-cerebral microinfusions of specific pharmacologic agents in the common marmoset. Following a description of the necessary methodology, including behavioural training and surgical details (Chapter 2), a causal role for vlPFC in performance of spatial-self ordered sequences was confirmed in Chapter 3 by demonstrating that local inactivation of vlPFC using muscimol/baclofen infusions impairs sequencing. This effect was shown to be selective to performance of sequences that varied spatially from trial to trial; thus, no effects of vlPFC inactivation were observed for performance of a fixed response sequence. Once animals could learn a heuristical strategy for a self-ordered fixed sequence, vlPFC inactivation no longer impaired performance. Chapter 4 investigated the effects of the chemical neuromodulation of vlPFC on self-ordered sequencing using microinfusions of dopamine receptor D2 antagonist, sulpiride, and 5HT2A receptor antagonist, M100907 on performance of variable sequences. These drugs produced contrasting, dose-dependent impairments. M100907 impaired accuracy, while sulpiride impaired error correction. Chapter 5 studied effects of blocking glutamatergic receptors in a region of the caudate nucleus to which the vlPFC projects, but no significant effects on sequencing accuracy were observed, although there were large effects on perseverative errors in 2 out of 3 animals. The findings are discussed in Chapter 6 in terms of the functioning of the vlPFC and its possible role in controlling flexible response sequencing and working memory. The findings are shown to be of relevance for psychiatric disorders such as obsessive compulsive disorder (OCD) and schizophrenia, which show functional dysconnectivity of the vlPFC in association with response sequencing impairments

Investigating the neural substrates of gambling disorder using multiple neuromodulation and neuroimaging approaches

Introduction : Le trouble du jeu de hasard et d'argent (GD) est caractérisé par un comportement de jeu inadapté qui interfère avec les activités personnelles ou professionnelles. Ce trouble psychiatrique est difficile à traiter avec les thérapies actuelles et les rechutes sont fréquentes. Les symptômes dépressifs et cognitifs (e.g., l'impulsivité), ainsi que le "craving" (désir intense de jouer) sont des facteurs prédictifs de rechutes. Une meilleure compréhension des substrats neuronaux et leurs significations cliniques pourraient mener au développement de nouveaux traitements. La stimulation transcrânienne à courant direct (tDCS) pourrait être l'un de ceux-ci car elle permet de cibler des circuits neuronaux spécifiques. De plus, la tDCS ciblant le cortex dorsolatéral préfrontal (DLPFC) pourrait améliorer les symptômes dépressifs et cognitifs et réduire le craving. Cependant, les effets précis de la tDCS sur la fonction cérébrale, ainsi que leurs significations cliniques, demeurent à être élucidés. Par ailleurs, étant donné que les patients avec GD présentent souvent des différences morphométriques par rapport aux individus en santé, il est possible de faire l'hypothèse que la morphométrie cérébrale influence les effets de la tDCS. Objectifs : Ce travail avait trois objectifs principaux. Le premier objectif était d'explorer s'il y avait des associations entre les substrats neuronaux et les symptômes cliniques et cognitifs. Le deuxième objectif était d'examiner les effets de la tDCS sur la fonction cérébrale. Le troisième objectif était d'explorer si la morphométrie du site de stimulation (DLPFC) pouvait influencer les effets de la tDCS sur les substrats neuronaux. Méthode : Nous avons réalisé quatre études différentes. Dans la première étude, nous avons mesuré la morphométrie cérébrale en utilisant l'imagerie par résonance magnétique (IRM) structurelle. Nous avons mesuré les corrélations entre la morphométrie et les symptômes cliniques (dépression, sévérité et durée du GD) et cognitifs (impulsivité). De plus, nous avons comparé la morphométrie des patients à celui d'une base de données normative (individus en santé) en contrôlant pour plusieurs facteurs comme l'âge. Dans la deuxième étude, nous avons mesuré la fonction cérébrale (connectivité fonctionnelle) des patients avec l'IRM fonctionnelle. Nous avons examiné s'il y avait des liens entre la connectivité fonctionnelle et les symptômes cognitifs (impulsivité et prise de risque) et cliniques (sévérité et durée du GD). Dans la troisième étude, nous avons étudié les effets de la tDCS sur la connectivité fonctionnelle et si la morphométrie du DLPFC pouvait influencer ces effets. Dernièrement, dans la quatrième étude, nous avons examiné si la morphométrie du DLPFC pouvait influencer les effets de la tDCS sur la neurochimie (avec la spectroscopie par résonance magnétique). Résultats : Nous avons démontré deux corrélations positives entre la superficie du cortex occipital et les symptômes dépressifs (étude I). Nous avons également mis en évidence une corrélation positive entre la connectivité fonctionnelle d'un réseau occipital et l'impulsivité (étude II). De plus, il y avait une corrélation positive entre la connectivité fonctionnelle de ce réseau et la sévérité du GD. Par ailleurs, il y avait des corrélations positives entre la connectivité fonctionnelle de l'opercule frontal droit et la prise de risque (étude II). En outre, la connectivité fonctionnelle d'un réseau cérébelleux était corrélée avec les symptômes dépressifs (étude II). Les patients avaient aussi plusieurs différences morphométriques par rapport aux individus en santé (cortex occipital, préfrontal, etc.). Nous avons démontré également que la tDCS appliquée sur le DLPFC a augmenté la connectivité fonctionnelle d'un réseau fronto-pariétal (étude III). Finalement, cette thèse a montré que la morphométrie du DLPFC influence les augmentations induites par la tDCS sur la connectivité fonctionnelle du réseau fronto-pariétal (étude III) et le niveau de GABA frontal (étude IV). Conclusions : Cette thèse démontre une importance clinique potentielle pour les régions occipitales, frontales et cérébelleuses, particulièrement pour les patients ayant des symptômes dépressifs ou cognitifs. De plus, elle montre que la tDCS peut renforcer le fonctionnement d'un réseau fronto-pariétal connu pour son rôle dans les fonctions exécutives. Il reste à déterminer si un plus grand nombre de sessions pourrait apporter des bénéfices cliniques additionnels afin d'aider les patients à résister le jeu. Finalement, les résultats de cette thèse suggèrent que la morphométrie des régions sous les électrodes pourrait aider à identifier les meilleurs candidats pour la tDCS et pourrait être considéré pour la sélection des cibles de stimulation.Introduction: Gambling disorder (GD) is characterised by maladaptive gambling behaviour that interferes with personal or professional activities. This psychiatric disorder is difficult to treat with currently available treatments and relapse rates are high. Several factors can predict relapse, including depressive and cognitive (e.g., impulsivity, risk taking) symptoms, in addition to craving (strong desire to gamble). A better understanding of neural substrates and their clinical significance could help develop new treatments. Transcranial direct current stimulation (tDCS) might be one of these since it can target specific neural circuits. In addition, tDCS targeting the dorsolateral prefrontal cortex (DLPFC) could improve depressive and cognitive symptoms as well as reduce craving. However, the precise effects of tDCS on brain function, as well as their clinical significance, remain to be elucidated. Furthermore, considering that patients with GD often display morphometric differences as compared to healthy individuals, it may be worth investigating whether brain morphometry influences the effects of tDCS. Objectives: This work had three main objectives. The first objective was to explore whether there were associations between neural substrates and clinical and cognitive symptoms. The second objective was to examine the effects of tDCS on brain function. The third objective was to explore whether morphometry of the stimulation site (DLPFC) influenced the effects of tDCS on neural substrates. Methods: We carried out four different studies. In the first study, we investigated brain morphometry using structural magnetic resonance imaging (MRI). We tested for correlations between morphometry and clinical symptoms (depression, GD severity, GD duration) and cognitive symptoms (impulsivity). In addition, we compared the morphometry of patients with GD to that of a normative database (healthy individuals) while controlling for several factors such as age. In a second study, we assessed brain function (functional connectivity) in patients with functional MRI (fMRI). We examined whether there were associations between brain function and cognitive symptoms (impulsivity and risk taking) as well as clinical symptoms (GD severity and duration). In the third study, we examined tDCS-induced effects on brain function and whether morphometry of the DLPFC influenced these effects. Lastly, in the fourth study, we examined whether DLPFC morphometry influenced tDCS-induced effects on neurochemistry (using magnetic resonance spectroscopy imaging). Results: Firstly, we found two positive correlations between surface area of the occipital cortex and depressive symptoms (study I). We also showed a positive correlation between functional connectivity of an occipital network and impulsivity (study II). In addition, there was a positive correlation between functional connectivity of this network and GD severity (study II). In addition, there were positive correlations between functional connectivity of the right frontal operculum and risk-taking (study II). Also, functional connectivity of a cerebellar network was positively correlated with depressive symptoms (study II). Moreover, patients with GD had several morphometric differences as compared to healthy individuals (occipital and prefrontal cortices, etc.). Furthermore, we observed that tDCS over the DLPFC increased functional connectivity of a fronto-parietal circuit during stimulation (study III). Lastly, this thesis indicated that DLPFC morphometry influenced tDCS-induced elevations on fronto-parietal functional connectivity (study III) and frontal GABA levels (study IV). Conclusions: This thesis suggests the potential clinical relevance of occipital, frontal, and cerebellar regions, particularly for those with depressive and cognitive symptoms. It also indicates that tDCS can strengthen the functioning of a fronto-parietal network known to be implicated in executive functions. It remains to be seen whether a greater number of tDCS sessions could lead to clinical benefits to help patients resist gambling. Finally, the results of this thesis suggest that morphometry of the regions under the electrodes might help predict better candidates for tDCS and could be considered to select stimulation targets

Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson’s disease, essential tremor, Alzheimer’s disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year’s international Think Tank, with a view toward current and near future advancement of the field

Redefining noradrenergic neuromodulation of behavior : impacts of a modular locus coeruleus architecture

Peer reviewe

Proceedings of the Third Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies

The proceedings of the 3rd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, imaging, and computational work on DBS for the treatment of neurological and neuropsychiatric disease. Significant innovations of the past year are emphasized. The Think Tank\u27s contributors represent a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers, and members of industry. Presentations and discussions covered a broad range of topics, including policy and advocacy considerations for the future of DBS, connectomic approaches to DBS targeting, developments in electrophysiology and related strides toward responsive DBS systems, and recent developments in sensor and device technologies

Otsustusprotsesside mõjutamine transkraniaalse magnetstimulatsiooniga

Väitekirja elektrooniline versioon ei sisalda publikatsiooneInimese käitumist kontrollivates otsustusprotsessides on oluline roll dorsolateraalsel prefrontaalkorteksil (DLPFK) ning sellega juhteteede kaudu seotud eemalasuvatel ajupiirkondadel, kuid otsustusprotsesside täpsemate neurobioloogiliste mehhanismide kohta on veel vähe teada. Otsustusprotsesside põhjalik uurimine on oluline nii täidesaatvate funktsioonide ja sihipärase käitumise mõistmiseks kui ka erinevate neuropsühholoogiale tuginevate ravimeetodite väljaarendamiseks. Käesolev väitekiri keskendus mitte-veridikaalsete otsustusprotsesside uurimisele, kasutades selleks transkraniaalse magnetstimulatsiooni (TMS) meetodit. Otsustusprotsessidega seotud DLPFK piirkondi magnetimpulssidega mõjutades on võimalik tuvastada otsustamise neurobioloogilisi korrelaate ning uurida veridikaalseid ja mitte-veridikaalseid otsusi vastandava teoreetilise mudeli paikapidavust. Uuring I näitas, et mitte-veridikaalseid otsustusprotsesse on võimalik TMS-i abil selektiivselt mõjutada, kusjuures vasakpoolne DLPFK näib olevat rohkem spetsialiseerunud mitte-veridikaalsetele kognitiivsetele otsustele kui veridikaalsetele, samas kui parempoolne DLPFK osaleb mõlemat tüüpi otsustes. Tulemused ilmestasid ka seda, et TMS rakendamine avaldab korteksi piirkondadele nii lokaalset kui distaalset, TMS lookusest eemalasuvalt realiseeruvat mõju. Uurimuses II leidis kinnitust parempoolse DLPFK oluline roll impulsiivses ja riskantses käitumises: parempoolse DLPFK neurofüsioloogilise erutuvuse pärssimine madalsagedusliku TMS-iga tõi kaasa käitumise pidurduse vähenemise ning oluliselt riskeerivama käitumisstrateegia. Uuring III kinnitas BDNF geeni olulist mõju nii mitte-veridikaalsetele otsustusprotsessidele kui ka sellele, kuidas prefrontaalsete piirkondade mõjutamine TMS-iga mitte-veridikaalset endofenotüübi mõjuga seotud käitumist muudab. Väitekirja uurimustest järeldub, et TMS meetodil DLPFK piirkondi mõjutades on võimalik otsustusprotsesse mõjutada, kuid vallanduvad käitumuslikud muutused sõltuvad nii ülesande iseloomust, ülesandega seotud kognitiivsete mehhanismide lateralisatsioonist, kui ka inimese neurobioloogilisest endofenotüübist.Human decision-making is known to depend on the prefrontal cortex and distal areas interconnected to it, but its specific neurobiological mechanisms are still largely unknown. Expanding our knowledge of decision-making processes contributes to understanding the neuropsychological principles of executive function and goal directed behaviour, as well as to advancing the clinical application of neurostimulation in this domain. Within empirical studies included in the current dissertation, repeated transcranial magnetic stimulation (rTMS) was applied to the dorsolateral prefrontal cortex (DLPFC) in order to evaluate potential effects on performance across various decision-making tasks. By observing how non-invasive modulation of neural activity in underlying cortical areas affects non-veridical cognition related behavioural choices, the thesis addressed the functional role of the DLPFC in decision-making processes. Results of Study I demonstrated that non-veridical and veridical decision-making both rely on the right DLPFC, whereas the left DLPFC is more specifically committed to non-veridical cognition. Study I findings also emphasised non-focal, distal effects of TMS, when applied to particularly richly interconnected cortical regions such as the DLPFC. Study II revealed that TMS-induced inhibition of the right DLPFC activity affects non-veridical risky behaviour, suggesting that the right DLPFC plays a role in execution and monitoring of performance in risky tasks with a motor response. Study III revealed that non-veridical behaviour is influenced by genetic differences related to the BDNF gene and that TMS stimulation enhances pre-existing genetically determined biases in decision-making preferences. In conclusion, decision-making behaviour can be modulated by applying TMS to the DLPFC, but the resulting behavioural effects depend on the characteristics of the task, the lateralization of task-specific cognitive mechanisms, as well as the neurobiological endophenotypes involved.https://www.ester.ee/record=b522936