PsychotherapyPlus: augmentation of cognitive behavioral therapy (CBT) with prefrontal transcranial direct current stimulation (tDCS) in major depressive disorder-study design and methodology of a multicenter double-blind randomized placebo-controlled trial.

Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders worldwide. About 20-30% of patients do not respond to the standard psychopharmacological and/or psychotherapeutic interventions. Mounting evidence from neuroimaging studies in MDD patients reveal altered activation patterns in lateral prefrontal brain areas. Successful cognitive behavioral therapy (CBT) is associated with a recovery of these neural alterations. Moreover, it has been demonstrated that transcranial direct current stimulation (tDCS) is capable of influencing prefrontal cortex activity and cognitive functions such as working memory and emotion regulation. Thus, a clinical trial investigating the effects of an antidepressant intervention combining CBT with tDCS seems promising. The present study investigates the antidepressant efficacy of a combined CBT-tDCS intervention as compared to CBT with sham-tDCS or CBT alone. A total of 192 patients (age range 20-65 years) with MDD (Hamilton Depression Rating Scale Score ≥ 15, 21-item version) will be recruited at four study sites across Germany (Berlin, Munich, Tuebingen, and Freiburg) and randomly assigned to one of the following three treatment arms: (1) CBT + active tDCS; (2) CBT + sham-tDCS; and (3) CBT alone. All participants will attend a 6-week psychotherapeutic intervention comprising 12 sessions of CBT each lasting 100 min in a closed group setting. tDCS will be applied simultaneously with CBT. Active tDCS includes stimulation with an intensity of 2 mA for 30 min with the anode placed over F3 and the cathode over F4 according to the EEG 10-20 system, if assigned. The primary outcome measure is the change in Montgomery-Åsberg Depression Rating Scale scores from baseline to 6, 18, and 30 weeks after the first session. Participants also undergo pre- and post-treatment neuropsychological testing and functional magnetic resonance imaging (fMRI) to assess changes in prefrontal functioning and connectivity. The study investigates whether CBT can be augmented by non-invasive brain stimulation techniques such as tDCS in the treatment of MDD. It is designed as a proof-of-principle trial for the combined tDCS-CBT treatment, but also allows the investigation of the neurobiological underpinnings of the interaction between both interventions in MDD. Trial registration ClinicalTrials.gov Identifier NCT02633449.

Adatoms underneath single porphyrin molecules on Au(111).

The adsorption of porphyrin derivatives on a Au(111) surface was studied by scanning tunneling microscopy and spectroscopy at low temperatures in combination with density functional theory calculations. Different molecular appearances were found and could be assigned to the presence of single gold adatoms bonded by a coordination bond underneath the molecular monolayer, causing a characteristic change of the electronic structure of the molecules. Moreover, this interpretation could be confirmed by manipulation experiments of individual molecules on and off a single gold atom. This study provides a detailed understanding of the role of metal adatoms in surface-molecule bonding and anchoring and of the appearance of single molecules, and it should prove relevant for the imaging of related molecule-metal systems.

Molecules with multiple switching units on a Au(111) surface: self-organization and single-molecule manipulation.

Three different molecules, each containing two azobenzene switching units, were synthesized, successfully deposited onto a Au(111) surface by sublimation and studied by scanning tunneling microscopy at low temperatures. To investigate the influence of electronic coupling between the switching units as well as to the surface, the two azo moieties were connected either via π-conjugated para-phenylene or decoupling meta-phenylene bridges, and the number of tert-butyl groups was varied in the meta-phenylene-linked derivatives. Single molecules were found to be intact after deposition as identified by their characteristic appearance in STM images. Due to their mobility on the Au(111) surface at room temperature, the molecules spontaneously formed self-organized molecular arrangements that reflected their chemical structure. While lateral displacement of the molecules was accomplished by manipulation, trans-cis isomerization processes, typical for azobenzene switches, could not be induced.

Island formation and manipulation of prochiral azobenzene derivatives on Au(111).

Based on previous work with very similar azobenzene derivatives, this study of para-TBA (2,2',5,5'-tetra-tert-butylazobenzene) molecules aims to identify single intact molecules and investigate their adsorption behavior on a Au(111) surface. The molecules are found to be mobile on the surface at the deposition temperature, leading to highly ordered and enantiomerically pure molecular islands. Voltage pulses between the surface and the tip of a scanning tunneling microscope are used to change the chirality of the adsorbate molecules. On the Cu(111) surface instead, single molecules are found on the terraces, which points to a stronger molecule-substrate interaction.

Electronic decoupling approach to quantitative photoswitching in linear multiazobenzene architectures.

A strategy to optimize the photoswitching efficiency of rigid, linear multiazobenzene constructs is presented. It consists of introducing large dihedral angles between azobenzene moieties linked via aryl-aryl connections in their para positions. Four bisazobenzenes exhibiting different dihedral angles as well as three single azobenzene reference compounds have been synthesized, and their switching behavior has been studied as well as experimentally and theoretically analyzed. As the dihedral angle between the two azobenzene units increases and consequently the electronic conjugation decreases, the photochromic characteristics improve, finally leading to individual azobenzene switches operating independently in the case of the perpendicular ortho,ortho,ortho',ortho'-tetramethyl biphenyl linker. The electronic decoupling leads to efficient separation of the absorption spectra of the involved switching states and hence by choosing the appropriate irradiation wavelength, an almost quantitative E → Z photoisomerization up to 97% overall Z-content can be achieved. In addition, thermal Z → E isomerization processes become independent of each other with increasing decoupling. The electronic decoupling could furthermore be proven by electrochemistry. The experimental data are supported by theory, and calculations additionally provide mechanistic insight into the preferred pathway for the thermal Z,Z → Z,E → E,E isomerization via inversion on the inner N-atoms. Our decoupling approach outlined herein provides the basis for constructing rigid rod architectures composed of multiple azobenzene photochromes, which display practically quantitative photoswitching properties, a necessary prerequisite to achieve highly efficient transduction of light energy directly into motion.

Quantum chemical investigation of thermal cis-to-trans isomerization of azobenzene derivatives: substituent effects, solvent effects, and comparison to experimental data.

Quantum chemical calculations of various azobenzene (AB) derivatives have been carried out with the goal to describe the energetics and kinetics of their thermal cis --> trans isomerization. The effects of substituents, in particular their type, number, and positioning, on activation energies have been systematically studied with the ultimate goal to tailor the switching process. Trends observed for mono- and disubstituted species are discussed. A polarizable continuum model is used to study, in an approximate fashion, the cis --> trans isomerization of azobenzenes in solution. The nature of the transition state(s) and its dependence on substituents and the environment is discussed. In particular for push-pull azobenzenes, the reaction mechanism is found to change from inversion in nonpolar solvents to rotation in polar solvents. Concerning kinetics, calculations based on the Eyring transition state theory give usually reliable activation energies and enthalpies when compared to experimentally determined values. Also, trends in the resulting rate constants are correct. Other computed properties such as activation entropies and thus preexponential rate factors are in only moderate agreement with experiment.

Photoswitchable catalysts: correlating structure and conformational dynamics with reactivity by a combined experimental and computational approach.

Photocontrol of a piperidine's Brønsted basicity was achieved by incorporation of a bulky azobenzene group and could be translated into pronounced reactivity differences between ON- and OFF-states in general base catalysis. This enabled successful photomodulation of the catalyst's activity in the nitroaldol reaction (Henry reaction). A modular synthetic route to the photoswitchable catalysts was developed and allowed for preparation and characterization of three azobenzene-derived bases as well as one stilbene-derived base. Solid-state structures obtained by X-ray crystal structure analysis confirmed efficient blocking of the active site in the E isomer representing the OFF-states, whereas a freely accessible active site was revealed for a representative Z isomer in the crystal. To correlate structure with reactivity of the catalysts, conformational dynamics were thoroughly studied in solution by NMR spectroscopy, taking advantage of residual dipolar couplings (RDCs), in combination with comprehensive DFT computational investigations of conformations and proton affinities.

Spatial periodicity in molecular switching.

The ultimate miniaturization of future devices will require the use of functional molecules at the nanoscale and their integration into larger architectures. Switches represent a prototype of such functional molecules because they exhibit characteristic states of different physical/chemical properties, which can be addressed reversibly. Recently, various switching entities have been studied and switching of single molecules on surfaces has been demonstrated. However, for functional molecules to be used in a future device, it will be necessary to selectively address individual molecules, preferentially in an ordered pattern. Here, we show that azobenzene derivatives in the trans form, adsorbed in a homogeneous two-dimensional layer, can be collectively switched with spatial selectivity, thus forming a periodic pattern of cis isomers. We find that the probability of a molecule switching is not equally distributed, but is strongly dependent on both the surrounding molecules and the supporting surface, which precisely determine the switching capability of each individual molecule. Consequently, exactly the same lattices of cis isomers are created in repeated erasing and re-switching cycles. Our results demonstrate a conceptually new approach to spatially addressing single functional molecules.

Nano-architectures by covalent assembly of molecular building blocks.

The construction of electronic devices from single molecular building blocks, which possess certain functions such as switching or rectifying and are connected by atomic-scale wires on a supporting surface, is an essential goal of molecular electronics. A key challenge is the controlled assembly of molecules into desired architectures by strong, that is, covalent, intermolecular connections, enabling efficient electron transport between the molecules and providing high stability. However, no molecular networks on surfaces 'locked' by covalent interactions have been reported so far. Here, we show that such covalently bound molecular nanostructures can be formed on a gold surface upon thermal activation of porphyrin building blocks and their subsequent chemical reaction at predefined connection points. We demonstrate that the topology of these nanostructures can be precisely engineered by controlling the chemical structure of the building blocks. Our results represent a versatile route for future bottom-up construction of sophisticated electronic circuits and devices, based on individual functionalized molecules.

Electric field-induced isomerization of azobenzene by STM.

The electric field applied between the tip of a scanning tunneling microscope and a metallic surface is shown to induce the reversible trans-cis isomerization of single azobenzene derivatives adsorbed on a Au(111) surface. The investigated molecule is symmetrically equipped with four tert-butyl groups, which decouple the azobenzene core from the metallic surface, facilitating the formation of highly ordered islands. Due to the spatial extension of the electric field, it is possible to switch many molecules within the same island simultaneously.

On the illusive nature of o-formylazobenzenes: exploiting the nucleophilicity of the azo group for cyclization to indazole derivatives.

Facile rearrangement of azobenzenes is shown to occur in cases where the azo group is placed in the ortho position to carbonyl electrophiles to furnish the indazole skeleton. While this study demonstrates the illusive nature of o-formylazobenzenes, it offers potential for the synthesis of indazoles and related heterocycles.

Synthesis and characterization of azobenzene-confined porphyrins.

A versatile synthetic method has been developed to incorporate photochromic azobenzene moieties into tetraphenylporphyrin frameworks in an orthogonal fashion, positioning the phenylazo substituents above and below the plane of the macrocycle. Surprisingly, photoisomerization is completely suppressed in the resulting azobenzene-confined porphyrins.