A latent pool of neurons silenced by sensory-evoked inhibition can be recruited to enhance perception.

To investigate which activity patterns in sensory cortex are relevant for perceptual decision-making, we combined two-photon calcium imaging and targeted two-photon optogenetics to interrogate barrel cortex activity during perceptual discrimination. We trained mice to discriminate bilateral whisker deflections and report decisions by licking left or right. Two-photon calcium imaging revealed sparse coding of contralateral and ipsilateral whisker input in layer 2/3, with most neurons remaining silent during the task. Activating pyramidal neurons using two-photon holographic photostimulation evoked a perceptual bias that scaled with the number of neurons photostimulated. This effect was dominated by optogenetic activation of non-coding neurons, which did not show sensory or motor-related activity during task performance. Photostimulation also revealed potent recruitment of cortical inhibition during sensory processing, which strongly and preferentially suppressed non-coding neurons. Our results suggest that a pool of non-coding neurons, selectively suppressed by network inhibition during sensory processing, can be recruited to enhance perception.

The influence of cortical activity on perception depends on behavioral state and sensory context.

The mechanistic link between neural circuit activity and behavior remains unclear. While manipulating cortical activity can bias certain behaviors and elicit artificial percepts, some tasks can still be solved when cortex is silenced or removed. Here, mice were trained to perform a visual detection task during which we selectively targeted groups of visually responsive and co-tuned neurons in L2/3 of primary visual cortex (V1) for two-photon photostimulation. The influence of photostimulation was conditional on two key factors: the behavioral state of the animal and the contrast of the visual stimulus. The detection of low-contrast stimuli was enhanced by photostimulation, while the detection of high-contrast stimuli was suppressed, but crucially, only when mice were highly engaged in the task. When mice were less engaged, our manipulations of cortical activity had no effect on behavior. The behavioral changes were linked to specific changes in neuronal activity. The responses of non-photostimulated neurons in the local network were also conditional on two factors: their functional similarity to the photostimulated neurons and the contrast of the visual stimulus. Functionally similar neurons were increasingly suppressed by photostimulation with increasing visual stimulus contrast, correlating with the change in behavior. Our results show that the influence of cortical activity on perception is not fixed, but dynamically and contextually modulated by behavioral state, ongoing activity and the routing of information through specific circuits.

Step-stool conformation of a cyclic Schiff base derived from ethylenediamine and heptane-2,4,6-trione: evidence for partial hydrolysis in metal coordination.

A Schiff base derived from ethylenediamine and heptane-2,4,6-trione, namely, 5,9,14,18-tetramethyl-1,4,10,13-tetraazacyclooctadeca-5,8,14,17-tetraene-7,16-dione (C18H28N4O2), abbreviated H4daaden, was prepared and characterized for the first time by single-crystal X-ray diffraction. The atoms of the Schiff base occupy two different planes and thus the molecule is essentially nonplanar. An axis running through the C-C atoms of the ethylenediamine groups separate the two planes and these two planes are connected by bridging ethylene groups showing an angle of 117.34 (8)°. As a result, the side view of the molecule shows a `step-stool' conformation. The nonplanar nature of the Schiff base plays an important role in metal coordination, which leads to partial hydrolysis of the ring structure.

All-optical interrogation of neural circuits in behaving mice.

Recent advances combining two-photon calcium imaging and two-photon optogenetics with computer-generated holography now allow us to read and write the activity of large populations of neurons in vivo at cellular resolution and with high temporal resolution. Such 'all-optical' techniques enable experimenters to probe the effects of functionally defined neurons on neural circuit function and behavioral output with new levels of precision. This greatly increases flexibility, resolution, targeting specificity and throughput compared with alternative approaches based on electrophysiology and/or one-photon optogenetics and can interrogate larger and more densely labeled populations of neurons than current voltage imaging-based implementations. This protocol describes the experimental workflow for all-optical interrogation experiments in awake, behaving head-fixed mice. We describe modular procedures for the setup and calibration of an all-optical system (~3 h), the preparation of an indicator and opsin-expressing and task-performing animal (~3-6 weeks), the characterization of functional and photostimulation responses (~2 h per field of view) and the design and implementation of an all-optical experiment (achievable within the timescale of a normal behavioral experiment; ~3-5 h per field of view). We discuss optimizations for efficiently selecting and targeting neuronal ensembles for photostimulation sequences, as well as generating photostimulation response maps from the imaging data that can be used to examine the impact of photostimulation on the local circuit. We demonstrate the utility of this strategy in three brain areas by using different experimental setups. This approach can in principle be adapted to any brain area to probe functional connectivity in neural circuits and investigate the relationship between neural circuit activity and behavior.

Simultaneous all-optical manipulation and recording of neural circuit activity with cellular resolution in vivo.

We describe an all-optical strategy for simultaneously manipulating and recording the activity of multiple neurons with cellular resolution in vivo. We performed simultaneous two-photon optogenetic activation and calcium imaging by coexpression of a red-shifted opsin and a genetically encoded calcium indicator. A spatial light modulator allows tens of user-selected neurons to be targeted for spatiotemporally precise concurrent optogenetic activation, while simultaneous fast calcium imaging provides high-resolution network-wide readout of the manipulation with negligible optical cross-talk. Proof-of-principle experiments in mouse barrel cortex demonstrate interrogation of the same neuronal population during different behavioral states and targeting of neuronal ensembles based on their functional signature. This approach extends the optogenetic toolkit beyond the specificity obtained with genetic or viral approaches, enabling high-throughput, flexible and long-term optical interrogation of functionally defined neural circuits with single-cell and single-spike resolution in the mouse brain in vivo.

An interpersonal model of psychotherapy: linking patient and therapist developmental history, therapeutic process, and types of outcome.

This study empirically evaluated a 3-stage causal model based on interpersonal theory that relates patient and therapist early parental relations, the therapeutic alliance, and outcome. Data were from the Vanderbilt II database and encompassed 64 psychodynamic psychotherapies. Interpersonal variables were assessed using the Structural Analysis of Social Behavior. Initial support for the model was found, suggesting a direct effect of patient early parental relations on process and outcome, a direct effect of therapist early parental relations on process, and a direct effect of process on outcome--and thus indirect effects of both patient and therapist early parental relations on outcome mediated by the process. The psychotherapy process was assessed from 3 perspectives: patient and therapist self-report and reports by independent observers. Little convergence was found between the 3 perspectives.

Structural analysis of social behavior as a common metric for programmatic psychopathology and psychotherapy research.

This article describes the use of Structural Analysis of Social Behavior (SASB; L. Benjamin, 1974) as applied to programmatic psychodynamic-interpersonal psychotherapy research. SASB fosters cumulative, theory-driven research by permitting problem-treatment-outcome (PTO) congruence--the conceptualization and measurement of patients' problems, treatment processes, and outcome in a common metric. In this explanation of the principle of PTO congruence, the following are discussed: a general model of interpersonal psychopathology and etiology, SASB-based assessment devices for measuring early history and formulating presenting problems, empirical studies of interpersonal process in therapy, the relationship between manual-guided training and interpersonal process, and the assessment of outcome. A generic interpersonal model of psychotherapy is proposed that theoretically links all of these elements. Finally, the use of these SASB-based models for cross-theory integrative research from a common-factors approach is discussed.

Effects of training in time-limited dynamic psychotherapy: changes in therapist behavior.

Sixteen therapists participated in a year-long manualized training program as part of the Vanderbilt II study of time-limited dynamic psychotherapy. Changes in therapist behavior were measured with the Vanderbilt Therapeutic Strategies Scale (an adherence measure), the Vanderbilt Psychotherapy Process Scale (VPPS), and interpersonal process codings using the Structural Analysis of Social Behavior (SASB). The training program successfully changed therapists' technical interventions in line with the manualized protocol. After training, there was increased emphasis on the expression of in-session affect, exploration of the therapeutic relationship, an improved participant-observer stance, and greater use of open-ended questions. There was also an indication of unexpected deterioration in certain interpersonal and interactional aspects of therapy as measured by the VPPS and SASB ratings. These results question the assumption that greater control of the therapy variable is straightforwardly achieved with manuals and adherence scales. Changing or dictating specific therapist behaviors to achieve technical adherence may alter other therapeutic variables in unexpected and even counterproductive ways.

Effects of training in time-limited dynamic psychotherapy: mediators of therapists' responses to training.

Sixteen therapists were enrolled in a year-long manualized training program as part of the Vanderbilt II study of time-limited dynamic psychotherapy (TLDP). The training program successfully changed therapists' interventions in line with prescriptions of the TLDP manual, but some unanticipated changes ran counter to the intent of the training, including increased negative interpersonal transactions as indicated by process measures such as the Structural Analysis of Social Behavior (SASB). We examined therapist variables, patient variables, and training variables that appeared to mediate therapist responses to the training program. Results indicate that patient difficulty may mediate certain aspects of therapists' responses to training. Therapists with self-reported hostile and controlling introjects showed the greatest technical adherence, which was intriguing because prior research has linked hostile therapist introject to greater frequency of counter-therapeutic interpersonal process. Of special interest were differences in effects of training associated with individual training faculty. This finding, if generalizable, has important implications for manualized therapy research, especially multisite trials.

Patient and therapist introject, interpersonal process, and differential psychotherapy outcome.

The Structural Analysis of Social Behavior (SASB; Benjamin, 1974, 1982, 1984) system was used to study the interpersonal process between patient and therapist in the 3rd session of 14 therapeutic dyads. Dyads were grouped into good and poor outcomes cases (n = 7) on the basis of the amount of change in the patients' introject as measured by the INTREX Introject Questionnaire (Benjamin, 1983). Strong support was found for the following hypotheses based on interpersonal theory, linking therapists' introject state, interpersonal process in therapy, and outcome: (a) Poor outcome cases (no introject change) were typified by interpersonal behaviors by the therapist that confirmed a negative patient introject; (b) the number of therapists' statements that were subtly hostile and controlling was highly correlated with the number of self-blaming statements by the patients; (c) therapists with disaffiliative introjects tended to engage in a much higher level of problematic interpersonal processes that have been associated with poor outcome. Implications for future research and therapist training are discussed.

[Structural analysis of social behavior in training and research. A contribution to the "functional histology" of the psychotherapy process]. / Die strukturale Analyse sozialen Verhaltens (SASB) in Ausbildung und Forschung. Ein Beitrag zur "funktionellen Histologie" des psychotherapeutischen Prozesses.

To be able to identify qualitative differences in the results of psychotherapeutic activity and to establish a relationship between those results and the particularities of the treatment process involved, the problems of the patient, the relevant events during therapy, and therapeutic results must be interrelatable both terminologically and theoretically (P-T-O congruence; Strupp et al., 1989). If, therefore, the relevant qualities of the relationships involved in interpersonal transactions during the therapeutic process are to be represented adequately and independently of schools, an appropriate instrument is required for both clinical and research use. This instrument is introduced here in the form of the Structural Analysis of Social Behavior (SASB) after Lorna Smith Benjamin by means of the key question: Who acts how toward whom and how does the latter react to this?

An appraisal of selection criteria for dynamic psychotherapies and implications for setting time limits.

Practitioners of short-term dynamic psychotherapies commonly hold the working assumption that through rigorous selection procedures the progress to be expected in a specified length of time can be predicted. We question this assumption and draw upon relevant findings from the psychotherapy research literature, as well as from our own clinical and research experiences, to support our skepticism. Without minimizing the demonstrated effectiveness of short-term therapies, we propose that setting prearranged time limits be either replaced or supplemented by the implementation of a "time limited attitude." We further propose that this attitude can contribute to more efficiently conducted treatment, regardless of length. The concept of a time-limited attitude is defined, and the suggestion is made to arrange therapy in defined but flexible durations of treatment rather than by either setting initial termination dates or leaving the time open-ended. Finally, we suggest that the initially proposed length of treatment be determined by the clarity with which a treatment focus can be established. Clinical vignettes are provided to illustrate the relationship between clarity of focus and initially proposed length of treatment.