Concerning neuromodulation as treatment of neurological and neuropsychiatric disorder: Insights gained from selective targeting of the subthalamic nucleus, para-subthalamic nucleus and zona incerta in rodents.

Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including Parkinson's disease, dystonia, tremor, and obsessive-compulsive disorder (OCD) for which DBS is already applied to alleviate severely afflicted individuals of symptoms. Tourette syndrome and drug addiction are two additional disorders for which DBS is in trial or proposed as treatment. However, some major remaining obstacles prevent this intervention from reaching its full therapeutic potential. Side-effects have been reported, and not all DBS-treated individuals are relieved of their symptoms. One major target area for DBS electrodes is the subthalamic nucleus (STN) which plays important roles in motor, affective and associative functions, with impact on for example movement, motivation, impulsivity, compulsivity, as well as both reward and aversion. The multifunctionality of the STN is complex. Decoding the anatomical-functional organization of the STN could enhance strategic targeting in human patients. The STN is located in close proximity to zona incerta (ZI) and the para-subthalamic nucleus (pSTN). Together, the STN, pSTN and ZI form a highly heterogeneous and clinically important brain area. Rodent-based experimental studies, including opto- and chemogenetics as well as viral-genetic tract tracings, provide unique insight into complex neuronal circuitries and their impact on behavior with high spatial and temporal precision. This research field has advanced tremendously over the past few years. Here, we provide an inclusive review of current literature in the pre-clinical research fields centered around STN, pSTN and ZI in laboratory mice and rats; the three highly heterogeneous and enigmatic structures brought together in the context of relevance for treatment strategies. Specific emphasis is placed on methods of manipulation and behavioral impact.

A role for the subthalamic nucleus in aversive learning.

The subthalamic nucleus (STN) is critical for behavioral control; its dysregulation consequently correlated with neurological and neuropsychiatric disorders, including Parkinson's disease. Deep brain stimulation (DBS) targeting the STN successfully alleviates parkinsonian motor symptoms. However, low mood and depression are affective side effects. STN is adjoined with para-STN, associated with appetitive and aversive behavior. DBS aimed at STN might unintentionally modulate para-STN, causing aversion. Alternatively, the STN mediates aversion. To investigate causality between STN and aversion, affective behavior is addressed using optogenetics in mice. Selective promoters allow dissociation of STN (e.g., Pitx2) vs. para-STN (Tac1). Acute photostimulation results in aversion via both STN and para-STN. However, only STN stimulation-paired cues cause conditioned avoidance and only STN stimulation interrupts on-going sugar self-administration. Electrophysiological recordings identify post-synaptic responses in pallidal neurons, and selective photostimulation of STN terminals in the ventral pallidum replicates STN-induced aversion. Identifying STN as a source of aversive learning contributes neurobiological underpinnings to emotional affect.

CCD-based imaging and 3D space-time mapping of terahertz fields via Kerr frequency conversion.

We investigate the spatially and temporally resolved four-wave mixing of terahertz (THz) fields and optical pulses in large-bandgap dielectrics, such as diamond. We show that it is possible to perform beam profiling and space-time resolved mapping of THz fields by encoding the spatial information into an optical signal, which can then be recorded by a standard CCD camera.

Counterpropagating frequency mixing with terahertz waves in diamond.

Frequency conversion by means of Kerr nonlinearity is one of the most common and exploited nonlinear optical processes in the UV, visible, IR, and mid-IR spectral regions. Here we show that wave mixing of an optical field and a terahertz wave can be achieved in diamond, resulting in the frequency conversion of the terahertz radiation either by sum- or difference-frequency generation. In the latter case, we show that this process is phase matched and most efficient in a counterpropagating geometry.

Spatiotemporal amplitude and phase retrieval of space-time coupled ultrashort pulses using the Shackled-FROG technique.

We demonstrate the validity of the Shackled-frequency-resolved-optical-gating technique for the complete characterization, both in space and in time, of ultrashort optical pulses that present strong angular dispersion. Combining a simple imaging grating with a Hartmann-Shack sensor and standard frequency-resolved-optical-gating detection at a single spatial position, we are able to retrieve the full spatiotemporal structure of a tilted pulse.