Deep TMS H1 Coil treatment for depression: Results from a large post marketing data analysis.

Phase IV study evaluated Deep TMS for major depression in community settings. Data were aggregated from 1753 patients at 21 sites, who received Deep TMS (high frequency or iTBS) using the H1 coil. Outcome measures varied across subjects and included clinician-based scales (HDRS-21) and self-assessment questionnaires (PHQ-9, BDI-II). 1351 patients were included in the analysis, 202 received iTBS. For participants with data from at least 1 scale, 30 sessions of Deep TMS led to 81.6% response and 65.3% remission rate. 20 sessions led to 73.6% response and 58.1% remission rate. iTBS led to 72.4% response and 69.2% remission. Remission rates were highest when assessed with HDRS (72%). In 84% of responders and 80% of remitters, response and remission was sustained in the subsequent assessment. Median number of sessions (days) for onset of sustained response was 16 (21 days) and for sustained remission 17 (23 days). Higher stimulation intensity was associated with superior clinical outcomes. This study shows that beyond its proven efficacy in RCTs, Deep TMS with the H1 coil is effective for treating depression under naturalistic conditions, and the onset of improvement is usually within 20 sessions. However, initial non-responders and non-remitters benefit from extended treatment.

Group II metabotropic glutamate receptors in anxiety circuitry: correspondence of physiological response and subcellular distribution.

Activation of group II metabotropic glutamate receptors (mGluR2/3) in the amygdala plays a critical role in the regulation of fear and anxiety states. Previous studies using nonselective agonists have suggested this action can result from activation of either pre- or postsynaptic mGluR2/3. Here, we have used a combination of whole-cell patch clamp recording with highly selective agonists (LY354740 and LY379268) and immunoelectron microscopy to examine structure-function relationships for mGluR2/3 in the basolateral amygdala (BLA) and bed nucleus of the stria terminalis (BNST). Stimulation of mGluR2/3 evoked a direct, TTX-insensitive membrane hyperpolarization in all BLA projection neurons tested, but only about half of BNST neurons. The membrane hyperpolarization was mediated by activation of an outward potassium current or blockade of a tonically active inward I(h) current in different groups of BLA neurons. In both regions, mGluR2/3 caused a long-lasting reduction of glutamate release from presynaptic afferent terminals even at concentrations that failed to elicit a direct postsynaptic response. The localization of mGluR2/3 differed regionally, with postsynaptic labeling significantly more common in BLA than BNST, corresponding to the strength of postsynaptic responses recorded there. Our results demonstrate a complex role for mGluR2/3 receptors in modulating anxiety circuitry, including direct inhibition and reduction of excitatory drive. The combination of direct inhibition of projection neurons within the BLA and suppression of excitatory neurotransmission in the BNST may be responsible for the anxiolytic actions of group II mGluR agonists.

Differential expression of intrinsic membrane currents in defined cell types of the anterolateral bed nucleus of the stria terminalis.

The anterolateral group of the bed nucleus of the stria terminalis (BNST(ALG)) plays a critical role in a diverse array of behaviors, although little is known of the physiological properties of neurons in this region. Using whole cell patch-clamp recordings from rat BNST(ALG) slices in vitro, we describe three distinct physiological cell types. Type I neurons were characterized by the presence of a depolarizing sag in response to hyperpolarizing current injection that resembled activation of the hyperpolarization-activated cation current I(h) and a regular firing pattern in response to depolarizing current injection. Type II neurons exhibited the same depolarizing sag in response to hyperpolarizing current injection, but burst-fired in response to depolarizing current injection, which was indicative of the activation of the low-threshold calcium current I(T). Type III neurons did not exhibit a depolarizing sag in response to hyperpolarizing current injection, but instead exhibited a fast time-independent rectification that became more pronounced with increased amplitude of hyperpolarizing current injection, and was indicative of activation of the inwardly rectifying potassium current I(K(IR)). Type III neurons also exhibited a regular firing pattern in response to depolarizing current. Using voltage-clamp analysis we further characterized the primary active currents that shaped the physiological properties of these distinct cell types, including I(h), I(T), I(K(IR)), the voltage-dependent potassium current I(A), and the persistent sodium current I(NaP). The functional relevance of each cell type is discussed in relation to prior anatomical studies, as well as how these currents may interact to modulate neuronal activity within the BNST(ALG).

Physiological and morphological characterization of parvalbumin-containing interneurons of the rat basolateral amygdala.

The basolateral amygdala (BLA) is critical for the generation of emotional behavior and the formation of emotional memory. Understanding the neuronal mechanisms that contribute to emotional information processing in the BLA will ultimately require knowledge of the anatomy and physiology of its constituent neurons. Two major cell classes exist in the BLA, pyramidal projection neurons and nonpyramidal interneurons. Although the properties of projection neurons have been studied in detail, little is known about the properties of BLA interneurons. We have used whole-cell patch clamp recording techniques to examine the physiological properties of 48 visually identified putative interneurons from the rat anterior basolateral amygdalar nucleus. Here, we report that BLA interneurons can be differentiated into four electrophysiologically distinct subtypes based on their intrinsic membrane properties and their response to afferent synaptic input. Interneuron subtypes were named according to their characteristic firing pattern generated in response to transient depolarizing current injection and were grouped as follows: 1) burst-firing interneurons (n = 13), 2) regular-firing interneurons (n = 11), 3) fast-firing interneurons (n = 10), and 4) stutter-firing interneurons (n = 14). Post hoc histochemical visualization confirmed that all 48 recorded neurons had morphological properties consistent with their being local circuit interneurons. Moreover, by using triple immunofluorescence (for biocytin, calcium-binding proteins, and neuropeptides) in conjunction with patch clamp recording, we further demonstrated that over 60% of burst-firing and stutter-firing interneurons also expressed the calcium-binding protein parvalbumin (PV(+)). These data demonstrate that interneurons of the BLA show both physiological and neurochemical diversity. Moreover, we demonstrate that the burst- and stutter-firing patterns positively correlate with PV(+) immunoreactivity, suggesting that these neurons may represent functionally distinct subpopulations.

Evidence for a perisomatic innervation of parvalbumin-containing interneurons by individual pyramidal cells in the basolateral amygdala.

The basolateral amygdala (ABL) contains pyramidal projection neurons (PNs) and several discrete subpopulations of nonpyramidal interneurons. Interneurons containing the calcium-binding protein parvalbumin (PV) constitute about half of all ABL interneurons, and provide a robust innervation of the perisomatic domain of PNs. Although it is known that PNs reciprocate this projection by innervating PV interneurons, little is known about the details of these connections. In the present study, we investigated the innervation of PV interneurons by individual PNs in rat amygdalar slices. PNs in the basolateral nucleus, identified in vitro by their distinctive electrophysiological characteristics in whole cell patch-clamp recordings, were filled with biocytin by diffusion from the patch electrode. PV interneurons and biocytin-labeled PNs were visualized with a two-color immunoperoxidase procedure using nickel-enhanced DAB (black) for biocytin and non-enhanced DAB (brown) for PV. In slices with well-stained PN axons and PV neurons, light microscopy revealed numerous synapse-like contacts between these structures. The main PV+ targets of PN axons were the somata and proximal dendrites of PV neurons, although there were also contacts with more distal PV dendrites. In many cases, the PN axons ran along PV somata and/or proximal dendrites, forming multiple contacts. However, the great majority the PN axon terminals did not contact PV neurons. These observations suggest that there are robust reciprocal perisomatic PN-to-PV connections that may be important for the precise timing of rhythmic activity in the basolateral amygdala.

Subtypes of substance P receptor immunoreactive interneurons in the rat basolateral amygdala.

Local injections of the neurotoxin SP-saporin into the basolateral amygdala (BLA) are reported to specifically lesion substance P receptor immunoreactive (SPR-IR) interneurons, and to reduce anxiety related behavior. Hence, this technique might provide a means to study how defined interneuron populations regulate neuronal activity in the BLA. However, what interneuron subgroups in the BLA might be targeted by SP-saporin lesions has not been established. This study has used dual-labeling immunofluorescence in the rat BLA to examine SPR-IR neurons for their colocalization with the calcium-binding proteins; calbindin-D28k (CB), parvalbumin (PV), and calretinin (CR); and the neuropeptides somatostatin (SOM) and neuropeptide Y (NPY). We found that all NPY-IR neurons and 45% of SOM-IR interneurons expressed SPR-IR, and that 50% and 51% of the SPR-IR interneuron population expressed NPY- and SOM-IR, respectively. Previous studies have reported that approximately a third of SOM-IR interneurons also express NPY, which suggests a large degree of overlap between the NPY, SOM and SPR expressing neurons in the BLA. We also found that the majority of SPR-IR cells were CB-IR (62%), but that these interneurons represented only 2.8% of the total CB-IR population. Moreover, SPR-IR interneurons did not express either PV-or CR- IR. Hence, SP-saporin lesions would ablate all interneurons in the BLA that contain NPY, but leave the majority of the CB-IR cells intact, and have no effect on the CR- and PV-IR populations. Consequently, these results support the use of SP-saporin lesions as a useful technique to study the role of NPY-IR interneurons in the BLA.