Treating low back pain with combined cerebral and peripheral electrical stimulation: A randomized, double-blind, factorial clinical trial.

BACKGROUND: Recent evidence suggests that chronic low back pain is associated with plastic changes in the brain that can be modified by neuromodulation strategies. This study investigated the efficacy of transcranial direct current stimulation (tDCS) combined simultaneously with peripheral electrical stimulation (PES) for pain relief, disability and global perception in patients with chronic low back pain (CLBP). METHODS: Ninety-two patients with CLBP were randomized to receive 12 sessions on nonconsecutive days of anodal tDCS (primary motor cortex, M1), 100 Hz sensory PES (lumbar spine), tDCS + PES or sham tDCS + PES. Pain intensity (11-point numerical rating scale), disability and global perception were applied before treatment and four weeks, three months and six months post randomization. RESULTS: A two points reduction was achieved only by the tDCS + PES (mean reduction [MR] = -2.6, CI95% = -4.4 to -0.9) and PES alone (MR = -2.2, CI95% = -3.9 to -0.4) compared with the sham group, but not of tDCS alone (MR = -1.7, CI95% = -3.4 to -0.0). In addition to maintaining the analgesic effect for up to three months, tDCS + PES had a higher proportion of respondents in different cutoff points. Global perception was improved at four weeks and maintained three months after treatment only with tDCS + PES. None of the treatments improved disability and the affective aspect of pain consistently with pain reduction. CONCLUSION: The results suggest that tDCS + PES and PES alone are effective in relieving CLBP in the short term. However, only tDCS + PES induced a long-lasting analgesic effect. tDCS alone showed no clinical meaningful pain relief. SIGNIFICANCE: Transcranial direct current stimulation combined simultaneously with PES leads to a significant and clinical pain relief that can last up to three months in chronic low back pain patients. For this article, a commentary is available at the Wiley Online Library.

Organization of ventral tegmental area projections to the ventral tegmental area-nigral complex in the rat.

The ventral tegmental area (VTA) is a nodal link in reward circuitry. Based on its striatal output, it has been subdivided in a caudomedial part which targets the ventromedial striatum, and a lateral part which targets the ventrolateral striatum [Ikemoto S (2007) Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev 56:27-78]. Whether these two VTA parts are interconnected and to what extent the VTA innervates the substantia nigra compacta (SNc) and retrorubral nucleus (RR) are critical issues for understanding information processing in the basal ganglia. Here, VTA projections to the VTA-nigral complex were examined in rats, using Phaseolus vulgaris leucoagglutinin (PHA-L) as anterograde tracer. The results show that the dorsolateral VTA projects to itself, as well as to the dorsal tier of the SNc and RR, largely avoiding the caudomedial VTA. The ventrolateral VTA innervates mainly the interfascicular nucleus. The components of the caudomedial VTA (the interfascicular, paranigral and caudal linear nuclei) are connected with each other. In addition, the caudomedial VTA (especially the paranigral and caudal linear nuclei) innervates the lateral VTA, and, to a lesser degree, the SNc and RR. The caudal pole of the VTA sends robust, bilateral projections to virtually all the VTA-nigral complex, which terminate in the dorsal and ventral tiers. Modest inputs from the medial supramammillary nucleus to ventromedial parts of the VTA-nigral complex were also identified. In double-immunostained sections, PHA-L-labeled varicosities were sometimes found apposed to tyrosine hydroxylase-positive neurons in the ventral mesencephalon. Overall, the results underscore that VTA projections to the VTA-nigral complex are substantial and topically organized. In general, these projections, like the spiralated striato-nigro-striatal loops, display a medial-to-lateral organization. This anatomical arrangement conceivably permits the ventromedial striatum to influence the activity of the lateral striatum. The caudal pole of the VTA appears to be a critical site for a global recruitment of the mesotelencephalic system.

Efferent connections of the rostral linear nucleus of the ventral tegmental area in the rat.

The ventral tegmental area (VTA) is crucially involved in brain reward, motivated behaviors, and drug addiction. This district is functionally heterogeneous, and studying the connections of its different parts may contribute to clarify the structural basis of intra-VTA functional specializations. Here, the efferents of the rostral linear nucleus (RLi), a midline VTA component, were traced in rats with the Phaseolus vulgaris leucoagglutinin (PHA-L) technique. The results show that the RLi heavily innervates the olfactory tubercle (mainly the polymorph layer) and the ventrolateral part of the ventral pallidum, but largely avoids the accumbens. The RLi also sends substantial projections to the magnocellular preoptic nucleus, lateral hypothalamus, central division of the mediodorsal thalamic nucleus, lateral part of the lateral habenula and supraoculomotor region, and light projections to the prefrontal cortex, basolateral amygdala, and dorsal raphe nucleus. A similar set of projections was observed after injections in rostromedial VTA districts adjacent to RLi, but these districts also send major outputs to the lateral ventral striatum. Overall, the data suggest that the RLi is a distinct VTA component in that it projects primarily to pallidal regions of the olfactory tubercle and to their diencephalic targets, the central division of the mediodorsal thalamic nucleus and the lateral part of the lateral habenula. Because the rat RLi reportedly contains a lower density of dopaminergic neurons as compared with most of the VTA, its unusual projections may reflect a non-dopaminergic, putative GABAergic, phenotype, and this distinctive cell population seemingly extends beyond RLi boundaries into the laterally adjacent VTA. By being connected to the central division of the mediodorsal thalamic nucleus (directly and via ventral striatopallidal system) and to the magnocellular preoptic nucleus, the RLi and its surroundings may play a role in olfactory-guided behaviors, which are part of the approach responses associated with appetitive motivational states.