Reversing pathological neural activity using targeted plasticity

Abstract

Brain changes in response to nerve damage or cochlear trauma can generate pathological neural activity that is believed to be responsible for many types of chronic pain and tinnitus. Several studies have reported that the severity of chronic pain and tinnitus is correlated with the degree of map reorganization in somatosensory and auditory cortex, respectively. Direct electrical or transcranial magnetic stimulation of sensory cortex can temporarily disrupt these phantom sensations. However, there is as yet no direct evidence for a causal role of plasticity in the generation of pain or tinnitus. Here we report evidence that reversing the brain changes responsible can eliminate the perceptual impairment in an animal model of noise-induced tinnitus. Exposure to intense noise degrades the frequency tuning of auditory cortex neurons and increases cortical synchronization. Repeatedly pairing tones with brief pulses of vagus nerve stimulation completely eliminated the physiological and behavioural correlates of tinnitus in noise-exposed rats. These improvements persisted for weeks after the end of therapy. This method for restoring neural activity to normal may be applicable to a variety of neurological disorders.

Figure 1. VNS–tone pairing causes map plasticity

Repeatedly pairing VNS with a tone increases the number of A1 recordings sites tuned to the paired frequency. a, VNS was paired with a 9-kHz tone 6,000 times over 20 days in eight rats. b, VNS was paired with a 19-kHz tone in five rats. This group heard 4-kHz tones equally often but without VNS pairing. Asterisks indicate significant (P < 0.05) increases in the fraction of A1 sites with characteristic frequencies near the paired tone. Error bars, s.e.m. This result in normal-hearing rats suggested that VNS–tone pairing might be used to reverse the map distortions induced by exposure to intense noise.

Figure 2. VNS/multiple tone pairing eliminates the behavioural correlate of tinnitus

Four weeks after noise exposure, each of the rats in both groups was unable to detect a gap in one or more of the narrowband noises tested (P > 0.05; Supplementary Fig. 8b). The frequency with the greatest impairment four weeks after noise exposure is the putative tinnitus frequency for each rat. For both groups, gap detection at the putative tinnitus frequency was significantly impaired in comparison to broadband noise (P < 0.05). The gap detection at the non-tinnitus frequency is based on gap detection in 16-kHz narrowband noise. a, Gap detection at the putative tinnitus frequency (dotted line) improved significantly after ten days of VNS–tone pairing, and the improvement persisted at least until the acute physiology experiment (n = 5 rats). b, The sham group (n = 9 rats) continued to be impaired. Two sham rats did not contribute data at the non-tinnitus frequency because they showed gap impairments at 16 kHz (as well as 8 and 10 kHz) four weeks after noise exposure. Black and grey horizontal bars represent duration of VNS and sham therapy, respectively. Asterisks represent significant differences (P < 0.05) in gap detection at the putative tinnitus frequency between VNS therapy and sham therapy rats. Error bars, s.e.m.

Figure 3. VNS/multiple tone pairing reverses map distortion

The increased response of A1 neurons to tones following noise exposure is reversed by VNS/multiple tone pairing. a, Colour indicates the percentage of A1 neurons in naive rats that respond to a tone of any frequency and intensity combination. b, Percentage of A1 neurons that respond to each tone in noise-exposed rats that received sham therapy. c, Percentage of A1 neurons that respond to each tone in noise-exposed rats that received the VNS/multiple tone therapy. Black contour linesindicate 20, 40, and 60% responses. The white linesin b surround theregions of tones that are significantly increased (P < 0.01) in comparison with naive rats. The white lines in c indicate significant decreases (P < 0.01) in comparison with noise-exposed sham therapy rats. The filled white circles indicate the tone for which the increase in the number of cortical neurons was greatest, which is used to quantify the degree of map distortion in Fig. 4a, b. The filled black circles indicate the tone for which the proportional increase was greatest.

Figure 4. Neurophysiological properties of naive, sham and therapy rats

a, c, e, g, i, Noise exposure caused a significant map distortion (a), decreased frequency selectivity (c), increased the tone-evoked response (e), increased the spontaneous rate (g) and increased the degree of cortical synchronization (i). VNS/multiple tone pairing returned each of these parameters, except spontaneous activity, to normal levels. b,d,f, Map organization (b), frequency selectivity (d) and tone-evoked response strength (f) were all correlated with the degree of gap impairment in individual rats. h, j, Spontaneous activity (h) and synchronization (j) were not significantly correlated with gap impairment. Each rat's gap detection ability was quantified as the average gap detection at the putative tinnitus frequency of each rat, averaged across the four time points collected after the beginning of therapy (Fig. 2). Error bars, s.e.m. Asterisks represent significant differences compared with naive rats (P values as indicated). Triangles and circles represent rats from the sham and therapy groups, respectively.