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You can click on 00:01:47.439 --> 00:01:51.540 the link in the show notes. The future of technology 00:01:51.540 --> 00:01:54.859 is already here with Daylight Computer Company. 00:01:56.319 --> 00:02:00.379 For today's episode, we will talk all about Audition. 00:02:01.140 --> 00:02:04.140 This will be an episode about autism and the 00:02:04.140 --> 00:02:09.659 auditory processes. We should begin in 1961 from 00:02:09.659 --> 00:02:14.539 Von Bekesee, who's a Nobel winner prize in Physiology 00:02:14.539 --> 00:02:19.780 or Medicine, and he was a biophysicist. In the 00:02:19.780 --> 00:02:24.159 spiral cochlea, it's a fluid -filled tunnel about 00:02:24.159 --> 00:02:27.819 the width of pencil lead, and sound is not simply 00:02:28.120 --> 00:02:31.860 just vibrate the entire structure uniformly. 00:02:32.919 --> 00:02:36.360 Instead it generates a traveling wave along the 00:02:36.360 --> 00:02:40.580 basilar membrane which is a 35 millimeter ribbon 00:02:40.580 --> 00:02:44.699 type that varies in stiffness from its base to 00:02:44.699 --> 00:02:50.060 its apex. High frequency sounds such as a whistle 00:02:50.060 --> 00:02:54.120 at 8 ,000 hertz cause the waves to peak near 00:02:54.120 --> 00:02:58.000 the stiff narrow base within 0 .3 milliseconds 00:02:58.000 --> 00:03:02.860 of entering this oval window. Low frequency sounds 00:03:02.860 --> 00:03:08.620 like the deep bass drum at 100 hertz. Travel 00:03:08.620 --> 00:03:12.139 the length to the peak at the floppy and the 00:03:12.139 --> 00:03:17.139 wide apex near the helicotrema. I know, lots 00:03:17.139 --> 00:03:20.360 of dense and strange words here, but we're going 00:03:20.360 --> 00:03:24.860 to make it. This mechanical frequency The separation 00:03:24.860 --> 00:03:29.759 is a tonotopy. Motion is the first act of the 00:03:29.759 --> 00:03:34.479 auditory coding. At the wave's peak, thousands 00:03:34.479 --> 00:03:41.219 of little hair cells bend in unison, while outer 00:03:41.219 --> 00:03:46.699 hair cells powered by electromotility amplify 00:03:46.699 --> 00:03:51.259 the motion by up to one thousand fold. While 00:03:51.259 --> 00:03:55.699 the inner hair cells transduce it into neural 00:03:55.699 --> 00:04:00.539 signals via glutamate, which remember is excitation, 00:04:01.419 --> 00:04:05.599 at a ribbon synapsis onto type 1 spiral ganglion 00:04:05.599 --> 00:04:09.099 neurons. This is a lot, but we're going to parse 00:04:09.099 --> 00:04:11.539 this out into different kind of sections and 00:04:11.539 --> 00:04:15.120 understanding. This process occurs within one 00:04:15.120 --> 00:04:20.240 millisecond of sound onset. The stria vascular, 00:04:20.860 --> 00:04:24.019 a three layered Epithelial structure lining the 00:04:24.019 --> 00:04:28.300 lateral wall is the underrated process, unknown 00:04:28.300 --> 00:04:33.300 process of hearing. This biological battery generates 00:04:33.300 --> 00:04:37.579 the plus 80 millivolt endocochlear potential. 00:04:38.420 --> 00:04:43.699 This is the highest DC voltage in the entire 00:04:43.699 --> 00:04:48.100 human body. This potential is not just a passive 00:04:48.100 --> 00:04:52.639 by -product but an actively maintained electrochemical 00:04:52.639 --> 00:04:57.000 gradient essential for auditory sensitivity. 00:04:58.740 --> 00:05:03.720 The endo -limp that bays in the hair cells contains 00:05:03.720 --> 00:05:09.680 150 millimolar potassium ions and sits at plus 00:05:09.680 --> 00:05:15.120 80 millivolts while the pero -limp has only 5 00:05:15.120 --> 00:05:19.519 millimolar of potassium ion and is only plus 00:05:19.519 --> 00:05:24.959 5 millivolts. Big contrast there. The hair cell 00:05:24.959 --> 00:05:29.379 interior rests at negative 70 millivolts and 00:05:29.379 --> 00:05:33.160 thus a total driving force across the gradient 00:05:33.160 --> 00:05:38.120 is plus 150 millivolts and this enables the potassium 00:05:38.120 --> 00:05:42.040 ion to rush through mechanically gated channels 00:05:42.040 --> 00:05:46.839 with explosive speed upon deflection. This ion 00:05:46.839 --> 00:05:51.389 influx depolarizes the inner hair cells and triggers 00:05:51.389 --> 00:05:55.470 a calcium -dependent glutamate. Remember excitation 00:05:55.470 --> 00:06:00.670 release at this so -called ribbon synapsis. There's 00:06:00.670 --> 00:06:04.550 lots of melanin here. The stria's marginal cells 00:06:04.550 --> 00:06:08.610 secrete the potassium ions in specific channels 00:06:08.610 --> 00:06:11.970 and the intermediate cells. These so -called 00:06:11.970 --> 00:06:14.730 melanocytes that we're going to get into buffer 00:06:14.730 --> 00:06:19.910 ions and provide antioxidant protection and transduction. 00:06:20.750 --> 00:06:24.709 And the basal cells pump out this potassium ion 00:06:24.709 --> 00:06:29.889 in a sodium potassium chloride co -transporter. 00:06:30.689 --> 00:06:34.149 Remember the episode with Dr. Ezekiel Ben -Ari. 00:06:34.569 --> 00:06:37.910 He's talked about these so -called pumps in quite 00:06:37.910 --> 00:06:41.149 detail with the excitation and inhibition cells. 00:06:41.709 --> 00:06:43.370 This is what we're going to talk about a lot 00:06:43.370 --> 00:06:46.649 because once again, the autistic phenotype is 00:06:46.649 --> 00:06:51.490 loaded with this excitation and inhibition. mismatch, 00:06:51.790 --> 00:06:55.769 this imbalance. There's lots of melanin here 00:06:55.769 --> 00:07:00.850 in the stria vascularis. See, Jack Cruz on this, 00:07:00.870 --> 00:07:03.370 he really highlights this better than anybody, 00:07:03.610 --> 00:07:07.709 I think, with melanin's role in auditory processes. 00:07:08.730 --> 00:07:11.490 This is a bioelectrical gradient that powers 00:07:11.490 --> 00:07:15.610 hearing transduction, a place of semi -conduction 00:07:15.610 --> 00:07:19.850 with little blood brain barrier. So that means 00:07:20.110 --> 00:07:24.430 There's lots of water here. See Decentralized 00:07:24.430 --> 00:07:29.009 Medicine 36 from Cruise's Patreon. Cruise's Patreon 00:07:29.009 --> 00:07:31.910 is probably the best $5 you can spend per month. 00:07:33.189 --> 00:07:36.250 Water is the key player here. It's a silent medium. 00:07:36.949 --> 00:07:43.290 Endo Lymph is 99 % H2O. This serves as both a 00:07:43.290 --> 00:07:47.470 solvent for the ion transport and hydraulic medium 00:07:47.470 --> 00:07:52.019 for the traveling wave. Without this water -based 00:07:52.019 --> 00:07:57.860 potassium ion, melanocyte stabilized 80 plus 00:07:57.860 --> 00:08:01.500 millivolts of bioelectrical gradient. There is 00:08:01.500 --> 00:08:06.420 no cochlear amplifier. There is no sound or wave 00:08:06.420 --> 00:08:09.839 transduction. There's no movement. There's no 00:08:09.839 --> 00:08:15.740 hearing, only silence. From the cochlea, the 00:08:15.740 --> 00:08:19.199 signal races up to the eighth cranial nerve. 00:08:19.610 --> 00:08:25.529 as glutamate driven action potentials by only 00:08:25.529 --> 00:08:31.189 1 .6 milliseconds. The distal eighth nerve generates 00:08:31.189 --> 00:08:36.250 auditory brainstem response wave one. We have 00:08:36.250 --> 00:08:39.889 a little whiteboard series on auditory brainstem 00:08:39.889 --> 00:08:44.110 responses. Remember wave one is the first wave 00:08:44.110 --> 00:08:51.460 and this is recorded via EEGs on the scalp. by 00:08:51.460 --> 00:08:56.220 2 .7 milliseconds, the proximal nerve fires wave 00:08:56.220 --> 00:09:00.639 two. And the first central synapse occurs in 00:09:00.639 --> 00:09:04.580 the cochlear nucleus, where bushy cells in the 00:09:04.580 --> 00:09:08.019 ventral division, the ventral cochlear nucleus, 00:09:08.559 --> 00:09:11.799 we mentioned this in the video, receive N bulb 00:09:11.799 --> 00:09:17.379 of held inputs and phase lock them to sound cycles 00:09:17.379 --> 00:09:21.480 below three kilohertz. And this is preserving 00:09:21.480 --> 00:09:26.379 time differences. Meanwhile, during this process, 00:09:26.940 --> 00:09:30.000 destilete cells. Remember the star -shaped shells 00:09:30.000 --> 00:09:33.419 we talked about in many columns? They're only 00:09:33.419 --> 00:09:36.000 in layer four of the many columns. These are 00:09:36.000 --> 00:09:40.620 cells that are shaped like stars. These release 00:09:40.620 --> 00:09:45.639 GABA to create sideband inhibition and sharpen 00:09:45.639 --> 00:09:51.620 the frequency tuning in the dorsal cochlear nucleus. 00:09:52.259 --> 00:09:57.379 Fuciform cells integrate spectral cues while 00:09:57.379 --> 00:10:01.279 cartwheel cells use GABA to suppress the echoes. 00:10:01.779 --> 00:10:06.740 GABA is inhibition. So, we need this to suppress 00:10:06.740 --> 00:10:10.860 echoes and this is the excitation inhibition 00:10:10.860 --> 00:10:15.720 balance. This is where EI comes into play most 00:10:15.720 --> 00:10:21.580 notably. Glutamate drives forward GABA carves 00:10:21.580 --> 00:10:26.100 clarity. Remember, the living organism, the human, 00:10:26.440 --> 00:10:31.600 our default is go. So the waves coming into the 00:10:31.600 --> 00:10:36.480 ear are wanting to go. It's the GABA that is 00:10:36.480 --> 00:10:40.799 used here to kind of channel them and help filter 00:10:40.799 --> 00:10:47.179 out any unwanted, unnecessary sounds. At the 00:10:47.179 --> 00:10:51.519 superior olivary complex, and this is the first 00:10:51.519 --> 00:10:55.940 brainstem station for this binaural processing, 00:10:56.360 --> 00:11:01.320 this binaural hearing. The medial superior olive 00:11:01.320 --> 00:11:06.860 uses glutamate to detect from both ears to code 00:11:06.860 --> 00:11:11.639 the time differences with microsecond precision, 00:11:11.639 --> 00:11:16.779 while the lateral superior olive compares level 00:11:16.779 --> 00:11:23.669 differences. via ipsilateral glutamate excitation, 00:11:24.149 --> 00:11:29.769 which means only one side and contralateral glycine 00:11:29.769 --> 00:11:34.289 plus GABA inhibition from the medial nucleus 00:11:34.289 --> 00:11:39.870 of the trapezoid body, sometimes called MNTB. 00:11:41.750 --> 00:11:44.389 So glycine is something we haven't discussed 00:11:44.389 --> 00:11:50.169 that much of or any. but this is acting as also 00:11:50.169 --> 00:11:54.110 extra inhibition. Glycine is sometimes inhibition. 00:11:56.490 --> 00:12:00.389 The calyx of held, which is the largest synapses 00:12:00.389 --> 00:12:04.009 in the brain, ensure sub -millisecond timing. 00:12:04.830 --> 00:12:09.669 And this is all happening before 3 .8 milliseconds. 00:12:10.230 --> 00:12:13.789 At 3 .8 milliseconds, the auditory brainstem 00:12:13.789 --> 00:12:19.759 response weight three. reflects this superior 00:12:19.759 --> 00:12:27.279 olive complex activity. And then the medial nucleus 00:12:27.279 --> 00:12:31.519 of the trapezoid body to the lateral superior 00:12:31.519 --> 00:12:35.500 olive pathway will co -release glycine, which 00:12:35.500 --> 00:12:39.159 is fast acting, and GABA, which is more slower 00:12:39.159 --> 00:12:44.120 acting, to shape and balance the excitatory and 00:12:44.120 --> 00:12:48.070 inhibitory profile. which is critical for sound, 00:12:48.090 --> 00:12:54.870 localization, and noise. When you speak, the 00:12:54.870 --> 00:12:59.509 brain activates the medial olivocochlear reflex 00:12:59.509 --> 00:13:04.690 via a corollary discharge from vocal motor areas. 00:13:05.250 --> 00:13:08.669 Corollary discharge is something in sensations, 00:13:09.570 --> 00:13:12.549 sensory neurons, sensory processes that is providing 00:13:12.549 --> 00:13:16.309 some prediction. so your sensory organs can predict 00:13:16.309 --> 00:13:19.590 kind of what happens next. They can be on alert 00:13:19.590 --> 00:13:23.009 and be prepared. This is big with the superior 00:13:23.009 --> 00:13:25.710 colliculus to the frontal eye fields as well 00:13:25.710 --> 00:13:33.769 for vision. The medial olivocochlear efferents 00:13:33.769 --> 00:13:37.090 release acetylcholine and this is very fast acting. 00:13:37.950 --> 00:13:45.080 Angaba for more sustained inhibition. This is 00:13:45.080 --> 00:13:49.039 hyperpolarizing them and reduces cochlear gain 00:13:49.039 --> 00:13:54.399 by 10 to 20 decibels. This prevents self -defining 00:13:54.399 --> 00:14:00.759 and allows you to hear others. The lateral olivocochlear 00:14:00.759 --> 00:14:05.080 system will activate during listening and use 00:14:05.080 --> 00:14:10.019 GABA to inhibit various dendrites and unmask 00:14:10.019 --> 00:14:15.529 speech transients in background noise. This efferent 00:14:15.529 --> 00:14:17.990 feedback is the first line of defense against 00:14:17.990 --> 00:14:21.769 listening dissonance. We'll parse out listening 00:14:21.769 --> 00:14:27.289 dissonance in a little bit. Upwards to the midbrain, 00:14:27.450 --> 00:14:32.049 the inferior colliculus. The auditory hub. Remember 00:14:32.049 --> 00:14:35.789 inferior colliculus is to auditory as superior 00:14:35.789 --> 00:14:38.690 colliculus is to vision. These are relay stations. 00:14:39.529 --> 00:14:44.049 The inferior colliculus receives 95 % of ascending 00:14:44.049 --> 00:14:49.730 fibers. In humans, one inferior colliculus contains 00:14:49.730 --> 00:14:55.309 approximately 13 .5 million cells, and 40 % of 00:14:55.309 --> 00:14:59.389 these are disc -shaped excitatory neurons. 9 00:14:59.389 --> 00:15:03.090 % of these are cellette cells, the star shapes, 00:15:03.590 --> 00:15:09.340 and 18 % are gabaergic. Out of the 18 % GABAergic, 00:15:09.919 --> 00:15:14.159 a majority of those are parvalbium interneurons. 00:15:14.500 --> 00:15:19.000 And then about half of many are somatostatin 00:15:19.000 --> 00:15:24.679 interneurons, and only roughly 2 % of those are 00:15:24.679 --> 00:15:31.659 vaso -intestinal peptide, the VIP. And then the 00:15:31.659 --> 00:15:34.480 inferior colliculus also has about 30 % glia 00:15:34.480 --> 00:15:42.200 cells. By 5 .6 milliseconds, the ABR, auditory 00:15:42.200 --> 00:15:46.480 brain stem response wave 5, marks the first inferior 00:15:46.480 --> 00:15:50.059 colliculus spike and is specifically from the 00:15:50.059 --> 00:15:55.139 central nucleus of the inferior colliculus. Glutamate 00:15:55.139 --> 00:15:58.960 from the lateral laminscus activate the noise 00:15:58.960 --> 00:16:03.480 while GABAergic from local interneurons creates 00:16:03.480 --> 00:16:09.019 duration tuning. Sideband suppression, so background 00:16:09.019 --> 00:16:14.639 noise and this EI response. High gamma oscillations 00:16:14.639 --> 00:16:19.340 of 70 to approximately 150 Hertz emerge here. 00:16:20.100 --> 00:16:24.460 So typically in sensory processing, gamma is 00:16:24.460 --> 00:16:27.879 risky and a lot of autistic phenotypes live in 00:16:27.879 --> 00:16:33.559 gamma. But in hearing, gamma is required because 00:16:33.559 --> 00:16:37.970 high gamma oscillations reflect local computation. 00:16:38.929 --> 00:16:41.190 So we're in the midbrain. Remember the inferior 00:16:41.190 --> 00:16:44.570 colliculus. Okay, the relay station for auditory. 00:16:45.029 --> 00:16:48.809 Remember the midbrain, the inferior colliculus, 00:16:48.850 --> 00:16:51.750 and the superior colliculus for vision. They 00:16:51.750 --> 00:16:54.330 are spatially relationship here. They can just 00:16:54.330 --> 00:16:58.309 reach out and high five the thalamus. The medial 00:16:58.309 --> 00:17:02.690 geniculate body of the thalamus receives the 00:17:02.690 --> 00:17:05.910 auditory. This is the relay station for the thalamus. 00:17:06.769 --> 00:17:09.589 Okay. So from the inferior culliculus to the 00:17:09.589 --> 00:17:13.750 medial geniculate nucleus, we're looking at now 00:17:13.750 --> 00:17:17.369 we're at six to upwards to nine milliseconds. 00:17:18.589 --> 00:17:23.269 Myelinated axons of the inferior culliculus carry 00:17:23.269 --> 00:17:28.630 glutamate signals up. Remember just to high five 00:17:28.630 --> 00:17:32.259 each other. The fusion tensor imaging Remember 00:17:32.259 --> 00:17:34.799 we've we've talked about this with sensory processing 00:17:34.799 --> 00:17:37.720 measurements and distal connection measurements. 00:17:38.380 --> 00:17:43.440 Diffusion is just nerd speak for movement. DTIs 00:17:43.440 --> 00:17:48.359 use a fractional antitrophy or FA and this measures 00:17:48.359 --> 00:17:54.720 0 .55 to 0 .65 in neurotypicals but a decrease 00:17:54.720 --> 00:17:59.140 in the autistic phenotype due to reduced myelination. 00:18:00.619 --> 00:18:05.660 The ventral division of the medial geniculate. 00:18:07.599 --> 00:18:12.579 Remember, ventral is bottom or floor, basement 00:18:12.579 --> 00:18:17.440 type of thing. So it makes sense that inputs 00:18:17.440 --> 00:18:20.140 are going to come in here because the inferior 00:18:20.140 --> 00:18:24.359 colliculus is just below. So inputs are coming 00:18:24.359 --> 00:18:29.029 in and multisensory kind of begins. The thalamic 00:18:29.029 --> 00:18:32.450 reticular nucleus uses the GABAergic to sculpt 00:18:32.450 --> 00:18:38.250 out the thalamic output. Measurement instruments 00:18:38.250 --> 00:18:42.049 here reveal huge things about the autistic phenotype. 00:18:43.710 --> 00:18:48.089 Auditory brainstem response can use EEGs and 00:18:48.089 --> 00:18:51.410 it shows the wave 5 delay in the autistic phenotype. 00:18:52.410 --> 00:18:59.069 MEGs captures reduced 40 Hz gamma. Remember in 00:18:59.069 --> 00:19:02.190 auditory you want gamma to be higher so you can 00:19:02.190 --> 00:19:05.210 help filter out because everything is so fast 00:19:05.210 --> 00:19:10.670 acting. You need a lot of power here. EEG tracks 00:19:10.670 --> 00:19:16.150 increased alpha effort. Event related potentials 00:19:16.150 --> 00:19:22.490 show an increase in N400 mismatch. Remember N400 00:19:22.490 --> 00:19:26.769 means roughly at 400 milliseconds, so we're much 00:19:26.769 --> 00:19:30.609 downstream from here, but these measuring instruments 00:19:30.609 --> 00:19:33.829 are just kind of highlighting distal connections, 00:19:34.309 --> 00:19:39.390 the overall complete auditory processing. FMRI 00:19:39.390 --> 00:19:43.069 maps the medial prefrontal cortex hyperactivity 00:19:43.069 --> 00:19:48.130 and the diffusion tensor imaging that FA reveals 00:19:48.130 --> 00:19:52.539 a reduced white matter integrity. the inferior 00:19:52.539 --> 00:19:56.599 colliculus to the medial geniculate nucleus so 00:19:56.599 --> 00:20:00.700 that's very close but there's already a reduced 00:20:00.700 --> 00:20:06.400 white matter track right there. So in the neurotypicals 00:20:06.400 --> 00:20:10.579 these systems are harmonized and glutamate drives 00:20:10.579 --> 00:20:15.039 that while GABA the inhibition sculpts out powers 00:20:15.039 --> 00:20:19.890 and unwanted noise. The auditory sector of the 00:20:19.890 --> 00:20:23.210 thalamic reticular nucleus, which is a thin GABAergic 00:20:23.210 --> 00:20:27.829 shell around the medial geniculate body, gets 00:20:27.829 --> 00:20:32.250 thalamic output and suppressing irrelevant frequencies. 00:20:32.950 --> 00:20:36.329 Remember the shell that is the thalamic reticular 00:20:36.329 --> 00:20:40.849 nucleus. This is all inhibition and has crucial 00:20:40.849 --> 00:20:44.130 roles for sensory gating and modulating signal 00:20:44.130 --> 00:20:48.250 to noise control. The TRN here is suppressing 00:20:48.250 --> 00:20:51.309 irrelevant or steady background sounds while 00:20:51.309 --> 00:20:56.670 amplifying sudden or attended sounds. Noises 00:20:56.670 --> 00:20:58.549 that you want to hear that you're sending your 00:20:58.549 --> 00:21:01.890 attention to. This is kind of assisting you with 00:21:01.890 --> 00:21:04.990 that. And this helps with selective attention 00:21:04.990 --> 00:21:09.329 as well. In auditory, the thalamic reticular 00:21:09.329 --> 00:21:12.190 nucleus is like noise -cancelling headphones. 00:21:13.069 --> 00:21:17.279 For all of the wild and uncontrollable background 00:21:17.279 --> 00:21:22.940 noise. From here, there's a kind of a system 00:21:22.940 --> 00:21:26.500 highlighted throughout various brainstem regions 00:21:26.500 --> 00:21:30.200 called the reticular activating system. And this 00:21:30.200 --> 00:21:33.799 spans the brainstem and the membrane, which modulates 00:21:33.799 --> 00:21:38.559 arousal and attention to the sound in hearing 00:21:38.559 --> 00:21:42.559 norepinephrine and cholinergic inputs from the 00:21:42.559 --> 00:21:47.519 locus aurelius and areas of the brainstem enhance 00:21:47.519 --> 00:21:51.980 inferior colliculus and auditory cortex 1 responding 00:21:51.980 --> 00:21:56.700 to alertness. So that leads us up to the thalamus. 00:21:56.779 --> 00:22:01.700 So from the cochlear all the way up to the brainstem, 00:22:02.079 --> 00:22:05.519 up the brainstem, and into the thalamus. We have 00:22:05.519 --> 00:22:10.619 the auditory brainstem response, ABR. This is 00:22:10.619 --> 00:22:13.680 something that's done in as soon as you're born 00:22:13.680 --> 00:22:18.390 within one to three days of life before the baby 00:22:18.390 --> 00:22:21.109 even leaves the hospital to go home. You can 00:22:21.109 --> 00:22:28.849 do this. A recent study in 2021 by Delgado et 00:22:28.849 --> 00:22:38.349 al had a subjects of 139 ,154 newborns in Florida, 00:22:38.630 --> 00:22:42.569 only Florida. Every baby received routine universal 00:22:42.569 --> 00:22:47.259 newborn hearing screening with an automated ABR, 00:22:47.500 --> 00:22:51.220 auditory brainstem response. And years later 00:22:51.220 --> 00:22:54.119 when preschool disability records were linked 00:22:54.119 --> 00:22:59.339 back to those specific subjects in the study, 00:23:00.759 --> 00:23:05.559 321 children who received an autism diagnosis 00:23:05.559 --> 00:23:10.680 had already on day one, two or three of live 00:23:10.680 --> 00:23:16.180 shown wave five latencies, prolonged by 0 .3 00:23:16.180 --> 00:23:20.700 to 0 .5 milliseconds. Now, you might think, well, 00:23:20.700 --> 00:23:23.880 that's not that long, but remember, it only took 00:23:23.880 --> 00:23:29.259 us about four milliseconds from cochlear to the 00:23:29.259 --> 00:23:33.559 thalamus. Hearing is a very powerful and fast 00:23:33.559 --> 00:23:40.359 -acting process. That delay It's so tiny, most 00:23:40.359 --> 00:23:43.420 clinicians wouldn't even notice it on a single 00:23:43.420 --> 00:23:46.940 tracing. But across hundreds of thousands of 00:23:46.940 --> 00:23:51.299 babies, it was unmistakable. There are no differences 00:23:51.299 --> 00:23:57.200 found in wave 1, so the periphery was fine. The 00:23:57.200 --> 00:23:59.759 problem was already central, already in the brain 00:23:59.759 --> 00:24:03.519 stem, already present before the child ever opened 00:24:03.519 --> 00:24:06.400 their eyes to the world or spoke their first 00:24:06.400 --> 00:24:10.230 words. And for the first time, there was proof 00:24:10.230 --> 00:24:13.809 that the auditory wiring differences in autism 00:24:13.809 --> 00:24:18.829 are prenatal and that a test we had already given 00:24:18.829 --> 00:24:22.049 in newborns in many different countries at many 00:24:22.049 --> 00:24:25.789 different times can flag risk for the autistic 00:24:25.789 --> 00:24:30.990 phenotype and be an early biomarker. The reticular 00:24:30.990 --> 00:24:34.430 activating system alerts the living organism. 00:24:34.970 --> 00:24:39.119 The thalamic reticular nucleus Fithers out noise. 00:24:40.220 --> 00:24:42.380 And distal connections like the medial prefrontal 00:24:42.380 --> 00:24:46.859 cortex helps predict. In the autistic phenotype, 00:24:47.220 --> 00:24:50.980 a decrease of inhibition creates a noisy and 00:24:50.980 --> 00:24:55.380 effortful dissonance world. Where something like 00:24:55.380 --> 00:24:59.359 porosity is lost. And noise is pain and triggers 00:24:59.359 --> 00:25:04.640 our threats. Sounds bland and so forth. So let's 00:25:04.640 --> 00:25:07.640 leave this to listening dissonance. We mentioned 00:25:07.640 --> 00:25:11.200 this in the Autistic Phenotype and the Adaptive 00:25:11.200 --> 00:25:13.579 Responses episode about the medial prefrontal 00:25:13.579 --> 00:25:17.880 cortex. Listening dissonance is a very uncomfortable 00:25:17.880 --> 00:25:21.859 neural friction that arises when the brain expects 00:25:21.859 --> 00:25:24.900 a clear auditory signal, but it's receiving a 00:25:24.900 --> 00:25:27.779 mixture of target sounds and competing background 00:25:27.779 --> 00:25:32.740 noises. It is not a formal diagnostic term, but 00:25:32.740 --> 00:25:36.420 very descriptive and accurate. This moment -to 00:25:36.420 --> 00:25:40.559 -moment struggle of extracting meaningful, expected 00:25:40.559 --> 00:25:45.819 and wanted sounds from the environment. This 00:25:45.819 --> 00:25:49.279 conflict begins in the cochlea, where loud noise 00:25:49.279 --> 00:25:53.440 saturates those outer hair cells and compresses 00:25:53.440 --> 00:25:57.119 the dynamic range and reduces the effectiveness 00:25:57.119 --> 00:26:00.980 of that plus 80 millivolt endocochlear potential 00:26:00.980 --> 00:26:07.210 that normally powers precise transduction but 00:26:07.210 --> 00:26:11.829 as a result of this faint cues are lost and noises 00:26:11.829 --> 00:26:15.930 are masked and mismatched and the auditory nerve 00:26:15.930 --> 00:26:21.990 fires less distinctively remember i say that 00:26:21.990 --> 00:26:25.069 in noisy environments or even if it's not that 00:26:25.069 --> 00:26:28.029 noisy but there is just multiple sources of sound 00:26:28.029 --> 00:26:32.869 maybe the noises and sound is functional and 00:26:32.869 --> 00:26:36.329 at healthy ranges, but there are many of them. 00:26:36.630 --> 00:26:39.170 Sounds will start to blend and it'll start sounding 00:26:39.170 --> 00:26:43.509 like a late Beatles track. Maybe something off 00:26:43.509 --> 00:26:47.269 of Sergeant Pepper's in 1967 or the White Album 00:26:47.269 --> 00:26:50.829 in 1968. They just began experimenting with different 00:26:50.829 --> 00:26:53.869 types of noises and instruments and then blending 00:26:53.869 --> 00:26:56.990 all of those together. They would do this later 00:26:56.990 --> 00:27:00.470 in the song. as the song ended and just carried 00:27:00.470 --> 00:27:04.710 on and make these funky different noises. That's 00:27:04.710 --> 00:27:09.509 what listening to sonnets is to me. By the time 00:27:09.509 --> 00:27:12.970 the signal reaches the brainstem, that superior 00:27:12.970 --> 00:27:16.589 olivary complex in the inferior colliculus attempt 00:27:16.589 --> 00:27:20.430 to suppress the mask through sideband inhibition 00:27:20.430 --> 00:27:23.529 and the duration tuning. Remember, this is what 00:27:23.529 --> 00:27:26.029 Gab is trying to do. And remember the autistic 00:27:26.029 --> 00:27:29.950 phenotype has low inhibition. If it's a seesaw, 00:27:30.630 --> 00:27:34.170 the excitation is on the high side of the seesaw. 00:27:34.490 --> 00:27:38.049 Inhibition is low towards the ground. And this 00:27:38.049 --> 00:27:41.190 is a frequent phenomena with the autistic phenotype 00:27:41.190 --> 00:27:46.349 where noise floods the central nucleus of the 00:27:46.349 --> 00:27:49.650 inferior colliculus, which is normally good for 00:27:49.650 --> 00:27:54.619 sharpening tunes and timing. is in a conundrum. 00:27:54.839 --> 00:27:57.940 It's a conflict. Lots of friction here. Remember, 00:27:58.259 --> 00:28:01.000 this is the auditory brainstem response wave 00:28:01.000 --> 00:28:04.819 five. This is what's happening here with this 00:28:04.819 --> 00:28:09.440 abnormal wave five. It's not the lack of hearing. 00:28:09.799 --> 00:28:13.299 It's not a hearing loss. It's hypersensitivity. 00:28:13.680 --> 00:28:17.279 It's blended noises. This is the big finding 00:28:17.279 --> 00:28:23.240 with the auditory brainstem response five. Okay, 00:28:23.240 --> 00:28:26.299 so we made it up through the thalamus and we're 00:28:26.299 --> 00:28:29.740 projecting out signals from the thalamus to things 00:28:29.740 --> 00:28:32.819 like the auditory cortex and we mentioned the 00:28:32.819 --> 00:28:36.900 medial prefrontal cortex. So, the auditory cortex 00:28:36.900 --> 00:28:41.259 is a so -called hallmark of the sonus. And this 00:28:41.259 --> 00:28:45.000 is where it becomes unmistakable. At 40 Hertz, 00:28:45.420 --> 00:28:49.859 gamma rhythm that normally binds syllables together 00:28:49.859 --> 00:28:54.680 collapses and phase locking weakens. Remember 00:28:54.680 --> 00:28:57.519 we talked about phase locking in speech and language 00:28:57.519 --> 00:29:01.460 or should be called language and speech and the 00:29:01.460 --> 00:29:05.019 brain loses its ability to track the speech sound 00:29:05.019 --> 00:29:08.960 and envelope, the meaning. What should be a coherent 00:29:08.960 --> 00:29:14.200 stream is perceived as a jumble of disconnection 00:29:14.200 --> 00:29:18.460 and fragments. And to compensate, the brain recruits 00:29:18.460 --> 00:29:23.559 higher order regions. Frontal alpha power increases 00:29:23.559 --> 00:29:28.680 as a marker of heightened cognitive effort. While 00:29:28.680 --> 00:29:32.539 the beta oscillations reflect top -down predictions 00:29:32.539 --> 00:29:37.279 from the medial prefrontal cortex. And this attempts 00:29:37.279 --> 00:29:42.160 to fill the gaps. The anterior cingulate cortex, 00:29:42.319 --> 00:29:46.400 the ACC, remember which is a subdivision. a little 00:29:46.400 --> 00:29:50.700 nuclei of the medial prefrontal cortex. This 00:29:50.700 --> 00:29:54.279 monitors the rising prediction error. Remember, 00:29:54.519 --> 00:29:57.720 some of the roles with the ACC, like error detection, 00:29:58.200 --> 00:30:01.819 conflict monitoring, evaluating risk reward. 00:30:02.700 --> 00:30:08.220 And it is attempting to sustain activation of 00:30:08.220 --> 00:30:11.599 the dorsal medial and the ventral medial prefrontal 00:30:11.599 --> 00:30:16.809 cortex. And this appears in fMRI. and it's kind 00:30:16.809 --> 00:30:22.490 of lit up, that effort -related glow will intensify 00:30:22.490 --> 00:30:26.769 with every decibel the signal -to -noise ratio 00:30:26.769 --> 00:30:33.109 falls. In the neurotypical individual, this balanced 00:30:33.109 --> 00:30:37.769 network can restore partially and take back control, 00:30:37.809 --> 00:30:41.829 but they do show fatigue and even elevated cortisol 00:30:41.829 --> 00:30:47.109 to reduce things like working memory. In the 00:30:47.109 --> 00:30:49.710 autistic phenotype, the same noisy environment 00:30:49.710 --> 00:30:54.990 triggers an exaggerated form of dissonance. Mainly 00:30:54.990 --> 00:30:58.490 because of parvalbum, positive GABAergic neurons 00:30:58.490 --> 00:31:02.130 are reduced in the inferior colliculus and the 00:31:02.130 --> 00:31:07.529 superior olive, which is inhibitory sculpting 00:31:07.529 --> 00:31:10.250 that is weaker. Remember, this is the rose here 00:31:10.250 --> 00:31:12.910 as the signals are being sent up through the 00:31:12.910 --> 00:31:17.500 brainstem to the thalamus. the luminous pathway 00:31:17.500 --> 00:31:22.099 is already slower and less synchronous. So noise 00:31:22.099 --> 00:31:25.980 that a neurotypical listener finds merely effortful 00:31:25.980 --> 00:31:30.279 can become overwhelming, driving frontal alpha 00:31:30.279 --> 00:31:34.819 power even higher and often leading to sensory 00:31:34.819 --> 00:31:40.480 shutdown and incomplete or loss of control. At 00:31:40.480 --> 00:31:45.160 this time, Particularly, the belt regions projecting 00:31:45.160 --> 00:31:48.720 to the amygdala, the insula, and the orbital 00:31:48.720 --> 00:31:53.759 frontal cortex are hyperconnected, so the unresolved 00:31:53.759 --> 00:31:58.160 auditory signal spills into emotional circuitry. 00:31:59.119 --> 00:32:02.880 In the background hum, or overlapping talker, 00:32:03.539 --> 00:32:07.059 the so -called sounds coming from the environment 00:32:07.059 --> 00:32:10.960 that are blending and are intensified, It's just 00:32:10.960 --> 00:32:13.819 not hard to understand. It can feel threatening 00:32:13.819 --> 00:32:18.480 or painful. I often have times where the ears 00:32:18.480 --> 00:32:22.480 were throbbing, it seems like. And a contribution 00:32:22.480 --> 00:32:25.539 to the higher rates of auditory hypersensitivity 00:32:25.539 --> 00:32:32.960 and misophonia is seen in autism. Ultimately, 00:32:33.400 --> 00:32:36.079 listening to sonas is the audible signature of 00:32:36.079 --> 00:32:40.940 an excitation -inhibition imbalance. under load 00:32:40.940 --> 00:32:45.319 and it explains why a classroom or a restaurant 00:32:45.319 --> 00:32:49.839 or family gatherings and so forth can be exhausting 00:32:49.839 --> 00:32:56.099 intolerable for some or most when the brainstem 00:32:56.099 --> 00:32:59.500 cannot adequately filter or the cortex can't 00:32:59.500 --> 00:33:03.640 provide top -down control and all of this noise 00:33:03.640 --> 00:33:06.680 is just coming and coming and coming and eventually 00:33:06.680 --> 00:33:10.190 you just can't take it I often leave things like 00:33:10.190 --> 00:33:12.970 family gatherings and so forth. It's just too 00:33:12.970 --> 00:33:18.309 much. The signal to noise is sort of like the 00:33:18.309 --> 00:33:22.309 excitation inhibition. It's just too much of 00:33:22.309 --> 00:33:26.670 the bad kind. So let's move into the auditory 00:33:26.670 --> 00:33:31.690 cortex 1. The primary auditory cortex, sometimes 00:33:31.690 --> 00:33:36.789 called A1, It is the first cortical station where 00:33:36.789 --> 00:33:40.450 raw acoustic energy is transformed into neural 00:33:40.450 --> 00:33:43.630 representations that we consciously perceive 00:33:43.630 --> 00:33:47.150 as sound. Remember the mini -columns. Remember 00:33:47.150 --> 00:33:50.390 the videos and the episodes about mini -columns. 00:33:50.650 --> 00:33:54.089 So let's build up a mini -column from the auditory 00:33:54.089 --> 00:33:59.069 cortex. Remember, each cortex, auditory, visual, 00:34:00.029 --> 00:34:02.890 cerebral cortex, and so forth, have different 00:34:02.890 --> 00:34:07.259 types of layers, mainly layer 4, where inputs 00:34:07.259 --> 00:34:14.659 are received. In layer 1, there are sparse, mostly 00:34:14.659 --> 00:34:21.519 feedback fibers. Layers 2 and 3 contain pyramidal 00:34:21.519 --> 00:34:27.019 neurons, sending association areas and contralateral 00:34:27.019 --> 00:34:30.920 information. This is just like we drew out in 00:34:30.920 --> 00:34:34.469 the whiteboard series. Lots of pyramidal neurons 00:34:34.469 --> 00:34:37.869 in layers two and three. Remember this is where 00:34:37.869 --> 00:34:42.969 consciousness and experiences and intelligence 00:34:42.969 --> 00:34:49.070 and so forth live in the living organism. Layer 00:34:49.070 --> 00:34:54.309 four has in the auditory cortex small stellette 00:34:54.309 --> 00:34:59.050 cells that receive direct thalamic input from 00:34:59.050 --> 00:35:03.369 the ventral medial Geniculate body. The first 00:35:03.369 --> 00:35:08.409 cortical synapses that are roughly 12 to 16 milliseconds 00:35:08.409 --> 00:35:13.809 after sound perceived. Layers five and six have 00:35:13.809 --> 00:35:18.130 large pyramids projecting back to the thalamus 00:35:18.130 --> 00:35:21.349 and to the inferior colliculus and to the superior 00:35:21.349 --> 00:35:25.309 olive and various regions of the cortex for feedback. 00:35:25.719 --> 00:35:28.599 The differences here mainly with these different 00:35:28.599 --> 00:35:33.260 many columns and locations is the layer 4. Stilett 00:35:33.260 --> 00:35:36.340 excitatory cells in layer 4 receive information 00:35:36.340 --> 00:35:39.719 from the medial geniculate nucleus that drive 00:35:39.719 --> 00:35:43.380 these local pyramids. Pyramidal excitatory cells 00:35:43.380 --> 00:35:47.300 in the layers 2 and 3 and 5 and 6 handle feet 00:35:47.300 --> 00:35:52.980 forward to belt areas and perceive neuroplasticity. 00:35:53.230 --> 00:35:56.010 How are you going to respond? How is this living 00:35:56.010 --> 00:36:03.110 organism equipped for this input coming in? Paralbium 00:36:03.110 --> 00:36:07.309 interneurons are found in all layers of the auditory 00:36:07.309 --> 00:36:11.510 cortex and this delivers fast GABA inhibition 00:36:11.510 --> 00:36:14.610 for that sharp tuning and gamma. So we have layers 00:36:14.610 --> 00:36:19.449 and layers of inhibition to help filter out noises 00:36:19.449 --> 00:36:24.280 at different epochs of the cochlear all the way 00:36:24.280 --> 00:36:27.840 up through the cortex and sensory perception, 00:36:28.019 --> 00:36:33.519 sensation perception process. Somatostatin enter 00:36:33.519 --> 00:36:37.780 neuron, those other GABA cells are in layers 00:36:37.780 --> 00:36:42.059 two and three and also five. This is providing 00:36:42.059 --> 00:36:47.880 inhibition at the dendrites and during duration 00:36:47.880 --> 00:36:55.409 of tuning. VIP cells, the vaso -intestinal peptides, 00:36:56.010 --> 00:36:59.210 the third kind of abundant cell type for inhibition 00:36:59.210 --> 00:37:02.349 are found in layers two and three. And this is 00:37:02.349 --> 00:37:06.809 providing disinhibition during attention. Remember, 00:37:07.130 --> 00:37:12.449 VIPs are disinhibition, which means stopping 00:37:12.449 --> 00:37:19.880 the stop signals. Inhibition of inhibition. A1 00:37:19.880 --> 00:37:25.619 is where sounds stop being vibrations and waves 00:37:25.619 --> 00:37:29.679 and becomes perception. Remember layers two and 00:37:29.679 --> 00:37:33.559 three. This is where our experiences and intelligence 00:37:33.559 --> 00:37:39.340 and memories and so forth live. This sound means 00:37:39.340 --> 00:37:46.739 this. X equals Y. These six layered gamma rhythmic 00:37:46.739 --> 00:37:50.260 gateways that turns the inferior colliculus's 00:37:50.260 --> 00:37:54.639 precise timing into rich and meaningful auditory 00:37:54.639 --> 00:37:58.500 world that we experience as individual living 00:37:58.500 --> 00:38:02.920 organisms. Everything higher in hearing, things 00:38:02.920 --> 00:38:07.260 like language, music, emotion, attention, is 00:38:07.260 --> 00:38:11.840 built on the foundation of A1. at about 50 milliseconds 00:38:11.840 --> 00:38:16.820 after sound reaches the cortex. Hearing is the 00:38:16.820 --> 00:38:19.800 most powerful thing happening in the human body. 00:38:20.159 --> 00:38:24.179 It's bioelectric, water -mediated, and excitation 00:38:24.179 --> 00:38:28.239 -inhibition kind of orchestra. From people like 00:38:28.239 --> 00:38:32.460 von Beckesies, mechanical wave, to auditory cortex 00:38:32.460 --> 00:38:38.300 1, powered by the stria, and all of those melanocytes 00:38:38.300 --> 00:38:43.690 and melanin. or shaped by GABA's ability to filter 00:38:43.690 --> 00:38:47.130 out, kind of channel out, while the goal signals 00:38:47.130 --> 00:38:51.230 go, because there's a lot of goal in hearing. 00:38:52.110 --> 00:38:55.090 With the Autistic Phenotype, the formula is easy. 00:38:55.530 --> 00:38:59.449 There's low GABA, low gamma, and high dissonance, 00:39:00.329 --> 00:39:04.989 and things like high misophonia. The formula 00:39:04.989 --> 00:39:10.230 is low inhibition plus high excitation Equals 00:39:10.230 --> 00:39:17.070 sensory overload So whenever you hear a parent 00:39:17.070 --> 00:39:19.789 say that their autistic child is in pain from 00:39:19.789 --> 00:39:24.090 the sound That pain is probably real remember 00:39:24.090 --> 00:39:28.110 Katie Asher She can be seen on the telepathy 00:39:28.110 --> 00:39:30.429 tapes and she has her own podcast. She has books 00:39:30.429 --> 00:39:34.230 written about this She is a very active person 00:39:34.230 --> 00:39:36.869 for the autistic phenotype. She said that her 00:39:36.869 --> 00:39:41.739 son Houston can hear Wi -Fi, and you should very 00:39:41.739 --> 00:39:46.440 much believe that. If you're listening to the 00:39:46.440 --> 00:39:49.159 podcast, listening to the episode, please feel 00:39:49.159 --> 00:39:52.659 free to leave a review or rating. In podcasting, 00:39:52.880 --> 00:39:55.159 reviews, ratings, and downloads are huge, and 00:39:55.159 --> 00:39:57.619 I very much appreciate your feedback. You can 00:39:57.619 --> 00:40:02.860 contact me on X at RPS 47586 where we can have 00:40:02.860 --> 00:40:06.079 discussions about autism or neuroscience, neurobiology 00:40:06.079 --> 00:40:09.380 even. You can check out the YouTube channel for 00:40:09.380 --> 00:40:13.719 all shorts, links, and clips about the videos 00:40:13.719 --> 00:40:16.679 and you can check out the new whiteboard series 00:40:16.679 --> 00:40:19.420 videos that I'm doing that attempt to kind of 00:40:19.420 --> 00:40:21.380 make this stuff easier to understand because 00:40:21.380 --> 00:40:23.900 I know that episodes are dense but I want people 00:40:23.900 --> 00:40:26.639 to understand the autistic phenotype and I want 00:40:26.639 --> 00:40:31.159 to be able to teach it accurately. You can email 00:40:31.159 --> 00:40:42.449 me info .fromthespectrum Thank you for listening 00:40:42.449 --> 00:40:44.809 to From the Spectrum Podcast.