Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography

Abstract

Spontaneous magnetoencephalographic activity was recorded in awake, healthy human controls and in patients suffering from neurogenic pain, tinnitus, Parkinson's disease, or depression. Compared with controls, patients showed increased low-frequency theta rhythmicity, in conjunction with a widespread and marked increase of coherence among high- and low-frequency oscillations. These data indicate the presence of a thalamocortical dysrhythmia, which we propose is responsible for all the above mentioned conditions. This coherent theta activity, the result of a resonant interaction between thalamus and cortex, is due to the generation of low-threshold calcium spike bursts by thalamic cells. The presence of these bursts is directly related to thalamic cell hyperpolarization, brought about by either excess inhibition or disfacilitation. The emergence of positive clinical symptoms is viewed as resulting from ectopic gamma-band activation, which we refer to as the "edge effect." This effect is observable as increased coherence between low- and high-frequency oscillations, probably resulting from inhibitory asymmetry between high- and low-frequency thalamocortical modules at the cortical level.

Figure 1

The whole-head MEG system and the cleaning procedures for MEG signals. (A) The Magnes 2500WH MEG system (Biomagnetic Technologies) shows a helmet design, including 148 signal and 11 reference channels. Recordings can be taken with subject in a seated or supine position with a noise level below 10 fT/Hz^1/2. (B) Raw data were further processed to remove heart artifact and contribution from distant sources.

Figure 2

Power spectra for control subjects and patients. Spectra are shown for one representative control subject and for one Parkinson patient (A and B); and for the average of all controls and all patients (C–E). The power was averaged over all rostral MEG channels (A and C), over all caudal channels (B and D), and averaged over all 148 channels for the entire brain (E). Note the shift toward the θ range and the increase in global power in the patient population. Also note small bumps in the 5- to 10-Hz range in the patients, indicating distinct peaks, depending on the pathology or level of severity. Dashed line indicates maximum of averaged α activity in controls.

Figure 3

Grouping of power spectral traces, indicating the distribution of all control subjects (blue dots) and all patients (red dots). The ratio 5–10 Hz power/10–15 Hz power is plotted against the total 5–15 Hz power averaged over MEG channels for the rostral pole (A), for the caudal pole (B), and for the entire brain (C). Patients' disorders are specified as T, tinnitus, D, major depression, P, neurogenic pain, and M, Parkinson's.

Figure 4

Correlation plots of power spectra over a period of 10 min. (A) One representative control subject. (B) One Parkinson patient. (C) The average of all controls. (D) The average of all patients. For clarity, the thickness of the white diagonal indicating the self-correlation was reduced. Note the wide range of correlation (from θ to γ) in the patient group.

Figure 5

Diagram of the thalamocortical circuits that support the positive symptoms hypothesis. Two thalamocortical systems are shown, the specific pathway (yellow) to layer IV of the cortex that activates layer VI cortical neurons; and feed-forward inhibition through inhibitory cortical interneurons (red). Collaterals of these projections produce thalamic feedback inhibition through the reticular nucleus (red at thalamic level). The return pathway (circular arrow on the right) re-enters this oscillation to specific- and reticularis-thalamic nuclei through layer VI pyramidal cells (blue). The second loop shows nonspecific nuclei (green), projecting to the most superficial layer of the cortex and giving collaterals to the reticular nucleus. The conjunction of the specific and nonspecific loops is proposed to generate temporal coherence (Center). Protracted thalamic cell hyperpolarization by altered synaptic input triggers low-frequency neuronal oscillation (Center). Either disfacilitation, as occurs after deafferentation (as in neurogenic pain or tinnitus), or excess inhibition caused by pallidal over-activity (as in Parkinson's disease), hyperpolarize the cells sufficiently to deinactivate T-type calcium channels, resulting in thalamic oscillation at θ range. Such oscillation can entrain corticothalamic loops (Left), generating increased coherence, as observed in this study. At the cortical level, low-frequency activation of cortico–cortical inhibitory interneurons, by reducing lateral inhibitory drive, can result in high-frequency, coherent activation of neighboring cortical modules, the “edge effect” (Right).