Abnormal Sleep Spindles, Memory Consolidation, and Schizophrenia

Abstract

There is overwhelming evidence that sleep is crucial for memory consolidation. Patients with schizophrenia and their unaffected relatives have a specific deficit in sleep spindles, a defining oscillation of non-rapid eye movement (NREM) Stage 2 sleep that, in coordination with other NREM oscillations, mediate memory consolidation. In schizophrenia, the spindle deficit correlates with impaired sleep-dependent memory consolidation, positive symptoms, and abnormal thalamocortical connectivity. These relations point to dysfunction of the thalamic reticular nucleus (TRN), which generates spindles, gates the relay of sensory information to the cortex, and modulates thalamocortical communication. Genetic studies are beginning to provide clues to possible neurodevelopmental origins of TRN-mediated thalamocortical circuit dysfunction and to identify novel targets for treating the related memory deficits and symptoms. By forging empirical links in causal chains from risk genes to thalamocortical circuit dysfunction, spindle deficits, memory impairment, symptoms, and diagnosis, future research can advance our mechanistic understanding, treatment, and prevention of schizophrenia.

Keywords: cognition; endophenotype; genetics; memory; schizophrenia; sleep; spindles.

Figure 1

Exponential growth of research on sleep and memory. Articles on sleep and learning listed in PubMed when searching for (memory[Title] OR learning[Title] AND sleep[Title]) have increased exponentially since the publication of a review on the topic in Science in 2001 (Stickgold et al. 2001), with a doubling time of just under 4 years. Cover reproduced with permission from Stickgold et al. 2001.

Figure 2

A good night’s sleep. (a) Hypnogram showing the distribution of sleep stages across a typical night. A typical night consists of five 90-min cycles that include REM sleep. Most of the deep slow-wave sleep (N3) occurs early in the night, and most of the REM sleep occurs later in the night. N1 is a transitional state from wake to sleep, characterized by the disappearance of 8–12 Hz (alpha) waves from the EEG and the appearance of >0.5-s slow, rolling eye movements (Iber et al. 2007). N2 is defined by the presence of isolated K-complexes—sharp negative waves followed by a positive component lasting >0.5-s—and sleep spindles. N3 is defined by the presence of large (>75-μV peak to peak), slow (1–4 Hz) waves occupying at least 20% of each 30-s epoch. (b) A typical sleep spindle recorded from a scalp EEG sensor. Abbreviations: EEG, electroencephalogram; REM, rapid eye movement.

Figure 3

A schematic illustration of the endophenotype concept in psychiatry. Endophenotypes are measurable traits, invisible to the unaided eye, along the pathway between disease and genotype (see Figure 7). They are simpler manifestations of the genetic underpinnings of a disorder than the syndrome itself. Shaded areas indicate the expected presence of an endophenotype (e.g., sleep spindle deficits) in individuals with schizophrenia, those with spectrum disorders, syndromally unaffected family members, and the general population. Existing evidence shows that sleep spindle deficits meet criteria 1, 2, and 5. Although spindles are trait-like across nights in studies of healthy individuals (e.g., Cox et al. 2017), stability of the deficit in longitudinal studies of individuals with schizophrenia across prodromal, psychotic, and remitted states would satisfy criterion 3. No study to date has addressed criterion 4. Definition and criteria adapted from Gottesman & Gould (2003).

Figure 4

Sleep in relation to cognition in schizophrenia. (a) The finger-tapping motor sequence task (MST) requires participants to repeatedly type a five-digit sequence (e.g., 4–1-3–2-4) on a keyboard with the left hand, as quickly and accurately as possible, for 12 30-s trials separated by 30-s rest periods. Participants train before sleep and test on an additional 12 trials after sleep. The primary outcome measure is overnight improvement, calculated as the percent increase in correctly typed sequences from the last three training trials to the first three test trials (Walker et al. 2002). (b) MST performance in schizophrenia (Manoach et al. 2004). The y axis is scaled separately for controls (left) and patients (right) to highlight the similarity of learning curves on day 1 and the failure of overnight improvement in the schizophrenia group only. The dashed line is positioned at the mean value of the last three training trials for both the control and patient groups. The break between the plots represents the passage of 24 hours, including a night of sleep. Patients and controls did not differ in the amount of learning during training, but only controls showed significant overnight improvement. (c) Sleep-dependent improvement in schizophrenia correlates with spindle density during N2 sleep in the posttraining night (r = 0.45, p = 0.04) (Wamsley et al. 2012). (d) Declarative memory evolution and sleep spindles. Compared to a day of wake, a night of sleep resulted in a 12% improvement in picture recognition accuracy (p < 0.001) in healthy participants. Schizophrenia patients showed no sleep-dependent benefit, and despite having comparable sleep architecture, they showed a 54% reduction in spindle density (p < 0.001). In both groups, the sleep-dependent change in recognition accuracy correlated with spindle density (Goder et al. 2015). (e) Regressions of estimated verbal IQ against spindle amplitude for early-course antipsychotic-naïve patients with schizophrenia, those with other psychotic disorders, young first-degree relatives of schizophrenia patients, and healthy controls (Manoach et al. 2014).

Figure 5

TRN circuitry for generating and synchronizing sleep spindles. The TRN, a net-like nucleus that sits between the rest of the thalamus and the neocortex, modulates thalamocortical communication. The TRN receives projections from thalamocortical and corticothalamic neurons. GABAergic TRN neurons inhibit thalamocortical relay neurons. Glutamatergic corticothalamic neurons send projections back to the TRN and other thalamic nuclei. Roman numerals indicate cortical layers. Abbreviations: GABA, gamma-amino butyric acid; Glu, glutamate; TRN, thalamic reticular nucleus. Figure adapted with permission from Pinault (2004).

Figure 6

Spindle deficits correlate with TC hyperconnectivity in schizophrenia. (a) Blue regions show significant TC hyperconnectivity in schizophrenia and include motor and somatosensory cortex. Yellow regions show a correlation of TC connectivity with average spindle density. Green regions show both significant hyperconnectivity in schizophrenia and a correlation of connectivity with average spindle density. (b) Average spindle density is plotted against TC connectivity in motor and somatosensory regions showing a significant inverse correlation. There were no regions of significantly positive correlation, and the slopes of the relations did not differ by group. Abbreviations: HC, healthy controls; SZ, schizophrenia; TC, thalamocortical.

Figure 7

From genes to diagnosis: a hypothetical causal chain. Risk genes result in thalamic reticular nucleus–mediated thalamocortical dysfunction, which, in turn, gives rise to candidate endophenotypes of schizophrenia including sleep spindle and sensory gating deficits, which contribute to fundamental cognitive deficits, symptoms, and ultimately diagnosis. Illustrations from left to right represent a strand of DNA, a Manhattan plot identifying risk genes, thalamocortical hyperconnectivity, a topographic electroencephalogram map of reduced spindle density, and the sleep-dependent memory consolidation deficit.

Figure 8

The coordination of sleep spindles with hippocampal ripples and neocortical slow oscillations in the service of consolidating new memories during sleep. During non-rapid eye movement sleep, neocortical slow oscillations drive the reactivation of hippocampal memory representations during sharp-wave ripples in the hippocampus together with spindles in the thalamic reticular nucleus. Hippocampal ripples nest in the troughs of spindles, which occur during the up states of slow oscillations. This dialogue between slow oscillations, spindles, and hippocampal ripples is thought to mediate the transfer of selected new memories from temporary dependence on the hippocampus to longer-term representation in the neocortex (Siapas & Wilson 1998). Figure adapted with permission from Born & Wilhelm (2012).