Logopenic variant primary progressive aphasia (lvPPA) is a neurodegenerative language disorder characterized by a gradual dissolution of phonological processing ability. Individuals with lvPPA present with reduced phonological working memory capacity, impaired lexical retrieval and, in many cases, phonemic paraphasias in spontaneous speech. Cortical atrophy is most prominent in left temporoparietal cortex and spreads to additional regions subserving language and memory with disease (usually Alzheimer's) progression (Rohrer et al., 2010; Gorno-Tempini et al., 2011). Although phonological processing deficits are the defining feature of lvPPA, studies deconstructing and characterizing these deficits are lacking, especially in receptive language processing.

Receptive language processing at the single-word level is relatively intact in lvPPA but deteriorates as a function of stimulus length. This pattern has been attributed to phonological working memory deficits rather than semantic or syntactic processing impairments (Lukic et al., 2019). To date, processing of speech beyond single sentences has not been investigated in lvPPA. Further, functional neuroimaging studies investigating language processing in lvPPA have only examined processing of single syllables or words (Hardy et al., 2017). In everyday communication, however, we are rarely presented with single syllables, words or sentences in isolation, limiting the generalizability of previous research (Hamilton and Huth, 2018).

Recent analytical advances allow for online assessment of cortical tracking of ecologically valid, continuous speech stimuli, with the potential to generate findings that can be generalized to real-world situations. This approach involves fitting a temporal response function (TRF) to map speech features derived from naturalistic stimuli (e.g., audiobooks, movies) to temporally-precise neurophysiological data (Crosse et al., 2016). For example, TRF analyses can be used to assess the fidelity of cortical tracking of the speech envelope, which contains quasi-rhythmic amplitude fluctuations that are critical for transforming acoustic input into discrete representations (Ding and Simon, 2014), and the TRF time course can be used to infer the temporal dynamics of speech envelope encoding across the auditory processing hierarchy (Ding and Simon, 2012; Puvvada and Simon, 2017).

Cortical tracking of the speech envelope depends on neural oscillations in the delta (1–4 Hz) and theta (4–8 Hz) range (Ding and Simon, 2014), which have been linked to parsing linguistic structures from heard speech (Giraud and Poeppel, 2012). Delta oscillations are linked to parsing speech at the level of words and phrases as well as processing prosodic cues that are vital for constructing higher-level linguistic structures (Ding and Simon, 2014; Ding et al., 2017; Teoh et al., 2019); theta oscillations track the primary energetic rhythm in speech that is driven by low-level segmental features (syllables) (Ghitza, 2017). TRF analyses examining cortical tracking of the speech envelope by delta and theta oscillations have been applied to studies of continuous speech perception in neurotypical (Di Liberto et al., 2015) and clinical (Di Liberto et al., 2018; Fuglsang et al., 2020) populations.

Here we assess cortical tracking of the speech envelope of naturalistic, continuous speech in individuals with lvPPA (relative to age-matched controls) using EEG. This objective is motivated by converging evidence. First, neurodegeneration in lvPPA is most prominent in left temporoparietal regions, including the superior temporal gyrus and sulcus, middle temporal gyrus, and inferior parietal lobule (Rohrer et al., 2010), regions hypothesized to subserve the parsing of continuous speech input into perceptually-relevant units (Mesgarani et al., 2014). Second, aberrant neural processing of syllables presented in isolation has been observed in individuals with lvPPA (Hardy et al., 2017). Lastly, individuals with lvPPA show resting-state delta-theta hyperactivity in relatively spared frontal cortex as well as hypersynchrony in medial frontal and posterior parietal regions (Ranasinghe et al., 2017). We thus predict aberrant cortical tracking of the speech envelope in individuals with lvPPA relative to controls. This may manifest differently across oscillatory frequencies, so we assess the specificity (or lack thereof) across delta (word/phrase-level) and theta (syllable-level) oscillations in tracking of the speech envelope. Crucially, we evaluate the stability of this neural signature across two independent continuous speech narratives that vary in acoustic and linguistic complexity.

For multiple-choice questions, the main effects of participant group [F_(1,18) = 25.21, p < 0.0001, ηG2= 0.53] and narrative [F_(1,18) = 22.43, p < 0.001, ηG2= 0.20] were significant, as was the interaction [F_(1,18) = 7.17, p = 0.02, ηG2 = 0.07]. HC performed similarly on the two narratives whereas individuals with lvPPA performed worse on narrative 1 (Figure 1C), although the effect size for the interaction was small.

All participants had above-chance-level prediction accuracies for full, delta, and theta bands (Figure 3A; see Supplementary Figure 4 for scalp distribution plots for the prediction accuracies). Prediction accuracies for both narratives were highly correlated (Figure 3B), indicating that this cortical tracking metric conveys reliable information about the encoding of the speech envelope irrespective of stimulus. For the full band, there was a significant main effect of narrative [F_(1,18) = 5.84, p = 0.03, ηG2 = 0.02]. The magnitude of cortical tracking was significantly larger for narrative 1, although the effect size was small. The main effect of participant group [F_(1,18) = 3.80, p = 0.07, ηG2 = 0.17] and the interaction [F_(1,18) = 1.10, p = 0.31, ηG2 = 0.004], however, were not significant. For the delta band, the main effect of narrative was significant [F_(1,18) = 18.43, p < 0.001, ηG2 = 0.05]; the magnitude of cortical tracking was significantly larger for narrative 2, although the effect size was small. The main effect of participant group [F_(1,18) = 0.04, p = 0.84, ηG2 = 0.002] and the interaction [F_(1,18) = 4.01, p = 0.06, ηG2 = 0.01] were not significant. For the theta band, the main effects of participant group [F_(1,18) = 10.75, p = 0.004, ηG2 = 0.34] and narrative were significant [F_(1,18) = 5.75, p = 0.03, ηG2 = 0.04], although the effect size for narrative was small. The main effects of participant group and narrative reflected a significantly larger magnitude of cortical tracking in the theta band for individuals with lvPPA and narrative 1, respectively. The interaction between participant group and narrative was not significant [F_(1,18) = 1.50, p = 0.24, ηG2 = 0.01].

For the theta band, we examined the TRFs to characterize the time-course of the neural dynamics underlying observed prediction accuracies. Consistent with prediction accuracy results, individuals with lvPPA had significantly higher beta weights than HC in the theta band (narrative 1: 16.4 ≤ z_clust ≤ 71.8, narrative 2: 16.4 ≤ z_clust ≤ 21.24), indicating increased cortical tracking. This difference was seen throughout the time-course of the TRF with no specific difference at early or late latencies (Figure 3C).

Phonological processing impairment is the hallmark of logopenic variant primary progressive aphasia (lvPPA). This impairment has been examined using various tasks that broadly assess phonological processing (e.g., repetition, confrontation naming, sentence comprehension, phoneme manipulation), but research seeking to deconstruct this deficit and characterize the level(s) of breakdown is lacking. We assessed narrative comprehension and utilized temporal response function (TRF) modeling to examine cortical tracking of the speech envelope for two continuous speech narratives. Relative to healthy controls (HC), we observed reduced comprehension in lvPPA, extending previous findings of impaired comprehension for long sentences (Henry and Gorno-Tempini, 2010; Rohrer et al., 2010) using more ecologically valid, naturalistic, continuous speech stimuli. Cortical tracking metrics differed between lvPPA and HC, with significantly larger cortical tracking within the theta band (4–8 Hz) in lvPPA, but no difference between the two groups in the full (1–8 Hz) or delta bands (1–4 Hz). We also examined the TRF time-course, as latencies of TRFs have been associated with hierarchical cortical processing of auditory objects (i.e., latencies increase along the cortical processing hierarchy) (Ding and Simon, 2012; Puvvada and Simon, 2017). We observed larger regression coefficients (beta weights) for TRFs in the theta band in lvPPA over a broad time region, reflecting increased cortical tracking along the cortical processing hierarchy in both primary auditory and higher-level cortical regions. This neural signature was robust and consistent across two narratives that differed in acoustic and linguistic complexity, despite differences in comprehension for the two narratives. The findings of this study have implications for the characterization of deficits observed in lvPPA.

Temporoparietal cortex, which is significantly atrophic in lvPPA, plays a critical role in speech envelope encoding and the transformation of features represented in the envelope into discrete, perceptually-meaningful units (Mesgarani et al., 2014). Unlike stroke-induced aphasia, PPA is characterized by progressive degeneration of the left hemisphere language network (Rohrer et al., 2010). Longitudinal brain imaging in semantic variant PPA indicates that there is a gradual shifting in network dynamics in the context of atrophic changes (Canu et al., 2020). In fact, there is evidence of altered network connectivity in all three PPA variants (Agosta et al., 2014; Ranasinghe et al., 2017; Mandelli et al., 2018; Tao et al., 2020). Specifically in lvPPA (relative to HC), increased connectivity in right frontoparietal cortex has been observed using resting-state fMRI (Tao et al., 2020) and resting-state MEG has revealed bilateral changes within delta-theta oscillations, comprising both hypersynchrony between medial frontal and temporoparietal cortex and hyperactivity in the frontal cortex (Ranasinghe et al., 2017). Changes in network connectivity have been linked to changes in behavior inside (Wilson et al., 2009; Borghesani et al., 2020; Canu et al., 2020) and outside (Mandelli et al., 2018; Battistella et al., 2019) the MRI scanner in semantic and non-fluent variant PPA. In some cases, the recruitment of additional regions beyond sites of significant atrophy is related to better performance on speech and language tasks (Mandelli et al., 2018; Canu et al., 2020). Alternatively, some studies have found that the shift of function leads to errors (e.g., in the case of surface dyslexia in semantic variant PPA) (Wilson et al., 2009; Borghesani et al., 2020).

One possibility is that speech envelope encoding in individuals with lvPPA shifts away from atrophic temporoparietal cortex to relatively spared cortex that is not ideally suited to process information contained within the envelope. One might predict that this would lead to a reduced magnitude of cortical tracking, rather than an increased magnitude of cortical tracking. However, there are at least two candidate mechanisms underlying this paradoxical finding. First, increased cortical tracking of the envelope has been observed in the aging literature and argued to be a consequence of network degeneration and an imbalance between excitation and inhibition leading to inefficient information processing (Brodbeck et al., 2018). Second, the increased cortical tracking of the envelope may reflect functional hemispheric asymmetries. There is evidence that the cortical oscillations that support speech envelope encoding are lateralized, with faster oscillations being left lateralized (i.e., gamma oscillations) and slower oscillations (i.e., delta-theta oscillations) being right lateralized (Gross et al., 2013). Because left temporoparietal cortex is significantly atrophic in lvPPA, there may be an increased reliance on the right hemisphere for speech envelope encoding, thereby leading to increased cortical tracking by slower oscillatory frequencies, such as the theta band. The spatial resolution of EEG is relatively poor, and future research seeking to disentangle potential mechanisms (“what and where”) underlying the neural signature observed in this study will benefit from the use of tools such as MEG and source-level analyses.

In sum, we posit that increased cortical tracking of the speech envelope in individuals with lvPPA relative to HC is likely a consequence of shifting of function away from atrophic temporoparietal cortex to relatively spared brain regions in both hemispheres. Of note, this does not occur at a global level but rather, selectively enhances tracking of the syllabic rhythm of speech (4–8 Hz), as evidenced by increased cortical tracking in the theta band only. Phonological processing deficits in developmental dyslexia are argued to be a consequence of reduced envelope tracking within the theta range, leading to an increased sensitivity to phonetic features (Goswami, 2011). Our findings in lvPPA may represent the opposite pattern—increased reliance on syllabic structure during envelope encoding as a consequence of impaired processing of phonetic features due to left temporoparietal atrophy. Evidence for aberrant neural processing of phonetic features has been observed in left temporoparietal cortex in lvPPA (Hardy et al., 2017), lending some support to this theory.

Cortical tracking metrics, like those used in the current study, may have potential for use as a neural signature to inform differential diagnosis in PPA. To determine the viability of using such an approach for differential diagnosis, future research will require examination of our findings in lvPPA relative to other PPA variants and related disorders (e.g., Alzheimer's dementia, posterior cortical atrophy) to determine whether this neural signature is specific to lvPPA. Moreover, these metrics may provide valuable insights into perceptual deficits in PPA in naturalistic listening conditions that are not easily assessed using conventional clinical approaches. In conclusion, the current study points to an increased reliance on the speech envelope during continuous speech perception in lvPPA, arising from inefficient processing of acoustic cues within the theta band. The current study thus marks an important step toward more precise characterization of speech processing deficits in lvPPA.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Institutional Review Board at the University of Texas at Austin. The patients/participants provided their written informed consent to participate in this study.

Data collection, analysis and background literature review were conducted by HD, GNG, and RT. Clinical diagnosis and characterization was conducted by HD, MG-T, and MH. Data interpretation and manuscript preparation were conducted by HD, GNG, RT, MG-T, BC, and MH. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.