The diagnostic performance of functional dopaminergic scintigraphic imaging in the diagnosis of dementia with Lewy bodies: an updated systematic review.

INTRODUCTION: Dopaminergic scintigraphic imaging is a cornerstone to support the diagnosis in dementia with Lewy bodies. To clarify the current state of knowledge on this imaging modality and its impact on clinical diagnosis, we performed an updated systematic review of the literature. METHODS: This systematic review was carried out according to PRISMA guidelines. A comprehensive computer literature search of PubMed/MEDLINE, EMBASE, and Cochrane Library databases for studies published through June 2022 was performed using the following search algorithm: (a) "Lewy body" [TI] OR "Lewy bodies" [TI] and (b) ("DaTscan" OR "ioflupane" OR "123ip" OR "123?ip" OR "123 ip" OR "123i-FP-CIT" OR "FPCIT" OR "FP-CIT" OR "beta?CIT" OR "beta CIT" OR "CIT?SPECT" OR "CIT SPECT" OR "Dat?scan*" OR "dat scan*" OR "dat?spect*" OR "SPECT"). Risk of bias and applicability concerns of the studies were evaluated using the QUADAS-2 tool. RESULTS: We performed a qualitative analysis of 59 studies. Of the 59 studies, 19 (32%) addressed the diagnostic performance of dopamine transporter imaging, 15 (25%) assessed the identification of dementia with Lewy bodies in the spectrum of Lewy body disease and 18 (31%) investigated the role of functional dopaminergic imaging in distinguishing dementia with Lewy bodies from other dementias. Dopamine transporter loss was correlated with clinical outcomes in 19 studies (32%) and with other functional imaging modalities in 15 studies (25%). Heterogeneous technical aspects were found among the studies through the use of various radioligands, the more prevalent being the [123I]N­ω­fluoropropyl­2ß­carbomethoxy­3ß­(4­iodophenyl) nortropane (123I-FP-CIT) in 54 studies (91.5%). Image analysis used visual analysis (9 studies, 15%), semi-quantitative analysis (29 studies, 49%), or a combination of both (16 studies, 27%). CONCLUSION: Our systematic review confirms the major role of dopaminergic scintigraphic imaging in the assessment of dementia with Lewy bodies. Early diagnosis could be facilitated by identifying the prodromes of dementia with Lewy bodies using dopaminergic scintigraphic imaging coupled with emphasis on clinical neuropsychiatric symptoms. Most published studies use a semi-quantitative analytical assessment of tracer uptake, while there are no studies using quantitative analytical methods to measure dopamine transporter loss. The superiority of a purely quantitative approach to assess dopaminergic transmission more accurately needs to be further clarified.

Increased Functional Connectivity of the Intraparietal Sulcus Underlies the Attenuation of Numerosity Estimations for Self-Generated Words.

Previous studies have shown that self-generated stimuli in auditory, visual, and somatosensory domains are attenuated, producing decreased behavioral and neural responses compared with the same stimuli that are externally generated. Yet, whether such attenuation also occurs for higher-level cognitive functions beyond sensorimotor processing remains unknown. In this study, we assessed whether cognitive functions such as numerosity estimations are subject to attenuation in 56 healthy participants (32 women). We designed a task allowing the controlled comparison of numerosity estimations for self-generated (active condition) and externally generated (passive condition) words. Our behavioral results showed a larger underestimation of self-generated compared with externally generated words, suggesting that numerosity estimations for self-generated words are attenuated. Moreover, the linear relationship between the reported and actual number of words was stronger for self-generated words, although the ability to track errors about numerosity estimations was similar across conditions. Neuroimaging results revealed that numerosity underestimation involved increased functional connectivity between the right intraparietal sulcus and an extended network (bilateral supplementary motor area, left inferior parietal lobule, and left superior temporal gyrus) when estimating the number of self-generated versus externally generated words. We interpret our results in light of two models of attenuation and discuss their perceptual versus cognitive origins.SIGNIFICANCE STATEMENT We perceive sensory events as less intense when they are self-generated compared with when they are externally generated. This phenomenon, called attenuation, enables us to distinguish sensory events from self and external origins. Here, we designed a novel fMRI paradigm to assess whether cognitive processes such as numerosity estimations are also subject to attenuation. When asking participants to estimate the number of words they had generated or passively heard, we found bigger underestimation in the former case, providing behavioral evidence of attenuation. Attenuation was associated with increased functional connectivity of the intraparietal sulcus, a region involved in numerosity processing. Together, our results indicate that the attenuation of self-generated stimuli is not limited to sensory consequences but is also impact cognitive processes such as numerosity estimations.

Wearable Cameras Are Useful Tools to Investigate and Remediate Autobiographical Memory Impairment: A Systematic PRISMA Review.

Autobiographical memory, central in human cognition and every day functioning, enables past experienced events to be remembered. A variety of disorders affecting autobiographical memory are characterized by the difficulty of retrieving specific detailed memories of past personal events. Owing to the impact of autobiographical memory impairment on patients' daily life, it is necessary to better understand these deficits and develop relevant methods to improve autobiographical memory. The primary objective of the present systematic PRISMA review was to give an overview of the first empirical evidence of the potential of wearable cameras in autobiographical memory investigation in remediating autobiographical memory impairments. The peer-reviewed literature published since 2004 on the usefulness of wearable cameras in research protocols was explored in 3 databases (PUBMED, PsycINFO, and Google Scholar). Twenty-eight published studies that used a protocol involving wearable camera, either to explore wearable camera functioning and impact on daily life, or to investigate autobiographical memory processing or remediate autobiographical memory impairment, were included. This review analyzed the potential of wearable cameras for 1) investigating autobiographical memory processes in healthy volunteers without memory impairment and in clinical populations, and 2) remediating autobiographical memory in patients with various kinds of memory disorder. Mechanisms to account for the efficacy of wearable cameras are also discussed. The review concludes by discussing certain limitations inherent to using cameras, and new research perspectives. Finally, ethical issues raised by this new technology are considered.

Numerosity estimation of virtual humans as a digital-robotic marker for hallucinations in Parkinson's disease.

Hallucinations are frequent non-motor symptoms in Parkinson's disease (PD) associated with dementia and higher mortality. Despite their high clinical relevance, current assessments of hallucinations are based on verbal self-reports and interviews that are limited by important biases. Here, we used virtual reality (VR), robotics, and digital online technology to quantify presence hallucination (vivid sensations that another person is nearby when no one is actually present and can neither be seen nor heard) in laboratory and home-based settings. We establish that elevated numerosity estimation of virtual human agents in VR is a digital marker for experimentally induced presence hallucinations in healthy participants, as confirmed across several control conditions and analyses. We translated the digital marker (numerosity estimation) to an online procedure that 170 PD patients carried out remotely at their homes, revealing that PD patients with disease-related presence hallucinations (but not control PD patients) showed higher numerosity estimation. Numerosity estimation enables quantitative monitoring of hallucinations, is an easy-to-use unobtrusive online method, reaching people far away from medical centers, translating neuroscientific findings using robotics and VR, to patients' homes without specific equipment or trained staff.

Sense of Agency during Encoding Predicts Subjective Reliving.

Autonoetic consciousness (ANC), the ability to re-experience personal past events links episodic memory and self-consciousness by bridging awareness of oneself in a past event (i.e., during its encoding) with awareness of oneself in the present (i.e., during the reliving of a past event). Recent neuroscience research revealed a bodily form of self-consciousness, including the sense of agency (SoA) and the sense of body ownership (SoO) that are based on the integration of multisensory bodily inputs and motor signals. However, the relation between SoA and/or SoO with ANC is not known. Here, we used immersive virtual reality technology and motion tracking and investigated the potential association of SoA/SoO with ANC. For this, we exposed participants to different levels of visuomotor and perspectival congruency, known to modulate SoA and SoO, during the encoding of virtual scenes and collected ANC ratings 1 week after the encoding session. In a total of 74 healthy participants, we successfully induced systematic changes in SoA and SoO during encoding and found that ANC depended on the level of SoA experienced during encoding. Moreover, ANC was positively associated with SoA, but only for the scene encoded with preserved visuomotor and perspectival congruency, and such SoA-ANC coupling was absent for SoO and control questions. Collectively, these data provide behavioral evidence in a novel paradigm that links a key subjective component of bodily self-consciousness during encoding, SoA, to the subjective reliving of those encoded events from one's past, ANC.

Real-time fMRI neurofeedback modulates induced hallucinations and underlying brain mechanisms.

Hallucinations can occur in the healthy population, are clinically relevant and frequent symptoms in many neuropsychiatric conditions, and have been shown to mark disease progression in patients with neurodegenerative disorders where antipsychotic treatment remains challenging. Here, we combine MR-robotics capable of inducing a clinically-relevant hallucination, with real-time fMRI neurofeedback (fMRI-NF) to train healthy individuals to up-regulate a fronto-parietal brain network associated with the robotically-induced hallucination. Over three days, participants learned to modulate occurrences of and transition probabilities to this network, leading to heightened sensitivity to induced hallucinations after training. Moreover, participants who became sensitive and succeeded in fMRI-NF training, showed sustained and specific neural changes after training, characterized by increased hallucination network occurrences during induction and decreased hallucination network occurrences during a matched control condition. These data demonstrate that fMRI-NF modulates specific hallucination network dynamics and highlights the potential of fMRI-NF as a novel antipsychotic treatment in neurodegenerative disorders and schizophrenia.

Embodiment in episodic memory through premotor-hippocampal coupling.

Episodic memory (EM) allows us to remember and relive past events and experiences and has been linked to cortical-hippocampal reinstatement of encoding activity. While EM is fundamental to establish a sense of self across time, this claim and its link to the sense of agency (SoA), based on bodily signals, has not been tested experimentally. Using real-time sensorimotor stimulation, immersive virtual reality, and fMRI we manipulated the SoA and report stronger hippocampal reinstatement for scenes encoded under preserved SoA, reflecting recall performance in a recognition task. We link SoA to EM showing that hippocampal reinstatement is coupled with reinstatement in premotor cortex, a key SoA region. We extend these findings in a severe amnesic patient whose memory lacked the normal dependency on the SoA. Premotor-hippocampal coupling in EM describes how a key aspect of the bodily self at encoding is neurally reinstated during the retrieval of past episodes, enabling a sense of self across time.

Phantom Boarder Relates to Experimentally-Induced Presence Hallucinations in Parkinson's Disease.

Background: Phantom boarder (PB) is the sensation that someone uninvited is in the patient's home despite evidence to the contrary. It is mostly reported by patients with neurodegenerative disorders such as Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease (PD). Presence hallucination (PH) is frequent in neurodegenerative disease, shares several aspects with PB, and is the sensation that someone is nearby, behind or next to the patient (when nobody is actually there). Recent work developed a sensorimotor method to robotically induce PH (robot-induced PH, riPH) and demonstrated that a subgroup of PD patients showed abnormal sensitivity for riPH. Objective: We investigated if PD patients with PB (PD-PB) would (1) show elevated sensitivity for riPH that (2) is comparable to that of patients reporting PH, but not PB (PD-PH). Methods: We studied the sensitivity of non-demented PD patients in a sensorimotor stimulation paradigm, during which three groups of patients (PD-PB; PD-PH; PD patients without hallucinations, PD-nPH) were exposed to different conditions of conflicting sensorimotor stimulation. Results: We show that PD-PB and PD-PH groups had a higher sensitivity to riPH (compared to PD-nPH). PD-PB and PD-PH groups did not differ in riPH sensitivity. Together with interview data, these behavioral data on riPH show that PB is associated with PH, suggesting that both share some underlying brain mechanisms, although interview data also revealed phenomenological differences. Conclusions: Because PD-PB patients did not suffer from dementia nor delusions, we argue that these shared mechanisms are of perceptual-hallucinatory nature, involving sensorimotor signals and their integration.

Distorted perception of the subjective temporal distance of autobiographical events in patients with schizophrenia.

Disturbances of perception of subjective time have been described in schizophrenia but have not been experimentally studied until now. We investigated how patients with schizophrenia estimate the subjective temporal distance (TD) of past personal events, i.e. how these events are perceived as subjectively close or distant in time. Twenty-five patients with schizophrenia and 25 control participants recalled 24 autobiographical memories from four different life periods. They estimated the subjective TD and rated the amount of detail of each memory. Results showed that patients with schizophrenia had a distorted perception of subjective TD. Their memories were significantly less detailed than those of controls and, unlike control participants, the amount of memory detail was not significantly correlated with subjective TD. Poor access to memory detail may account for distortions of perception of subjective time in patients with schizophrenia.

Neuroscience robotics for controlled induction and real-time assessment of hallucinations.

Although hallucinations are important and frequent symptoms in major psychiatric and neurological diseases, little is known about their brain mechanisms. Hallucinations are unpredictable and private experiences, making their investigation, quantification and assessment highly challenging. A major shortcoming in hallucination research is the absence of methods able to induce specific and short-lasting hallucinations, which resemble clinical hallucinations, can be elicited repeatedly and vary across experimental conditions. By integrating clinical observations and recent advances in cognitive neuroscience with robotics, we have designed a novel device and sensorimotor method able to repeatedly induce a specific, clinically relevant hallucination: presence hallucination. Presence hallucinations are induced by applying specific conflicting (spatiotemporal) sensorimotor stimulation including an upper extremity and the torso of the participant. Another, MRI-compatible, robotic device using similar sensorimotor stimulation permitted the identification of the brain mechanisms of these hallucinations. Enabling the identification of behavioral and a frontotemporal neural biomarkers of hallucinations, under fully controlled experimental conditions and in real-time, this method can be applied in healthy participants as well as patients with schizophrenia, neurodegenerative disease or other hallucinations. The execution of these protocols requires intermediate-level skills in cognitive neuroscience and MRI processing, as well as minimal coding experience to control the robotic device. These protocols take ~3 h to be completed.

Self-defining memories related to illness and their integration into the self in patients with schizophrenia.

Although schizophrenia alters the sense of personal identity, little is known about the impact of illness-related autobiographical events on patients' self-representation. We investigated self-defining memories (SDM) in 24 patients with schizophrenia and 24 controls to explore how illness-related SDM were integrated into the self at both the cognitive (how participants are able to give a meaning to past events: meaning making) and affective levels (how participants can re-experience past negative events as less negative: redemption and benefaction effects). We found that 26% of freely recalled SDM referred to their illness in patients. Further, while meaning making was impaired in patients for both illness-related and other SDM, illness-related SDM were characterized by a higher redemption and benefaction effects than other SDM. Our results highlight that despite a reduced ability to give a meaning to illness-related episodes, emotional processing seems to allow these events to become positively integrated into patients' life stories. This study provides new findings about the construction of the self in relation to psychotic episodes in patients with schizophrenia. We discuss clinical implications of our results that are helpful to guide cognitive interventions.

Impaired ability to give a meaning to personally significant events in patients with schizophrenia.

Schizophrenia is a severe mental illness affecting sense of identity. Autobiographical memory deficits observed in schizophrenia could contribute to this altered sense of identity. The ability to give a meaning to personally significant events (meaning making) is also critical for identity construction and self-coherence. Twenty-four patients with schizophrenia and 24 control participants were asked to recall five self-defining memories. We assessed meaning making in participants' narratives (spontaneous meaning making) and afterwards asked them explicitly to give a meaning to their memories (cued meaning making). We found that both spontaneous and cued meaning making were impaired in patients with schizophrenia. This impairment was correlated with executive dysfunctions and level of negative symptoms. Our results suggest that patients' difficulties in drawing lessons about past experiences could contribute to explain the lack of coherence observed in their life trajectories and their impaired social adjustment abilities. Implications for psychotherapy are also discussed.

Fronto-Temporal Disconnection Within the Presence Hallucination Network in Psychotic Patients With Passivity Experiences.

Psychosis, characterized by hallucinations and delusions, is a common feature of psychiatric disease, especially schizophrenia. One prominent theory posits that psychosis is driven by abnormal sensorimotor predictions leading to the misattribution of self-related events. This misattribution has been linked to passivity experiences (PE), such as loss of agency and, more recently, to presence hallucinations (PH), defined as the conscious experience of the presence of an alien agent while no person is actually present. PH has been observed in schizophrenia, Parkinson's disease, and neurological patients with brain lesions and, recently, the brain mechanisms of PH (PH-network) have been determined comprising bilateral posterior middle temporal gyrus (pMTG), inferior frontal gyrus (IFG), and ventral premotor cortex (vPMC). Given that the experience of an alien agent is a common feature of PE, we here analyzed the functional connectivity within the PH-network in psychotic patients with (N = 39) vs without PE (N = 26). We observed reduced fronto-temporal functional connectivity in patients with PE compared to patients without PE between the right pMTG and the right and left IFG of the PH-network. Moreover, when seeding from these altered regions, we observed specific alterations with brain regions commonly linked to auditory-verbal hallucinations (such as Heschl's gyrus). The present connectivity findings within the PH-network extend the disconnection hypothesis for hallucinations to the specific case of PH and associates the PH-network with key brain regions for frequent psychotic symptoms such as auditory-verbal hallucinations, showing that PH are relevant to the study of the brain mechanisms of psychosis and PE.

Robot-induced hallucinations in Parkinson's disease depend on altered sensorimotor processing in fronto-temporal network.

Hallucinations in Parkinson's disease (PD) are disturbing and frequent non-motor symptoms and constitute a major risk factor for psychosis and dementia. We report a robotics-based approach applying conflicting sensorimotor stimulation, enabling the induction of presence hallucinations (PHs) and the characterization of a subgroup of patients with PD with enhanced sensitivity for conflicting sensorimotor stimulation and robot-induced PH. We next identify the fronto-temporal network of PH by combining MR-compatible robotics (and sensorimotor stimulation in healthy participants) and lesion network mapping (neurological patients without PD). This PH-network was selectively disrupted in an additional and independent cohort of patients with PD, predicted the presence of symptomatic PH, and associated with cognitive decline. These robotics-neuroimaging findings extend existing sensorimotor hallucination models to PD and reveal the pathological cortical sensorimotor processes of PH in PD, potentially indicating a more severe form of PD that has been associated with psychosis and cognitive decline.

From a Lived Event to Its Autobiographical Memory: An Ecological Study Using Wearable Camera in Schizophrenia.

Cognitive disorders are considered as a core symptom of schizophrenia. Importantly, episodic autobiographical memory deficits are strongly related to patients' social dysfunction. Although the cognitive mechanisms underlying autobiographical memory deficit are highly important to open the door for specific cognitive remediation, they are yet to be understood. The present study focused on event segmentation to check to which extent possible impairments in temporal ordering and segmenting in patients hinder memories construction. Twenty-seven patients with schizophrenia and 27 matched controls took part in an outdoor circuit while wearing a wearable camera. A week later, their memory and the temporal organization of this event have been assessed. Results showed that patients, compared with control participants, reported a reduced amount of details, especially less actions with interaction related to the event. Contrary to our initial hypotheses, event segmentation abilities in patients were not affected. The relationship between event segmentation and memory is discussed.

A Meta-Analysis of Autobiographical Memory Studies in Schizophrenia Spectrum Disorder.

Meta-analyses and reviews on cognitive disorders in schizophrenia have shown that the most robust and common cognitive deficits are found in episodic memory and executive functions. More complex memory domains, such as autobiographical memory (AM), are also impaired in schizophrenia, but such impairments are reported less often despite their negative impact on patients' outcome. In contrast to episodic memory, assessed in laboratory tasks, memories of past personal events are much more complex and directly relate to the self. The meta-analysis included 20 studies, 571 patients with schizophrenia spectrum disorder, and 503 comparison subjects. It found moderate-to-large effect sizes with regard to the 3 parameters commonly used to assess AM: memory specificity (g = -0.97), richness of detail (g = -1.40), and conscious recollection (g = -0.62). These effect sizes were in the same range as those found in other memory domains in schizophrenia; for this reason, we propose that defective memories of personal past events should be regarded as a major cognitive impairment in this illness.

Impaired coherence of life narratives of patients with schizophrenia.

Self-narratives of patients have received increasing interest in schizophrenia since they offer unique material to study patients' subjective experience related to their illness, in particular the alteration of self that accompanies schizophrenia. In this study, we investigated the life narratives and the ability to integrate and bind memories of personal events into a coherent narrative in 27 patients with schizophrenia and 26 controls. Four aspects of life narratives were analyzed: coherence with cultural concept of biography, temporal coherence, causal-motivational coherence and thematic coherence. Results showed that in patients cultural biographical knowledge is preserved, whereas temporal coherence is partially impaired. Furthermore, causal-motivational and thematic coherence are significantly impaired: patients have difficulties explaining how events have modeled their identity, and integrating different events along thematic lines. Impairment of global causal-motivational and thematic coherence was significantly correlated with patients' executive dysfunction, suggesting that cognitive impairment observed in patients could affect their ability to construct a coherent narrative of their life by binding important events to their self. This study provides new understanding of the cognitive deficits underlying self-disorders in patients with schizophrenia. Our findings suggest the potential usefulness of developing new therapeutic interventions to improve autobiographical reasoning skills.

Effectiveness of a specific cueing method for improving autobiographical memory recall in patients with schizophrenia.

Autobiographical memory deficits in schizophrenia have a significant impact on patients' daily life. Our study was aimed at testing the effectiveness of a specific cueing (SC) method for improving autobiographical memory recall in patients with schizophrenia, particularly the phenomenological details of their memories. Twenty-five patients with schizophrenia and 25 comparison participants took part in the study. They recalled 6 specific autobiographical events which occurred during 3 different life periods. After each memory recall, participants were given a general cue which allowed them to add further information to their narration. The SC was then applied by means of a series of specific questions to elicit more precise memory detail. The overall memory specificity as well as the number and richness of 5 categories of memory detail (perceptual/sensory, temporal, contextual, emotional, and cognitive) were assessed before and after the SC phase. Before SC, patients' memories were less specific and less detailed. SC had a beneficial effect on patients' memory recall. The overall memory specificity of patients improved. The gain in the number and richness of memory details was comparable between patients and comparison participants. The difference between groups in terms of the number of memory details was not significant. Richness of details was still lower in patients, except for emotional and cognitive details, which were similarly rich in both groups. The cueing method reduces the autobiographical memory impairment of patients with schizophrenia and paves the way for developing specific cognitive remediation therapies to help patients in their daily life.