ArticlePDF AvailableLiterature Review

Exploring Cognitive Deficits and Neuromodulation in Schizophrenia: A Narrative Review

Authors:

Abstract and Figures

Cognitive deficits are emerging as critical targets for managing schizophrenia and enhancing clinical and functional outcomes. These deficits are pervasive among individuals with schizophrenia, affecting various cognitive domains. Traditional pharmacotherapy and cognitive behavioral therapy (CBT) have limitations in effectively addressing cognitive impairments in this population. Neuromodulation techniques show promise in improving certain cognitive domains among patients with schizophrenia spectrum disorders. Understanding the mechanisms of neural circuits that underlie cognitive enhancement is essential for elucidating the pathophysiological processes of the disorder, and these insights could significantly optimize strategies for managing schizophrenia. Meanwhile, although there is an increasing body of evidence demonstrating the therapeutic effects of neuromodulation in this area, further research is still needed, particularly regarding topics such as different treatment protocols and the long-term effects of treatment.
Content may be subject to copyright.
Citation: Hung, C.-C.; Lin, K.-H.;
Chang, H.-A. Exploring Cognitive
Deficits and Neuromodulation in
Schizophrenia: A Narrative Review.
Medicina 2024,60, 2060. https://
doi.org/10.3390/medicina60122060
Academic Editors: Anna Capasso and
Keming Gao
Received: 2 October 2024
Revised: 7 December 2024
Accepted: 11 December 2024
Published: 14 December 2024
Copyright: © 2024 by the authors.
Published by MDPI on behalf of
the Lithuanian University of Health
Sciences. Licensee MDPI, Basel,
Switzerland. This article is an open
access article distributed under the
terms and conditions of the Creative
Commons Attribution (CC BY) license
(https://creativecommons.org/
licenses/by/4.0/).
Review
Exploring Cognitive Deficits and Neuromodulation in
Schizophrenia: A Narrative Review
Chien-Chen Hung 1, Ko-Huan Lin 1, 2, * and Hsin-An Chang 2, 3, *
1Department of Psychiatry, Tzu Chi General Hospital, Hualien 970, Taiwan; s0987769818@gmail.com
2Non-Invasive Neuromodulation Consortium for Mental Disorders, Society of Psychophysiology,
Taipei 114, Taiwan
3
Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan
*Correspondence: wolfensteinalice@gmail.com (K.-H.L.); chang.ha@mail.ndmctsgh.edu.tw (H.-A.C.)
Abstract: Cognitive deficits are emerging as critical targets for managing schizophrenia and en-
hancing clinical and functional outcomes. These deficits are pervasive among individuals with
schizophrenia, affecting various cognitive domains. Traditional pharmacotherapy and cognitive
behavioral therapy (CBT) have limitations in effectively addressing cognitive impairments in this pop-
ulation. Neuromodulation techniques show promise in improving certain cognitive domains among
patients with schizophrenia spectrum disorders. Understanding the mechanisms of neural circuits
that underlie cognitive enhancement is essential for elucidating the pathophysiological processes of
the disorder, and these insights could significantly optimize strategies for managing schizophrenia.
Meanwhile, although there is an increasing body of evidence demonstrating the therapeutic effects of
neuromodulation in this area, further research is still needed, particularly regarding topics such as
different treatment protocols and the long-term effects of treatment.
Keywords: cognitive impairment; neuromodulation; schizophrenia; repetitive transcranial magnetic
stimulation (rTMS); transcranial direct current stimulation (tDCS); transcranial alternating current
stimulation (tACS); deep brain stimulation (DBS); electroconvulsive therapy
1. Introduction
Schizophrenia is a severe mental disorder affecting approximately 1% of the global
population [
1
]. The symptoms of schizophrenia are diverse and debilitating. They are
generally categorized as positive symptoms, such as hallucinations and delusions, and
negative symptoms, like emotional flatness and social withdrawal. The repercussions of
schizophrenia reach far beyond the individual, profoundly influencing families, communi-
ties, and healthcare systems alike. Schizophrenia imposes a significant economic burden [
2
],
characterized by elevated healthcare expenses stemming from recurrent hospitalizations,
ongoing medication requirements, and the demand for specialized mental health services.
Though not listed in formal diagnostic criteria (DSM-V), pervasive cognitive impair-
ments are a core feature of schizophrenia. Cognitive deficits associated with schizophrenia
may manifest before the initial acute episode and persist for decades [
3
]. While some
studies suggest that cognitive impairment remains static throughout the disease trajec-
tory [
4
], others indicate a gradual deterioration in the later stages [
5
]. Even in the remission
state of positive symptoms, schizophrenic patients still struggle with persistent cognitive
deficits and associated functional impairments [
6
]. The chronic progression of cognitive
deficits in schizophrenia leads to increasing difficulty in personal care, social interactions,
and employment, further isolating individuals with the disorder. Compared to other
psychotic symptoms, cognitive impairment is more closely linked to prognosis and func-
tional outcomes [
7
,
8
] and can result in prolonged institutionalization, heightening demand
for mental health resources and contributing to a greater disease burden and increased
economic costs [9].
Medicina 2024,60, 2060. https://doi.org/10.3390/medicina60122060 https://www.mdpi.com/journal/medicina
Medicina 2024,60, 2060 2 of 15
Cognitive deficits in schizophrenia encompass a range of symptoms that may arise
from specific brain region damage or more widespread functional disruptions within brain
circuits. Traditional treatments for schizophrenia, primarily pharmacotherapy and cogni-
tive behavioral therapy, have shown limited efficacy in addressing cognitive impairments.
Consequently, neuromodulation targeting specific brain regions or circuits has been ex-
plored as a potential treatment for these symptoms. In this narrative review, we compile
the relevant literature and systematically organize it to enable readers to grasp the key
knowledge regarding cognitive impairment in schizophrenia effectively. We will begin
by discussing the different domains of cognitive deficits in schizophrenia, linking various
symptoms to specific brain regions and circuits. Subsequently, we will present existing evi-
dence on neuromodulation as a treatment approach. Although some preliminary findings
are promising, further research is necessary to substantiate these results.
2. Materials and Methods
We conducted a comprehensive literature search using PubMed to identify rele-
vant studies published between 1995 and 2024. The search utilized keywords including
schizophrenia, cognitive impairment, pharmacotherapy, specific brain circuits, specific
brain regions, and specific neuromodulations. Our focus was directed towards several
well-established brain regions and circuits that are known to be associated with cognitive
deficits in schizophrenia. We included pertinent literature while systematically removing
duplicate studies to ensure the integrity of our review. In organizing the literature, we first
cataloged the various cognitive impairment symptoms and correlated these symptoms
with specific brain regions. Subsequently, we compiled current evidence regarding neuro-
modulation approaches targeting cognitive impairments in schizophrenia, highlighting
existing treatment evidence.
3. Domains of Cognitive Impairment in Schizophrenia
Cognitive impairments in schizophrenia are multifaceted and can be categorized into
different domains, including attention, memory, executive function, social cognition, and
perceptual–motor function. The importance of recognizing impaired cognitive domains is
relevant to treatment.
3.1. Attention
Attention deficits are common in schizophrenia, with underlying factors such as
difficulties in maintaining task focus and limitations in working memory. The study of
attentional lapses and mind wandering in vigilance highlights the complexity of atten-
tion impairments in this disorder [
10
]. Brain imaging research has consistently shown
that individuals with schizophrenia exhibit distinct patterns of brain activity compared to
healthy controls during attention-related tasks. These differences are particularly evident in
areas associated with attention, such as the dorsolateral prefrontal cortex (DLPFC), insula,
anterior cingulate gyrus (ACG), amygdala, hippocampus, ventral striatum, thalamus, and
cerebellum [
11
]. Our team found that lagged phase synchronization of high-frequency
resting-state electroencephalography in the right hemispheric cuneus, superior temporal
gyrus, and transverse temporal gyrus is associated with poor focused attention in stabi-
lized schizophrenics [
12
]. This finding suggests a compensatory increase in functional
connectivity among these structures.
3.2. Memory
Memory dysfunction in schizophrenia may have shared origins for deficits in working
and episodic memory, as evidenced by prefrontal activation abnormalities [
13
]. Individuals
with schizophrenia exhibit working memory deficits characterized by decreased perfor-
mance accuracy and prolonged response times. Neuroimaging studies have shown dorsal
frontal–parietal network dysfunction may be associated with working memory impairment.
An inverted U-shaped activation of DLPFC has been linked to defected working memory
Medicina 2024,60, 2060 3 of 15
in schizophrenics [
14
]. Episodic memory is often noted as exhibiting the most significant
impact among the cognitive deficits observed in schizophrenia [
15
]. The characteristic
episodic memory impairment in schizophrenia is marked by reduced accuracy, prolonged
response times, deficient conscious recollection, failure of strategic encoding, and difficulty
processing contextual information [
16
,
17
]. Deficits in episodic memory are likely best
interpreted within the framework of a wider range of impairments in higher cognitive
functions associated with schizophrenia (Sz). These deficits are often linked to dysfunction
in the dorsolateral prefrontal cortex (DLPFC) and tend to become more apparent when
there are significant demands for organization and cognitive control [13].
3.3. Executive Function
Executive function (EF) refers to mental abilities that help establish and achieve goals
and encompasses a wide set of cognitive processes, including attention, working memory,
decision-making, and mental flexibility. Deficits of executive function are prevalent in
schizophrenia across stages, affecting tasks like conceptualization and planning [18,19].
Among various brain regions involved in executive function, including the limbic
system and frontal cortex, the prefrontal cortex plays the most important role. The DLPFC
is involved in working memory, reasoning, and thematic understanding, and the ventro-
medial prefrontal cortex (VMPFC) is involved in motivation and reward [
20
]. While the
DLPFC is regarded as the most prevalent with executive dysfunction in schizophrenia,
based on neuroimaging and neurophysiological studies [
21
], functional dysconnectiv-
ity between the prefrontal cortex and striatum, which is primarily involved in positive
symptoms in schizophrenia, is highly associated with working memory impairment in
schizophrenia [
22
]. Neuroimaging studies confirm dysfunction in the prefrontal cortex,
which correlates with impairments in various neural networks.
3.4. Social Cognition
Social cognition involves a multifaceted array of mental capacities that underpin the
perception, processing, interpretation, and response to social stimuli. Collectively, these
abilities facilitate the acquisition of appropriate social skills and adaptability. Impaired
social cognition is a key feature of schizophrenia, affecting the ability to perceive, interpret,
and respond to social interactions [
23
], significantly impacting interpersonal relationships,
employment, and independent living. Social cognition is contributed by several different
cognitive processes, including emotional recognition, intention recognition, and under-
standing of others’ perspectives and mental states. Hence, the brain regions involved in
social cognition are extensive, including the amygdala, posterior superior temporal sulcus,
temporoparietal junction, prefrontal medial region, and mirror neuron system involving
inferior frontal gyrus, precentral gyrus, inferior parietal lobule, and temporal, occipital,
and parietal visual areas [24,25].
3.5. Perceptual–Motor Function
Motor dysfunction is evident in schizophrenia [
26
]. Several mechanisms are postu-
lated to be involved in motor dysfunction, including prediction errors, motor processing,
and control [
27
]. The prediction–error hypothesis provides a framework to understand how
the brain minimizes prediction errors to make adaptive decisions [
28
]. In schizophrenia,
this theory suggests that disconnection in network connectivity can lead to the spontaneous
generation of uncompensated prediction errors, which then causes unpredictable behav-
ior [
29
]. The deficit of motor processing and control in schizophrenic patients is another
significant aspect of the disorder [
26
]. Studies have consistently shown that patients with
schizophrenia exhibit impairments in motor control, which can be attributed to abnor-
malities in various brain regions and neural systems, including the primary motor cortex,
supplementary motor area, anterior cingulate cortex, prefrontal cortex, basal ganglia, and
cerebellum [30,31].
Medicina 2024,60, 2060 4 of 15
4. Brain Circuits Involved in Cognitive Impairment in Schizophrenia
Cognitive impairment in schizophrenia is widespread, affecting various domains of
cognition. Although different domains are primarily associated with specific brain areas,
multiple brain circuits involving diverse brain structures play a crucial role in cognitive
functions. In schizophrenia, cognitive impairment is closely linked to abnormalities in
several key brain circuits. Dysconnectivity within and between specific brain regions
and networks may contribute to cognitive deficits observed in schizophrenia. A concise
visual representation of the various brain structures and networks involved in cognitive
functioning in this disorder is illustrated in Figure 1.
Medicina 2024, 60, x FOR PEER REVIEW 5 of 16
Figure 1. Diagrammatic representation of key brain regions and circuits involving cognitive
impairment in schizophrenia. DMN = default mode network; SN = salience network; CEN = central
executive network; ACC = anterior cingulate cortex; DLPFC = dorsolateral prefrontal cortex.
4.1. Prefrontal Cortex (PFC)
Key regions of the PFC include DLPFC, VMPFC, medial prefrontal cortex (mPFC),
and ACC. The PFC is essential for higher-order cognitive functions such as decision-
making, problem-solving, and working memory [32]. In individuals with schizophrenia,
there is often reduced gray maer volume in the PFC, which can aect these cognitive
functions [33]. Working memory has also been considered a fundamental element of
higher cognitive abilities [34] and functional magnetic resonance imaging study has
shown that the dorsolateral prefrontal cortex (DLPFC) is involved in the defected working
memory [35]. The VMPFC and mPFC are critical for self-referential thought and social
cognition; abnormalities in these regions can result in decits in self-awareness and
perspective-taking, thereby exacerbating social isolation [36]. The anterior cingulate
cortex (ACC) plays a crucial role in cognitive processes such as error detection, conict
monitoring, and aention regulation. Dysfunction within the ACC can lead to signicant
impairments in these cognitive functions, resulting in diculties with decision-making
and adaptive behavior [37]. This disruption in connectivity can signicantly impact
cognitive processes, including memory formation and retrieval, aentional control, and
executive functioning. Specically, alterations in PFC-hippocampal connectivity may
contribute to decits in working memory and learning, while changes in PFC-thalamic
connections can aect the regulation of sensory information and aention. These
connectivity disturbances are indicative of the broader network dysfunctions that
underlie the cognitive impairments frequently observed in individuals with
schizophrenia [38]. Dysregulation of key neurotransmier systems, particularly
dopamine and glutamate, further impairs PFC function, leading to decits in executive
functioning and cognitive control [39].
4.2. Hippocampal Circuitry
Figure 1. Diagrammatic representation of key brain regions and circuits involving cognitive im-
pairment in schizophrenia. DMN = default mode network; SN = salience network; CEN = central
executive network; ACC = anterior cingulate cortex; DLPFC = dorsolateral prefrontal cortex.
4.1. Prefrontal Cortex (PFC)
Key regions of the PFC include DLPFC, VMPFC, medial prefrontal cortex (mPFC), and
ACC. The PFC is essential for higher-order cognitive functions such as decision-making,
problem-solving, and working memory [
32
]. In individuals with schizophrenia, there
is often reduced gray matter volume in the PFC, which can affect these cognitive func-
tions [
33
]. Working memory has also been considered a fundamental element of higher
cognitive abilities [
34
] and functional magnetic resonance imaging study has shown that the
dorsolateral prefrontal cortex (DLPFC) is involved in the defected working memory [
35
].
The VMPFC and mPFC are critical for self-referential thought and social cognition; abnor-
malities in these regions can result in deficits in self-awareness and perspective-taking,
thereby exacerbating social isolation [
36
]. The anterior cingulate cortex (ACC) plays a
crucial role in cognitive processes such as error detection, conflict monitoring, and attention
regulation. Dysfunction within the ACC can lead to significant impairments in these cogni-
tive functions, resulting in difficulties with decision-making and adaptive behavior [
37
].
This disruption in connectivity can significantly impact cognitive processes, including
memory formation and retrieval, attentional control, and executive functioning. Specifi-
Medicina 2024,60, 2060 5 of 15
cally, alterations in PFC-hippocampal connectivity may contribute to deficits in working
memory and learning, while changes in PFC-thalamic connections can affect the regulation
of sensory information and attention. These connectivity disturbances are indicative of the
broader network dysfunctions that underlie the cognitive impairments frequently observed
in individuals with schizophrenia [
38
]. Dysregulation of key neurotransmitter systems,
particularly dopamine and glutamate, further impairs PFC function, leading to deficits in
executive functioning and cognitive control [39].
4.2. Hippocampal Circuitry
The hippocampus is critical for the formation and retrieval of memories, particularly
episodic and spatial memory [
40
]. Reduced volume in the hippocampus is frequently
observed in schizophrenia [
41
]. These structural abnormalities are linked to disrupted
connectivity between the hippocampus and the PFC, contributing to difficulties in memory
processes and spatial navigation [
42
]. This disruption can impair the ability to form new
memories and recall past events accurately [13].
4.3. Thalamo-Cortical Circuitry
The thalamus functions as a relay station, processing and transmitting sensory infor-
mation to the cortex and playing a role in consciousness regulation [
43
]. Schizophrenia is
associated with abnormal thalamic volume and disrupted thalamo-cortical connectivity [
44
].
These alterations affect sensory gating mechanisms, which are crucial for filtering out irrel-
evant stimuli and focusing on important sensory inputs [
45
]. As a result, individuals with
schizophrenia may experience sensory processing deficits and cognitive fragmentation,
where thoughts become disjointed and incoherent [46].
4.4. Default Mode Network (DMN)
The default mode network (DMN), which includes regions such as the medial pre-
frontal cortex, posterior cingulate cortex, precuneus, and lateral parietal cortex, is most
active during rest and is essential for self-referential thinking, mind-wandering, and in-
trospection [
47
]. In schizophrenia, DMN connectivity is often disrupted, resulting in
significant cognitive and social impairments [
48
]. This dysfunction affects tasks that re-
quire introspection, such as understanding one’s own thoughts and feelings, and theory of
mind, which involves attributing mental states to oneself and others [
49
]. Consequently,
individuals with schizophrenia struggle with social cognition, making it difficult to inter-
pret and respond appropriately to social cues [
23
]. These impairments can manifest as
inappropriate or intrusive thoughts during social interactions and contribute to difficulties
in forming and maintaining relationships. Additionally, the inability to engage in effective
self-reflection and social understanding exacerbates social withdrawal and isolation [
50
],
further impacting the quality of life for those with schizophrenia.
4.5. Salience Network (SN)
The salience network (SN), which includes the anterior frontoinsular cortex, supple-
mentary motor area, and anterior cingulate cortex, plays a crucial role in detecting and
prioritizing important stimuli, thus aiding in focusing attention on relevant environmental
cues [
51
]. In schizophrenia, dysregulated SN activity disrupts this filtering process, lead-
ing to an overwhelming influx of stimuli and causing attentional deficits and cognitive
disorganization [
52
]. Neuroimaging studies highlight the SN’s consistent connectivity
patterns essential for dynamic brain state transitions [
53
]. While dysconnectivity within SN
structures, such as the supplementary motor area, has been reported to be related to global
cognition [
54
], the modulation of the central executive network and DMN via anterior
insula has been attributed to defected attention in schizophrenia [
55
]. Brain networks,
including SN and DMN, are crucial in cognitive deficit in schizophrenia.
Medicina 2024,60, 2060 6 of 15
4.6. Central Executive Network (CEN)
The central executive network (CEN) is vital for cognitive functions, especially in the
context of schizophrenia. This network, primarily located in the dorsolateral prefrontal cor-
tex (DLPFC) and posterior parietal cortex, is essential for higher-order cognitive processes,
including working memory, attention management, and decision-making. In individuals
with schizophrenia, notable disruptions within the CEN have been identified, correlating
with the cognitive impairments frequently observed in this disorder.
Recent investigations employing resting-state functional magnetic resonance imaging
have uncovered abnormal connectivity patterns within the CEN and its interactions with
other significant brain networks, particularly the default mode network (DMN) and the
salience network (SN). Specifically, hypo-connectivity has been noted between the SN
and both the DMN and CEN, suggesting a dysfunctional interplay that may contribute to
cognitive deficits observed in schizophrenia [56].
4.7. Circuit Disruptions in Schizophrenia Animal Models
Animal models of schizophrenia have illuminated significant disruptions across sev-
eral key brain circuits, including the prefrontal cortex (PFC), hippocampus, thalamo-cortical
circuitry, default mode network (DMN), and salience network, all critical for cognitive,
emotional, and sensory functions. The PFC, essential for executive function and working
memory, exhibits reduced synaptic connectivity and dendritic spine density in models
using NMDA receptor antagonists [
57
], mimicking hypofrontality seen in schizophrenia,
while DISC1 mutant and COMT knockout models demonstrate impaired glutamatergic
signaling and altered dopamine metabolism, leading to cognitive deficits [
58
,
59
]. The
hippocampus, vital for memory and spatial navigation, shows disrupted long-term po-
tentiation (LTP) and reduced connectivity with the PFC in neonatal ventral hippocampal
lesion (NVHL) and NRG1 knockout models, paralleling schizophrenia-related memory
deficits [
60
,
61
]. Thalamo-cortical circuits, which integrate sensory information and regu-
late attention, are impaired in NMDA antagonist and maternal immune activation (MIA)
models, highlighting abnormal sensory gating and attentional processes [
62
,
63
]. DMN
dysfunction, characterized by hyperconnectivity and reduced task engagement, is observed
in prenatal stress models, linking developmental disruptions to attentional deficits [
64
].
Similarly, salience network dysfunction, critical for identifying and prioritizing stimuli, is
evident in amphetamine-induced dopaminergic hyperactivity models, reflecting impaired
anterior cingulate and insular activity [
65
]. Together, these findings underscore widespread
neural disruptions in schizophrenia and provide a foundation for developing targeted
therapeutic interventions.
5. Treatment for Cognitive Impairment
Conventional treatment for cognitive deficits in schizophrenia is a multifaceted ap-
proach that involves pharmacological interventions and behavioral therapies. Pharma-
cotherapy is the primary treatment for schizophrenia, with antipsychotic medications
being the most widely used treatment [
66
]. Although antipsychotics had been proven
to be effective for positive symptoms, they have limited beneficial efficacy on improving
cognitive ability in schizophrenia [
64
,
67
]. Some studies even pointed out that antipsychotic
agents might cause further cognitive impairment [
68
,
69
]. Atypical antipsychotics, com-
pared to first-generation antipsychotics, have been shown to bring slight improvement in
cognitive impairment in schizophrenia [
70
]. Cognitive enhancers, such as cholinesterase
inhibitors and N-Methyl-D-aspartate receptor antagonists, have been investigated for their
proven efficacy in cognitive deficit in neurodegenerative disorders [71]. However, a meta-
analysis showed only a small significant effect size of cognitive enhancers on cognitive
improvement [
72
]. On the other hand, cognitive behavioral therapy (CBT) has emerged as
a promising adjunctive treatment for cognitive deficits in schizophrenia [
73
]. CBT focuses
on improving cognitive skills through practice and learning strategies. Additionally, CBT
can help individuals with schizophrenia develop better coping mechanisms and problem-
Medicina 2024,60, 2060 7 of 15
solving strategies to manage their symptoms [
74
]. CBT has been shown to be effective on
social impairment in schizophrenia [
75
] and used as an adjuvant treatment for symptom-
related cognitive deficit in schizophrenia [
74
]. However, like psychotherapies of other
modalities, CBT is subjected to labor-intensity, limiting its use in this aspect.
6. Neuromodulation
Neuromodulation techniques show promise for improving cognitive impairment in
schizophrenia treatment. These techniques can regulate cortical excitability and neuroplas-
ticity and promote brain connectivity [
76
]. On one hand, since different cognitive processes
are controlled by unique brain areas, it is possible to enhance specific domains of cognitive
function through a precise neuromodulation technique. On the other hand, cognition is
complex and most cognitive processes are regulated by the interplay of multiple brain
structures [
77
]. A broad-range and generalized brain stimulation might be helpful in this
notion. A summary of different neuromodulations based on current evidence is listed in
Table 1.
Table 1. Summary of different neuromodulations in treating cognitive impairment in schizophrenia.
Target Region Modality Improved Cognitive Domains
rTMS DLPFC
High-frequency rTMS
iTBS
Working memory
Language function
Executive dysfunction
Social cognition
tDCS DLPFC Anadol, 1–2 mA
Working memory
Attention
Social cognition
tACS left frontoparietal areas 2 mA Working memory
Processing speed
ECT
Bitemporal
Bifrontal
Right unilateral
(Electrode placement)
General (not specified)
rTMS = repetitive transcranial magnetic stimulation; tDCS = transcranial direct current stimulation; ECT = electro-
convulsive therapy; DLPFC = dorsolateral prefrontal cortex; iTBS = intermittent theta-burst stimulation. Due to
lacking evidence of deep transcranial magnetic stimulation and deep brain stimulation, the two treatments are
not listed in this summary table.
6.1. Repetitive Transcranial Magnetic Stimulation (rTMS)
Repetitive transcranial magnetic stimulation (rTMS) employs rapidly changing mag-
netic fields to generate electrical currents in targeted brain regions. This non-invasive
technique involves placing a coil near the scalp through which an electric current passes to
create a magnetic field that penetrates the skull and induces a secondary electric current in
the brain tissue beneath the coil [
78
]. It can either excite or inhibit neural activity depending
on the frequency and intensity of the magnetic pulses [
78
]. Compared with traditional
suprathreshold brain stimulation, like electroconvulsive therapy (ECT), we can target rTMS
on specific brain regions involved in different psychopathologies. High frequency rTMS
brings about activation of the targeted brain area, and, by contrast, low frequency rTMS
induces the suppression of the targeted brain area [
79
,
80
]. The treatment effect of rTMS
is supposed to be mediated by modulation of the local brain areas and the functional
connectivity between multiple involved brain structures [81].
This therapy has been applied to different psychiatric disorders [
82
]. In the con-
text of cognitive deficit in schizophrenia, it is primarily applied to the DLPFC, a brain
region crucial for executive functions, working memory, and other cognitive processes
that are often impaired in individuals with this disorder [
83
]. High-frequency rTMS to the
DLPFC also activates brain networks contributing to cognitive enhancement effect [
84
].
High-frequency rTMS applied to the DLPFC has shown potential in alleviating cognitive
Medicina 2024,60, 2060 8 of 15
symptoms such as working memory deficits and executive dysfunction, which are com-
mon in schizophrenia and significantly impact patients’ daily functioning and quality of
life [
85
]. A meta-analysis including nine clinical trials with sham controls showed high-
frequency rTMS (left DLPFC and the total pulses < 30,000) has a significant acute effect
on working memory and a significant long-term (2 weeks to 3 months) effect on working
memory and language function in schizophrenic patients [
86
]. Intermittent theta-burst
stimulation (iTBS), a variant protocol of rTMS which simulates the long-term potentia-
tion in synaptic plasticity, showed a significant effect on social cognition when applied in
the left DLPFC of patients with schizophrenia [
87
]. While traditional TMS is limited in
effective electromagnetic field depth, approximately 2–3 cm beneath the sculp, deep TMS,
utilizing combined and specialized coils, provides deep magnetic penetration and reaches
deeper brain structures [
88
]. Hence, TMS is theoretically a powerful tool in enhancing
subcortical regions and multiple brain networks. One pilot trial without controls including
10 schizophrenic patients found high-frequency deep TMS to prefrontal cortex improves
executive function and sustained attention [
89
]. However, a subsequent double-blinded
randomized controlled trial conducted by the same team found no significant effect of
20 Hz deep TMS on cognitive improvement in schizophrenia [
90
]. Further study is needed
to verify the efficacy of deep TMS with different coils and treatment protocols. In general,
rTMS has shown to have good safety and tolerability in multiple studies targeting patients
with schizophrenia. The therapeutic potential of rTMS in cognitive deficit in schizophrenia
is increasingly recognized, offering a promising complement to traditional pharmacological
treatments [
91
]. Further research is crucial to fully comprehend the long-term benefits and
optimize treatment protocols for individuals with schizophrenia.
6.2. Transcranial Electrical Stimulation (tES)
Transcranial electrical stimulation encompasses two distinct modalities: transcranial
direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS).
The tDCS delivers a constant, low-intensity direct electric current through electrodes placed
on the scalp, which modulates neuronal excitability [
92
]. This modulation depends on
the polarity of the stimulation: anodal stimulation typically enhances cortical activity by
depolarizing neurons and making them more likely to fire, while cathodal stimulation
generally suppresses cortical activity by hyperpolarizing neurons and making them less
likely to fire [
92
]. In the context of schizophrenia, tDCS is primarily applied to the DLPFC
or other cortical areas implicated in cognitive processes [
93
]. Research has shown that tDCS
can potentially improve these cognitive functions [
94
]. For instance, anodal stimulation of
the DLPFC has been associated with enhancements in working memory and attention [
95
].
Some studies have also noted improvements in social cognition, which is critical for daily
functioning and quality of life [
96
]. Our previous randomized sham-controlled trial found
that schizophrenic patients who underwent tDCS experienced a rapid improvement in
planning abilities and cognitive insight [
97
]. While initial results are promising, more
research is needed to optimize tDCS protocols, determine the most effective stimulation
parameters, and understand the long-term effects and safety of repeated tDCS sessions [
98
].
Additionally, further studies are necessary to identify which patients are most likely to
benefit from this intervention and to elucidate the underlying mechanisms through which
tDCS exerts its effects on the brain [99].
The tACS delivers low-amplitude biphasic electric currents to the scalp, which can
modulate the activity of cortical neurons. This modulation is believed to occur through
the entrainment of brain oscillations, potentially inducing long-term synaptic plasticity
and enhancing cognitive functions and behavioral outcomes [
100
]. In our previous study,
theta-frequency tACS improved working memory capacity of schizophrenia [
101
]. In
addition, add-on theta-frequency tACS with pharmacotherapy improved working memory
and processing speed in schizophrenia [102].
Medicina 2024,60, 2060 9 of 15
6.3. Deep Brain Stimulation (DBS)
Deep brain stimulation (DBS) represents a frontier in psychiatric treatment, involving
the surgical insertion of electrodes into targeted brain regions critical to the pathophysi-
ology of schizophrenia, such as the thalamus and hippocampus [
103
]. These electrodes
deliver tailored electrical impulses, which can be adjusted for frequency and intensity,
to modulate neural circuits that are dysfunctional in schizophrenia [
104
]. Compared to
non-invasive brain stimulations such as rTMS and tDCS, DBS offers a direct stimulation
over much deeper brain structures. Targeting brain regions and networks involved in
cognitive function, this modulation has the potential to significantly enhance cognitive
capabilities, including memory, attention, and executive function [
105
]. DBS has been
tested for effectiveness on cognitive enhancement and the literature showed that DBS to
fornix slows cognitive decline in patients with Alzheimer’s disease [
106
]. DBS’s capacity
to reach deeper brain structures directly and adjust their activity makes it a particularly
promising option for patients whose severe symptoms are resistant to pharmacological
treatment [
107
]. However, there is currently a lack of evidence regarding the impact of DBS
on cognitive deficits in schizophrenia. Further studies are needed to address this issue.
6.4. Electroconvulsive Therapy (ECT)
Electroconvulsive therapy (ECT) involves inducing controlled seizures through elec-
trical currents administered to the brain [
108
]. While the precise mechanism of action
is not fully understood, it likely involves a combination of neurochemical changes, neu-
roendocrine alterations, and enhanced neuroplasticity, which collectively contribute to
its therapeutic effects [
109
]. In the context of schizophrenia, ECT is typically reserved for
severe affective symptoms or cases that are resistant to other treatments [
110
]. Rajagopalan
et al. reported cognitive improvement in patients with schizophrenia undergoing ECT.
However, it remains challenging to ascertain whether the observed cognitive enhancement
is directly attributable to the ECT treatment itself or if it is mediated by the improvement
in negative or mood symptoms [
111
]. It is promising for ECT to ameliorate cognitive
impairment linked to refractory psychotic symptoms.
6.5. Pharmacological Neuromodulation
Traditional schizophrenia treatments primarily target dopamine receptors to manage
positive symptoms like hallucinations and delusions by blocking dopamine D2 receptors
to reduce dopamine overactivity [
112
]. New treatments are investigating the roles of gluta-
mate and acetylcholine in schizophrenia-related cognitive impairments [
113
]. Glutamate,
the brain’s primary excitatory neurotransmitter, is crucial for cognitive processes, and dys-
regulation of glutamatergic neurotransmission, particularly NMDA receptor dysfunction,
contributes to cognitive deficits in schizophrenia [
114
]. In response, novel pharmaco-
logical agents are being developed to target the glutamatergic system, aiming to correct
hypoactivity in NMDA receptors [
115
]. These agents, including glycine site agonists and
NMDA receptor co-agonists like D-serine, act as positive modulators of NMDA receptor
function [
116
,
117
]. These molecules aim to improve cognitive deficits in schizophrenia by
boosting NMDA receptor activity, correcting synaptic dysfunction, promoting synaptic
plasticity, and restoring normal neural network function [118,119].
Moreover, the cholinergic system, including nicotinic and muscarinic acetylcholine
receptors, is implicated in cognitive processes apart from its impact on positive symp-
toms [
120
,
121
]. Modulating these receptors offers a promising strategy, as nicotinic recep-
tors enhance neurotransmission and synaptic plasticity, and muscarinic receptors influence
cognitive pathways [
122
,
123
]. Effective treatments must boost cholinergic activity without
causing anticholinergic effects, aiming to improve cognitive outcomes in individuals with
schizophrenia. A summary of antipsychotics, including categories, mechanisms, advan-
tages, and limitations, is presented in Table 2, offering a clear overview of pharmacological
treatment options.
Medicina 2024,60, 2060 10 of 15
Table 2. Summary of different antipsychotics in treating cognitive impairment in schizophrenia.
Mechanism Advantages Limitations
FGAs Block D2 receptors -
High EPS,
hyperprolactinemia risk,
Minimal
negative/cognitive
efficacy
SGAs
Block D2, 5-HT2A,
glutamate,
histamine receptors
Lower EPS risk
Improve negative
symptoms, mood
Risk of metabolic
syndrome Mixed
cognitive efficacy
DRPAs
Partial D2/D3 agonists
Balance dopamine
activity
Lower EPS risk
Improve negative
symptoms, mood
Limited cognitive efficacy
Akathisia
GMA NMDA receptor
co-agonist
Better for
negative/cognitive
symptoms than
traditional antipsychotics
Inconsistent efficacy
Often adjunctive
Emerging
treatments
muscarinic, GABA,
Sigma-1 receptors
Potential for cognitive
symptoms improvement
and modulating other
deficits in schizophrenia
Early-stage trials with
uncertain long-term
safety and efficacy
FGAs = first generation antipsychotics (e.g., Haloperidol, Chlorpromazine, Fluphenazine); SGAs = second
generation antipsychotics (e.g., Risperidone, Olanzapine, Quetiapine, Clozapine); DRPAs = Dopamine receptor
partial agonists (e.g., Aripiprazole, Brexpiprazole, Cariprazine); GMA = Glutamate-modulating agents; Emerging
treatments = Muscarinic receptor modulators (e.g., Xanomeline), GABAergic agents, Sigma-1 receptor agonists.
7. Conclusions
Our review underscores the critical importance of addressing cognitive deficits in
schizophrenia, which pervasively and profoundly impact patients’ functional outcomes
and quality of life. Cognitive impairments, affecting domains such as attention, memory,
executive function, social cognition, and perceptual–motor functions, are core features of
schizophrenia that remain inadequately treated by traditional antipsychotic medications.
The PFC, hippocampal circuitry, thalamo-cortical connectivity, DMN, CEN, and SN
are all implicated in the cognitive deficits observed in schizophrenia. Understanding the
intricate relationships and dysfunctions within these networks is essential for developing
targeted neuromodulation interventions. While rTMS and tES have shown promise in
enhancing working memory, attention, and social cognition, the efficacy and optimal
protocols for these treatments require further investigation. DBS, though still experimental,
and ECT, traditionally used for severe affective symptoms, also offer potential benefits for
cognitive enhancement in some cases.
Pharmacological neuromodulation, focusing on the glutamatergic and cholinergic
systems, presents additional strategies for cognitive improvement. Targeting NMDA
receptor dysfunction and enhancing cholinergic activity are promising areas of research
that could complement neuromodulation techniques and traditional pharmacotherapy.
In conclusion, the integration of neuromodulation techniques with existing treatments
represents a significant advancement in the management of cognitive deficits in schizophre-
nia. Future research should focus on optimizing these interventions, understanding their
long-term effects, and identifying patient subgroups most likely to benefit. By addressing
cognitive impairments effectively, we can improve the clinical and functional outcomes for
individuals with schizophrenia, ultimately enhancing their quality of life and reducing the
overall burden of the disorder.
Medicina 2024,60, 2060 11 of 15
Author Contributions: Conceptualization, H.-A.C., literature search and writing-original draft
preparation, C.-C.H.; visualization and writing-review and editing, K.-H.L.; supervision, K.-H.L and
H.-A.C.; funding acquisition, H.-A.C. All authors have read and agreed to the published version of
the manuscript.
Funding: This study was supported in part by grants from Advanced National Defense Technology &
Research Program, National Science and Technology Council of Taiwanese Government (NSTC-112-
2314-B-016-017-MY3). The funders had no role in the design of the study; in the collection, analyses,
or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Velligan, D.I.; Rao, S. The Epidemiology and Global Burden of Schizophrenia. J. Clin. Psychiatry 2023,84, MS21078COM5.
[CrossRef] [PubMed]
2.
Kotzeva, A.; Mittal, D.; Desai, S.; Judge, D.; Samanta, K. Socioeconomic burden of schizophrenia: A targeted literature review of
types of costs and associated drivers across 10 countries. J. Med. Econ. 2023,26, 70–83. [CrossRef] [PubMed]
3.
Simon, A.E.; Cattapan-Ludewig, K.; Zmilacher, S.; Arbach, D.; Gruber, K.; Dvorsky, D.N.; Roth, B.; Isler, E.; Zimmer, A.; Umbricht,
D. Cognitive functioning in the schizophrenia prodrome. Schizophr. Bull. 2007,33, 761–771. [CrossRef] [PubMed]
4.
Velthorst, E.; Mollon, J.; Murray, R.M.; de Haan, L.; Germeys, I.M.; Glahn, D.C.; Arango, C.; van der Ven, E.; Di Forti, M.; Bernardo,
M.; et al. Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their
unaffected siblings. Mol. Psychiatry 2021,26, 4529–4543. [CrossRef] [PubMed]
5.
McCutcheon, R.A.; Keefe, R.S.E.; McGuire, P.K. Cognitive impairment in schizophrenia: Aetiology, pathophysiology, and
treatment. Mol. Psychiatry 2023,28, 1902–1918. [CrossRef]
6.
Harvey, P.D.; Strassnig, M.T.; Silberstein, J. Prediction of disability in schizophrenia: Symptoms, cognition, and self-assessment. J.
Exp. Psychopathol. 2019,10. [CrossRef]
7.
Bowie, C.R.; Harvey, P.D. Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr. Dis. Treat. 2006,2, 531–536.
[CrossRef]
8.
Aghotor, J.; Pfueller, U.; Moritz, S.; Weisbrod, M.; Roesch-Ely, D. Metacognitive training for patients with schizophrenia (MCT):
Feasibility and preliminary evidence for its efficacy. J. Behav. Ther. Exp. Psychiatry 2010,41, 207–211. [CrossRef]
9.
Czepielewski, L.S.; Alliende, L.M.; Castaneda, C.P.; Castro, M.; Guinjoan, S.M.; Massuda, R.; Berberian, A.A.; Fonseca, A.O.;
Gadelha, A.; Bressan, R.; et al. Effects of socioeconomic status in cognition of people with schizophrenia: Results from a Latin
American collaboration network with 1175 subjects. Psychol. Med. 2022,52, 2177–2188. [CrossRef]
10.
Dutterer, J.; Bansal, S.; Robinson, B.; Gold, J.M. Sustained attention deficits in schizophrenia: Effect of memory load on the
Identical Pairs Continuous Performance Test. Schizophr. Res. Cogn. 2023,33, 100288. [CrossRef]
11.
Liddle, P.F.; Laurens, K.R.; Kiehl, K.A.; Ngan, E.T. Abnormal function of the brain system supporting motivated attention in
medicated patients with schizophrenia: An fMRI study. Psychol. Med. 2006,36, 1097–1108. [CrossRef] [PubMed]
12.
Yeh, T.C.; Huang, C.C.; Chung, Y.A.; Park, S.Y.; Im, J.J.; Lin, Y.Y.; Ma, C.-C.; Tzeng, N.-S.; Chang, H.-A. Resting-State EEG
Connectivity at High-Frequency Bands and Attentional Performance Dysfunction in Stabilized Schizophrenia Patients. Medicina
2023,59, 737. [CrossRef] [PubMed]
13.
Guo, J.Y.; Ragland, J.D.; Carter, C.S. Memory and cognition in schizophrenia. Mol. Psychiatry 2019,24, 633–642. [CrossRef]
[PubMed]
14.
Deserno, L.; Sterzer, P.; Wustenberg, T.; Heinz, A.; Schlagenhauf, F. Reduced prefrontal-parietal effective connectivity and working
memory deficits in schizophrenia. J. Neurosci. 2012,32, 12–20. [CrossRef]
15.
Heinrichs, R.W.; Zakzanis, K.K. Neurocognitive Deficit in Schizophrenia: A Quantitative Review of the Evidence. Neuropsychology
1998,12, 426–445. [CrossRef]
16.
Imamoglu, A.; Foubert, C.; Healey, M.K.; Langella, S.; Belger, A.; Giovanello, K.S.; Wahlheim, C.N. Episodic memory impairment
in children and adolescents at risk for schizophrenia: A role for context processing. Schizophr. Res. Cogn. 2022,28, 100241.
[CrossRef]
17.
Danion, J.-M.; Huron, C.; Vidailhet, P.; Berna, F. Functional Mechanisms of Episodic Memory Impairment in Schizophrenia. Can.
J. Psychiatry 2007,52, 693–701. [CrossRef]
18. Orellana, G.; Slachevsky, A. Executive functioning in schizophrenia. Front. Psychiatry 2013,4, 35. [CrossRef]
19.
Bielecki, M.; Tyburski, E.; Plichta, P.; Mak, M.; Kucharska-Mazur, J.; Podwalski, P.; Rek-Owodzi ´n, K.; Waszczuk, K.; Sagan, L.;
Mueller, S.T.; et al. Executive Functions and Psychopathology Dimensions in Deficit and Non-Deficit Schizophrenia. J. Clin. Med.
2023,12, 1998. [CrossRef]
20. Grafman, J.; Litvan, I. Importance of deficits in executive functions. Lancet 1999,354, 1921–1923. [CrossRef]
21.
Smucny, J.; Dienel, S.J.; Lewis, D.A.; Carter, C.S. Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive
dysfunction in schizophrenia. Neuropsychopharmacology 2022,47, 292–308. [CrossRef] [PubMed]
22.
Quide, Y.; Morris, R.W.; Shepherd, A.M.; Rowland, J.E.; Green, M.J. Task-related fronto-striatal functional connectivity during
working memory performance in schizophrenia. Schizophr. Res. 2013,150, 468–475. [CrossRef] [PubMed]
Medicina 2024,60, 2060 12 of 15
23.
Langdon, R.; Connors, M.H.; Connaughton, E. Social cognition and social judgment in schizophrenia. Schizophr. Res. Cogn. 2014,
1, 171–174. [CrossRef] [PubMed]
24. Rajmohan, V.; Mohandas, E. Mirror neuron system. Indian. J. Psychiatry 2007,49, 66–69. [CrossRef]
25.
García, R.R.; Aliste, F.; Soto, G. Social cognition in schizophrenia: Cognitive and neurobiological aspects. Rev. Colomb. Psiquiatr.
(Engl. Ed.) 2018,47, 170–176. [CrossRef]
26.
Abboud, R.; Noronha, C.; Diwadkar, V.A. Motor system dysfunction in the schizophrenia diathesis: Neural systems to neuro-
transmitters. Eur. Psychiatry 2017,44, 125–133. [CrossRef]
27.
Bernard, J.A.; Mittal, V.A. Cerebellar-motor dysfunction in schizophrenia and psychosis-risk: The importance of regional cerebellar
analysis approaches. Front. Psychiatry 2014,5, 160. [CrossRef]
28.
Millard, S.J.; Bearden, C.E.; Karlsgodt, K.H.; Sharpe, M.J. The prediction-error hypothesis of schizophrenia: New data point to
circuit-specific changes in dopamine activity. Neuropsychopharmacology 2022,47, 628–640. [CrossRef]
29. Yamashita, Y.; Tani, J. Spontaneous prediction error generation in schizophrenia. PLoS ONE 2012,7, e37843. [CrossRef]
30.
Halperin, L.; Falk-Kessler, J. Schizophrenia Spectrum Disorders: Linking Motor and Process Skills, Sensory Patterns, and
Psychiatric Symptoms. Open J. Occup. Ther. 2020,8, 1–13. [CrossRef]
31.
Lu, P.Y.; Huang, Y.L.; Huang, P.C.; Liu, Y.C.; Wei, S.Y.; Hsu, W.Y.; Chen, K.C.; Chen, P.S.; Wu, W.-C.; Yang, Y.K.; et al. Association
of visual motor processing and social cognition in schizophrenia. NPJ Schizophr. 2021,7, 21. [CrossRef] [PubMed]
32.
Friedman, N.P.; Robbins, T.W. The role of prefrontal cortex in cognitive control and executive function. Neuropsychopharmacology
2022,47, 72–89. [CrossRef] [PubMed]
33.
Kumra, S.; Ashtari, M.; Wu, J.; Hongwanishkul, D.; White, T.; Cervellione, K.; Cottone, J.; Szeszko, P.R. Gray matter volume
deficits are associated with motor and attentional impairments in adolescents with schizophrenia. Prog. Neuropsychopharmacol.
Biol. Psychiatry 2011,35, 939–943. [CrossRef] [PubMed]
34. Oberauer, K. Working Memory and Attention—A Conceptual Analysis and Review. J. Cogn. 2019,2, 36. [CrossRef]
35.
Blumenfeld, R.S.; Ranganath, C. Dorsolateral prefrontal cortex promotes long-term memory formation through its role in working
memory organization. J. Neurosci. 2006,26, 916–925. [CrossRef]
36.
Tripathi, A.; Kar, S.K.; Shukla, R. Cognitive Deficits in Schizophrenia: Understanding the Biological Correlates and Remediation
Strategies. Clin. Psychopharmacol. Neurosci. 2018,16, 7–17. [CrossRef]
37.
Paus, T. Primate anterior cingulate cortex: Where motor control, drive and cognition interface. Nat. Rev. Neurosci. 2001,2, 417–424.
[CrossRef]
38.
Sakurai, T.; Gamo, N.J.; Hikida, T.; Kim, S.H.; Murai, T.; Tomoda, T.; Sawa, A. Converging models of schizophrenia--Network
alterations of prefrontal cortex underlying cognitive impairments. Prog. Neurobiol. 2015,134, 178–201. [CrossRef]
39.
Huber, N.; Korhonen, S.; Hoffmann, D.; Leskela, S.; Rostalski, H.; Remes, A.M.; Honkakoski, P.; Solje, E.; Haapasalo, A. Deficient
neurotransmitter systems and synaptic function in frontotemporal lobar degeneration-Insights into disease mechanisms and
current therapeutic approaches. Mol. Psychiatry 2022,27, 1300–1309. [CrossRef]
40.
Dickerson, B.C.; Eichenbaum, H. The episodic memory system: Neurocircuitry and disorders. Neuropsychopharmacology 2010,35,
86–104. [CrossRef]
41.
Arnold, S.J.; Ivleva, E.I.; Gopal, T.A.; Reddy, A.P.; Jeon-Slaughter, H.; Sacco, C.B.; Francis, A.N.; Tandon, N.; Bidesi, A.S.; Witte,
B.; et al. Hippocampal volume is reduced in schizophrenia and schizoaffective disorder but not in psychotic bipolar I disorder
demonstrated by both manual tracing and automated parcellation (FreeSurfer). Schizophr. Bull. 2015,41, 233–249. [CrossRef]
[PubMed]
42.
Ledoux, A.A.; Boyer, P.; Phillips, J.L.; Labelle, A.; Smith, A.; Bohbot, V.D. Structural hippocampal anomalies in a schizophrenia
population correlate with navigation performance on a wayfinding task. Front. Behav. Neurosci. 2014,8, 88. [CrossRef] [PubMed]
43.
Mitchell, A.S.; Sherman, S.M.; Sommer, M.A.; Mair, R.G.; Vertes, R.P.; Chudasama, Y. Advances in understanding mechanisms of
thalamic relays in cognition and behavior. J. Neurosci. 2014,34, 15340–15346. [CrossRef] [PubMed]
44.
Zhang, Y.; Su, T.P.; Liu, B.; Zhou, Y.; Chou, K.H.; Lo, C.Y.; Hung, C.-C.; Chen, W.-L.; Jiang, T.; Lin, C.-P. Disrupted thalamo-cortical
connectivity in schizophrenia: A morphometric correlation analysis. Schizophr. Res. 2014,153, 129–135. [CrossRef] [PubMed]
45.
Uhlhaas, P.J.; Roux, F.; Singer, W. Thalamocortical synchronization and cognition: Implications for schizophrenia? Neuron 2013,
77, 997–999. [CrossRef]
46.
Javitt, D.C.; Freedman, R. Sensory processing dysfunction in the personal experience and neuronal machinery of schizophrenia.
Am. J. Psychiatry 2015,172, 17–31. [CrossRef]
47.
Xu, X.; Yuan, H.; Lei, X. Activation and Connectivity within the Default Mode Network Contribute Independently to Future-
Oriented Thought. Sci. Rep. 2016,6, 21001. [CrossRef]
48.
Hu, M.L.; Zong, X.F.; Mann, J.J.; Zheng, J.J.; Liao, Y.H.; Li, Z.C.; He, Y.; Chen, X.-G.; Tang, J.-S. A Review of the Functional and
Anatomical Default Mode Network in Schizophrenia. Neurosci. Bull. 2017,33, 73–84. [CrossRef]
49.
Nair, A.; Jolliffe, M.; Lograsso, Y.S.S.; Bearden, C.E. A Review of Default Mode Network Connectivity and Its Association With
Social Cognition in Adolescents With Autism Spectrum Disorder and Early-Onset Psychosis. Front. Psychiatry 2020,11, 614.
[CrossRef]
50.
Dimaggio, G.; Vanheule, S.; Lysaker, P.H.; Carcione, A.; Nicolo, G. Impaired self-reflection in psychiatric disorders among adults:
A proposal for the existence of a network of semi independent functions. Conscious. Cogn. 2009,18, 653–664. [CrossRef]
Medicina 2024,60, 2060 13 of 15
51.
Schimmelpfennig, J.; Topczewski, J.; Zajkowski, W.; Jankowiak-Siuda, K. The role of the salience network in cognitive and
affective deficits. Front. Hum. Neurosci. 2023,17, 1133367. [CrossRef] [PubMed]
52.
Palaniyappan, L.; Liddle, P.F. Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular
dysfunction. J. Psychiatry Neurosci. 2012,37, 17–27. [CrossRef] [PubMed]
53.
Huang, H.; Chen, C.; Rong, B.; Wan, Q.; Chen, J.; Liu, Z.; Zhou, Y.; Wang, G.; Wang, H. Resting-state functional connectivity of
salience network in schizophrenia and depression. Sci. Rep. 2022,12, 11204. [CrossRef] [PubMed]
54.
Schiwy, L.C.; Forlim, C.G.; Fischer, D.J.; Kühn, S.; Becker, M.; Gallinat, J. Aberrant functional connectivity within the salience
network is related to cognitive deficits and disorganization in psychosis. Schizophr. Res. 2022,246, 103–111. [CrossRef]
55.
Moran, L.V.; Tagamets, M.A.; Sampath, H.; O’Donnell, A.; Stein, E.A.; Kochunov, P.; Hong, L.E. Disruption of anterior insula
modulation of large-scale brain networks in schizophrenia. Biol. Psychiatry 2013,74, 467–474. [CrossRef]
56.
Ha, M.; Park, S.H.; Park, I.; Kim, T.; Lee, J.; Kim, M.; Kwon, J.S. Aberrant cortico-thalamo-cerebellar network interactions and
their association with impaired cognitive functioning in patients with schizophrenia. Schizophrenia 2023,9, 50. [CrossRef]
57.
Zhang, K.; Liao, P.; Wen, J.; Hu, Z. Synaptic plasticity in schizophrenia pathophysiology. IBRO Neurosci. Rep. 2023,14, 244–252.
[CrossRef]
58.
Bilder, R.M.; Volavka, J.; Lachman, H.M.; Grace, A.A. The catechol-O-methyltransferase polymorphism: Relations to the
tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 2004,29, 1943–1961. [CrossRef]
59.
Lipina, T.V.; Niwa, M.; Jaaro-Peled, H.; Fletcher, P.J.; Seeman, P.; Sawa, A.; Roder, J.C. Enhanced dopamine function in DISC1-
L100P mutant mice: Implications for schizophrenia. Genes. Brain Behav. 2010,9, 777–789. [CrossRef]
60.
Mei, L.; Xiong, W.C. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat. Rev. Neurosci. 2008,9,
437–452. [CrossRef]
61.
Lecourtier, L.; Antal, M.C.; Cosquer, B.; Schumacher, A.; Samama, B.; Angst, M.J.; Ferrandon, A.; Koning, E.; Cassel, J.-C.;
Nehlig, A. Intact neurobehavioral development and dramatic impairments of procedural-like memory following neonatal ventral
hippocampal lesion in rats. Neuroscience 2012,207, 110–123. [CrossRef] [PubMed]
62.
Dickerson, D.D.; Bilkey, D.K. Aberrant neural synchrony in the maternal immune activation model: Using translatable measures
to explore targeted interventions. Front. Behav. Neurosci. 2013,7, 217. [CrossRef] [PubMed]
63.
Gogos, A.; Sbisa, A.; van den Buuse, M. Disruption of NMDA receptor-mediated regulation of PPI in the maternal immune
activation model of schizophrenia is restored by 17beta-estradiol and raloxifene. Schizophr. Res. 2024,267, 432–440. [CrossRef]
64.
Missault, S.; Anckaerts, C.; Ahmadoun, S.; Blockx, I.; Barbier, M.; Bielen, K.; Shah, D.; Kumar-Singh, S.; De Vos, W.H.; Van der
Linden, A.; et al. Hypersynchronicity in the default mode-like network in a neurodevelopmental animal model with relevance
for schizophrenia. Behav. Brain Res. 2019,364, 303–316. [CrossRef]
65.
Kesby, J.P.; Eyles, D.W.; McGrath, J.J.; Scott, J.G. Dopamine, psychosis and schizophrenia: The widening gap between basic and
clinical neuroscience. Transl. Psychiatry 2018,8, 30. [CrossRef]
66.
Toto, S.; Grohmann, R.; Bleich, S.; Frieling, H.; Maier, H.B.; Greil, W.; Cordes, J.; Schmidt-Kraepelin, C.; Kasper, S.; Stübner, S.;
et al. Psychopharmacological Treatment of Schizophrenia Over Time in 30 908 Inpatients: Data From the AMSP Study. Int. J.
Neuropsychopharmacol. 2019,22, 560–573. [CrossRef]
67.
Blackman, R.K.; Dickinson, D.; Eisenberg, D.P.; Gregory, M.D.; Apud, J.A.; Berman, K.F. Antipsychotic medication-mediated
cognitive change in schizophrenia and polygenic score for cognitive ability. Schizophr. Res. Cogn. 2022,27, 100223. [CrossRef]
68.
Husa, A.P.; Moilanen, J.; Murray, G.K.; Marttila, R.; Haapea, M.; Rannikko, I.; Barnett, J.H.; Jones, P.B.; Isohanni, M.; Remes, A.M.;
et al. Lifetime antipsychotic medication and cognitive performance in schizophrenia at age 43 years in a general population birth
cohort. Psychiatry Res. 2017,247, 130–138. [CrossRef]
69.
MacKenzie, N.E.; Kowalchuk, C.; Agarwal, S.M.; Costa-Dookhan, K.A.; Caravaggio, F.; Gerretsen, P.; Chintoh, A.; Remington,
G.J.; Taylor, V.H.; Müeller, D.J.; et al. Antipsychotics, Metabolic Adverse Effects, and Cognitive Function in Schizophrenia. Front.
Psychiatry 2018,9, 622. [CrossRef]
70.
Fujimaki, K.; Takahashi, T.; Morinobu, S. Association of typical versus atypical antipsychotics with symptoms and quality of life
in schizophrenia. PLoS ONE 2012,7, e37087. [CrossRef]
71.
Recio-Barbero, M.; Segarra, R.; Zabala, A.; Gonzalez-Fraile, E.; Gonzalez-Pinto, A.; Ballesteros, J. Cognitive Enhancers in
Schizophrenia: A Systematic Review and Meta-Analysis of Alpha-7 Nicotinic Acetylcholine Receptor Agonists for Cognitive
Deficits and Negative Symptoms. Front. Psychiatry 2021,12, 631589. [CrossRef] [PubMed]
72.
Sinkeviciute, I.; Begemann, M.; Prikken, M.; Oranje, B.; Johnsen, E.; Lei, W.U.; Hugdahl, K.; Kroken, R.A.; Rau, C.; Jacobs, J.D.;
et al. Efficacy of different types of cognitive enhancers for patients with schizophrenia: A meta-analysis. NPJ Schizophr. 2018,4, 22.
[CrossRef] [PubMed]
73.
Kart, A.; Ozdel, K.; Turkcapar, M.H. Cognitive Behavioral Therapy in Treatment of Schizophrenia. Noro Psikiyatr. Ars. 2021,58,
S61–S65. [PubMed]
74.
Xu, F.; Zhang, H. The application of cognitive behavioral therapy in patients with schizophrenia: A review. Medicine 2023,102,
e34827. [CrossRef]
75.
Velligan, D.I.; Tai, S.; Roberts, D.L.; Maples-Aguilar, N.; Brown, M.; Mintz, J.; Turkington, D. A randomized controlled trial
comparing cognitive behavior therapy, cognitive adaptation training, their combination and treatment as usual in chronic
schizophrenia. Schizophr. Bull. 2015,41, 597–603. [CrossRef]
Medicina 2024,60, 2060 14 of 15
76.
Chen, R.; Huang, L.; Wang, R.; Fei, J.; Wang, H.; Wang, J. Advances in Non-Invasive Neuromodulation Techniques for Improving
Cognitive Function: A Review. Brain Sci. 2024,14, 354. [CrossRef]
77.
Salzman, C.D.; Fusi, S. Emotion, cognition, and mental state representation in amygdala and prefrontal cortex. Annu. Rev.
Neurosci. 2010,33, 173–202. [CrossRef]
78.
Siebner, H.R.; Funke, K.; Aberra, A.S.; Antal, A.; Bestmann, S.; Chen, R.; Classen, J.; Davare, M.; Di Lazzaro, V.; Fox, P.T.; et al.
Transcranial magnetic stimulation of the brain: What is stimulated?—A consensus and critical position paper. Clin. Neurophysiol.
2022,140, 59–97. [CrossRef]
79.
Pal, P.K.; Hanajima, R.; Gunraj, C.A.; Li, J.Y.; Wagle-Shukla, A.; Morgante, F.; Chen, R. Effect of low-frequency repetitive
transcranial magnetic stimulation on interhemispheric inhibition. J. Neurophysiol. 2005,94, 1668–1675. [CrossRef]
80.
Pazzaglia, C.; Vollono, C.; Testani, E.; Coraci, D.; Granata, G.; Padua, L.; Valeriani, M. Low-Frequency rTMS of the Primary
Motor Area Does Not Modify the Response of the Cerebral Cortex to Phasic Nociceptive Stimuli. Front. Neurosci. 2018,12, 878.
[CrossRef]
81.
Sun, W.; Wu, Q.; Gao, L.; Zheng, Z.; Xiang, H.; Yang, K.; Yu, B.; Yao, J. Advancements in Transcranial Magnetic Stimulation
Research and the Path to Precision. Neuropsychiatr. Dis. Treat. 2023,19, 1841–1851. [CrossRef] [PubMed]
82. Richter, K.; Kellner, S.; Licht, C. rTMS in mental health disorders. Front. Netw. Physiol. 2023,3, 943223. [CrossRef] [PubMed]
83.
Li, X.; Honda, S.; Nakajima, S.; Wada, M.; Yoshida, K.; Daskalakis, Z.J.; Mimura, M.; Noda, Y. TMS-EEG Research to Elucidate the
Pathophysiological Neural Bases in Patients with Schizophrenia: A Systematic Review. J. Pers. Med. 2021,11, 388. [CrossRef]
[PubMed]
84.
Kim, T.D.; Hong, G.; Kim, J.; Yoon, S. Cognitive Enhancement in Neurological and Psychiatric Disorders Using Transcranial
Magnetic Stimulation (TMS): A Review of Modalities, Potential Mechanisms and Future Implications. Exp. Neurobiol. 2019,28,
1–16. [CrossRef]
85.
Gan, H.; Zhu, J.; Zhuo, K.; Zhang, J.; Tang, Y.; Qian, Z.; Xiang, Q.; Li, X.; Zhu, Y.; Wang, J.; et al. High frequency repetitive
transcranial magnetic stimulation of dorsomedial prefrontal cortex for negative symptoms in patients with schizophrenia: A
double-blind, randomized controlled trial. Psychiatry Res. 2021,299, 113876. [CrossRef]
86.
Jiang, Y.; Guo, Z.; Xing, G.; He, L.; Peng, H.; Du, F.; McClure, M.A.; Mu, Q. Effects of High-Frequency Transcranial Magnetic
Stimulation for Cognitive Deficit in Schizophrenia: A Meta-Analysis. Front. Psychiatry 2019,10, 135. [CrossRef]
87.
Jin, Y.; Tong, J.; Huang, Y.; Shi, D.; Zhu, N.; Zhu, M.; Liu, M.; Liu, H.; Sun, X. Effectiveness of accelerated intermittent theta burst
stimulation for social cognition and negative symptoms among individuals with schizophrenia: A randomized controlled trial.
Psychiatry Res. 2023,320, 115033. [CrossRef]
88.
Deng, Z.D.; Lisanby, S.H.; Peterchev, A.V. Coil design considerations for deep transcranial magnetic stimulation. Clin. Neurophysiol.
2014,125, 1202–1212. [CrossRef]
89.
Levkovitz, Y.; Rabany, L.; Harel, E.V.; Zangen, A. Deep transcranial magnetic stimulation add-on for treatment of negative
symptoms and cognitive deficits of schizophrenia: A feasibility study. Int. J. Neuropsychopharmacol. 2011,14, 991–996. [CrossRef]
90.
Rabany, L.; Deutsch, L.; Levkovitz, Y. Double-blind, randomized sham controlled study of deep-TMS add-on treatment for
negative symptoms and cognitive deficits in schizophrenia. J. Psychopharmacol. 2014,28, 686–690. [CrossRef]
91.
Dougall, N.; Maayan, N.; Soares-Weiser, K.; McDermott, L.M.; McIntosh, A. Transcranial magnetic stimulation (TMS) for
schizophrenia. Cochrane Database Syst. Rev. 2015,2015, CD006081. [CrossRef] [PubMed]
92.
Thair, H.; Holloway, A.L.; Newport, R.; Smith, A.D. Transcranial Direct Current Stimulation (tDCS): A Beginner’s Guide for
Design and Implementation. Front. Neurosci. 2017,11, 641. [CrossRef] [PubMed]
93.
Mervis, J.E.; Capizzi, R.J.; Boroda, E.; MacDonald, A.W., 3rd. Transcranial Direct Current Stimulation over the Dorsolateral
Prefrontal Cortex in Schizophrenia: A Quantitative Review of Cognitive Outcomes. Front. Hum. Neurosci. 2017,11, 44. [CrossRef]
[PubMed]
94.
Sacca, V.; Maleki, N.; Wen, Y.; Hodges, S.; Kong, J. Modulation Effects of Repeated Transcranial Direct Current Stimulation at the
Dorsolateral Prefrontal Cortex: A Pulsed Continuous Arterial Spin Labeling Study. Brain Sci. 2023,13, 395. [CrossRef] [PubMed]
95.
Bogdanov, M.; Schwabe, L. Transcranial Stimulation of the Dorsolateral Prefrontal Cortex Prevents Stress-Induced Working
Memory Deficits. J. Neurosci. 2016,36, 1429–1437. [CrossRef]
96.
Clausi, S.; Lupo, M.; Funghi, G.; Mammone, A.; Leggio, M. Modulating mental state recognition by anodal tDCS over the
cerebellum. Sci. Rep. 2022,12, 22616. [CrossRef]
97.
Chang, C.C.; Kao, Y.C.; Chao, C.Y.; Chang, H.A. Enhancement of cognitive insight and higher-order neurocognitive function by
fronto-temporal transcranial direct current stimulation (tDCS) in patients with schizophrenia. Schizophr. Res. 2019,208, 430–438.
[CrossRef]
98.
Shekhawat, G.S.; Vanneste, S. Optimization of Transcranial Direct Current Stimulation of Dorsolateral Prefrontal Cortex for
Tinnitus: A Non-Linear Dose-Response Effect. Sci. Rep. 2018,8, 8311. [CrossRef]
99.
Antonenko, D.; Fromm, A.E.; Thams, F.; Grittner, U.; Meinzer, M.; Floel, A. Microstructural and functional plasticity following
repeated brain stimulation during cognitive training in older adults. Nat. Commun. 2023,14, 3184. [CrossRef]
100.
Elyamany, O.; Leicht, G.; Herrmann, C.S.; Mulert, C. Transcranial alternating current stimulation (tACS): From basic mechanisms
towards first applications in psychiatry. Eur. Arch. Psychiatry Clin. Neurosci. 2021,271, 135–156. [CrossRef]
Medicina 2024,60, 2060 15 of 15
101.
Chang, C.C.; Huang, C.C.; Chung, Y.A.; Im, J.J.; Lin, Y.Y.; Ma, C.C.; Tzeng, N.-S.; Chang, H.-A. Online Left-Hemispheric In-Phase
Frontoparietal Theta tACS for the Treatment of Negative Symptoms of Schizophrenia. J. Pers. Med. 2021,11, 1114. [CrossRef]
[PubMed]
102.
Shanbhag, V.; Sreeraj, S.V.; Bose, A.; Narayanswamy, J.; Rao, N.; Kesavan, M.; Venkatasubramanian, G. Effect of tACS on Working
Memory and Processing speed in Schizophrenia: An Open Label Study. Brain Stimul. 2019,12, 520. [CrossRef]
103.
Udupa, K.; Chen, R. The mechanisms of action of deep brain stimulation and ideas for the future development. Prog. Neurobiol.
2015,133, 27–49. [CrossRef]
104.
Corripio, I.; Roldan, A.; McKenna, P.; Sarro, S.; Alonso-Solis, A.; Salgado, L.; Álvarez, E.; Molet, J.; Pomarol-Clotet, E.; Portella, M.
Target selection for deep brain stimulation in treatment resistant schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2022,
112, 110436. [CrossRef]
105.
Sullivan, C.R.P.; Olsen, S.; Widge, A.S. Deep brain stimulation for psychiatric disorders: From focal brain targets to cognitive
networks. Neuroimage 2021,225, 117515. [CrossRef]
106.
Hescham, S.; Liu, H.; Jahanshahi, A.; Temel, Y. Deep brain stimulation and cognition: Translational aspects. Neurobiol. Learn.
Mem. 2020,174, 107283. [CrossRef]
107.
Corripio, I.; Roldan, A.; Sarro, S.; McKenna, P.J.; Alonso-Solis, A.; Rabella, M.; Díaz, A.; Puigdemont, D.; Pérez-Solà, V.; Álvarez,
E.; et al. Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial. EBioMedicine
2020,51, 102568. [CrossRef]
108.
Singh, A.; Kar, S.K. How Electroconvulsive Therapy Works?: Understanding the Neurobiological Mechanisms. Clin. Psychophar-
macol. Neurosci. 2017,15, 210–221. [CrossRef]
109.
Ousdal, O.T.; Brancati, G.E.; Kessler, U.; Erchinger, V.; Dale, A.M.; Abbott, C.; Oltedal, L. The Neurobiological Effects of
Electroconvulsive Therapy Studied Through Magnetic Resonance: What Have We Learned, and Where Do We Go? Biol.
Psychiatry 2022,91, 540–549. [CrossRef]
110.
Grover, S.; Sahoo, S.; Rabha, A.; Koirala, R. ECT in schizophrenia: A review of the evidence. Acta Neuropsychiatr. 2019,31, 115–127.
[CrossRef]
111.
Rajagopalan, A.; Lim, K.W.K.; Tan, X.W.; Martin, D.; Lee, J.; Tor, P.C. Predictors of cognitive changes in patients with schizophrenia
undergoing electroconvulsive therapy. PLoS ONE 2023,18, e0284579. [CrossRef] [PubMed]
112.
Stepnicki, P.; Kondej, M.; Kaczor, A.A. Current Concepts and Treatments of Schizophrenia. Molecules 2018,23, 2087. [CrossRef]
[PubMed]
113.
Martinez, A.L.; Brea, J.; Rico, S.; de Los Frailes, M.T.; Loza, M.I. Cognitive Deficit in Schizophrenia: From Etiology to Novel
Treatments. Int. J. Mol. Sci. 2021,22, 9905. [CrossRef]
114. Kruse, A.O.; Bustillo, J.R. Glutamatergic dysfunction in Schizophrenia. Transl. Psychiatry 2022,12, 500. [CrossRef]
115.
Zhand, N.; Attwood, D.G.; Harvey, P.D. Glutamate modulators for treatment of schizophrenia. Pers. Med. Psychiatry 2019,15–16,
1–12. [CrossRef]
116.
Goh, K.K.; Wu, T.H.; Chen, C.H.; Lu, M.L. Efficacy of N-methyl-D-aspartate receptor modulator augmentation in schizophrenia:
A meta-analysis of randomised, placebo-controlled trials. J. Psychopharmacol. 2021,35, 236–252. [CrossRef]
117.
Pei, J.C.; Luo, D.Z.; Gau, S.S.; Chang, C.Y.; Lai, W.S. Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate
NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia. Front. Psychiatry 2021,12, 742058.
[CrossRef]
118.
Hunt, D.L.; Castillo, P.E. Synaptic plasticity of NMDA receptors: Mechanisms and functional implications. Curr. Opin. Neurobiol.
2012,22, 496–508. [CrossRef]
119.
Yao, L.; Zhou, Q. Enhancing NMDA Receptor Function: Recent Progress on Allosteric Modulators. Neural Plast. 2017,2017,
2875904. [CrossRef]
120.
Tani, M.; Akashi, N.; Hori, K.; Konishi, K.; Kitajima, Y.; Tomioka, H.; Inamoto, A.; Hirata, A.; Tomita, A.; Koganemaru, T.; et al.
Anticholinergic Activity and Schizophrenia. Neurodegener. Dis. 2015,15, 168–174. [CrossRef]
121.
Jones, S.E.; Harvey, P.D. Cross-diagnostic determinants of cognitive functioning: The muscarinic cholinergic receptor as a model
system. Transl. Psychiatry 2023,13, 100. [CrossRef] [PubMed]
122.
Foster, D.J.; Bryant, Z.K.; Conn, P.J. Targeting muscarinic receptors to treat schizophrenia. Behav. Brain Res. 2021,405, 113201.
[CrossRef] [PubMed]
123.
Granger, K.T.; Sand, M.; Caswell, S.; Lizarraga-Valderrama, L.R.; Barnett, J.H.; Moran, P.M. A new era for schizophrenia drug
development—Lessons for the future. Drug Discov. Today 2023,28, 103603. [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Non-invasive neuromodulation techniques are widely utilized to study and improve cognitive function, with the aim of modulating different cognitive processes. For workers performing high-intensity mental and physical tasks, extreme fatigue may not only affect their working efficiency but may also lead to cognitive decline or cognitive impairment, which, in turn, poses a serious threat to their physical health. The use of non-invasive neuromodulation techniques has important research value for improving and enhancing cognitive function. In this paper, we review the research status, existing problems, and future prospects of transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial magnetic stimulation (TMS), and transcutaneous acupoint stimulation (TAS), which are the most studied physical methods in non-invasive neuromodulation techniques to improve and enhance cognition. The findings presented in this paper will be of great reference value for the in-depth study of non-invasive neuromodulation techniques in the field of cognition.
Article
Full-text available
Transcranial magnetic stimulation (TMS) has become increasingly popular in clinical practice in recent years, and there have been significant advances in the principles and stimulation modes of TMS. With the development of multi-mode and precise stimulation technology, it is crucial to have a comprehensive understanding of TMS. The neuroregulatory effects of TMS can vary depending on the specific mode of stimulation, highlighting the importance of exploring these effects through multimodal application. Additionally, the use of precise TMS therapy can help enhance our understanding of the neural mechanisms underlying these effects, providing us with a more comprehensive perspective. This article aims to review the mechanism of action, stimulation mode, multimodal application, and precision of TMS.
Article
Full-text available
Evidence indicating abnormal functional connectivity (FC) among the cortex, thalamus, and cerebellum in schizophrenia patients has increased. However, the role of the thalamus and cerebellum when integrated into intrinsic networks and how those integrated networks interact in schizophrenia patients are largely unknown. We generated an integrative network map by merging thalamic and cerebellar network maps, which were parcellated using a winner-take-all approach, onto a cortical network map. Using cognitive networks, the default mode network (DMN), the dorsal attention network (DAN), the salience network (SAL), and the central executive network (CEN) as regions of interest, the FC of 48 schizophrenia patients was compared with that of 57 healthy controls (HCs). The association between abnormal FC and cognitive impairment was also investigated in patients. FC was lower between the SAL-CEN, SAL-DMN, and DMN-CEN and within-CEN in schizophrenia patients than in HCs. Hypoconnectivity between the DMN-CEN was correlated with impaired cognition in schizophrenia patients. Our findings broadly suggest the plausible role of the thalamus and cerebellum in integrative intrinsic networks in patients, which may contribute to the disrupted triple network and cognitive dysmetria in schizophrenia.
Preprint
Full-text available
Transcranial magnetic stimulation (TMS) is an innovative and non-invasive technique used in the diagnosis and treatment of psychiatric and neurological disorders. Repetitive TMS (rTMS) can modulate neuronal activity, neuroplasticity and arousal of the waking and sleeping brain and, more generally, overall mental health. There have been numerous studies examining predictors of the efficacy of rTMS on clinical outcome variables in various psychiatric disorders. These predictors often encompass the stimulated brain region's location, EEG activity patterns, potential morphological and neurophysiological anomalies, and individual patient's response to treatment. Most commonly, rTMS is used in awake patients with depression, catatonia and tinnitus. Interestingly, rTMS has also shown promise in inducing slow-wave oscillations in insomnia patients, opening avenues for future research into the potential beneficial effects of these oscillations on reports of non-restorative sleep. Further, neurophysiological measures emerge as potential, disease-specific biomarkers, aiding in predicting treatment response and monitoring post-treatment changes. The study posits the convergence of neurophysiological biomarkers and individually tailored rTMS treatments as a gateway to a new era in psychiatric care. The potential of rTMS to induce slow-wave activity also surfaces as a significant contribution to personalized treatment approaches. Further investigations are called for to validate the imaging and electrophysiological biomarkers associated with rTMS. In conclusion, the potential for rTMS to significantly redefine treatment strategies through personalized approaches could enhance outcomes in neuropsychiatric disorders.
Article
Full-text available
Background: Sustained attention and vigilance impairments are well documented in people with schizophrenia (PSZ). The processes implicated in this impairment remain unclear. Here we investigated whether vigilance performance varied as a function of working memory load, and also examined the role of attentional lapsing that might arise from a loss of task set resulting in mind wandering. Method: We examined Continuous Performance Test Identical Pairs (CPT-IP) data from a cumulative sample of 247 (PSZ) and 238 healthy control (HC) participants collected over a series of studies. Results: PSZ performed more poorly that HC across conditions with signal/noise discrimination (d') decreasing with increasing working memory load across both groups However, there was a significant interaction of group and load suggesting that performance of PSZ was more negatively impacted by increasing load. We also found that PSZ has a significantly higher rate of attention lapsing than did HC. Discussion: Our results suggest that difficulties maintaining task set and working memory limitations are implicated in the impairments observed on the Identical Pairs CPT. Difficulties with task set maintenance appear to explain the majority of between-group variance, with a more subtle impact of increasing working memory load.
Article
Full-text available
The combination of repeated behavioral training with transcranial direct current stimulation (tDCS) holds promise to exert beneficial effects on brain function beyond the trained task. However, little is known about the underlying mechanisms. We performed a monocenter, single-blind randomized, placebo-controlled trial comparing cognitive training to concurrent anodal tDCS (target intervention) with cognitive training to concurrent sham tDCS (control intervention), registered at ClinicalTrial.gov (Identifier NCT03838211). The primary outcome (performance in trained task) and secondary behavioral outcomes (performance on transfer tasks) were reported elsewhere. Here, underlying mechanisms were addressed by pre-specified analyses of multimodal magnetic resonance imaging before and after a three-week executive function training with prefrontal anodal tDCS in 48 older adults. Results demonstrate that training combined with active tDCS modulated prefrontal white matter microstructure which predicted individual transfer task performance gain. Training-plus-tDCS also resulted in microstructural grey matter alterations at the stimulation site, and increased prefrontal functional connectivity. We provide insight into the mechanisms underlying neuromodulatory interventions, suggesting tDCS-induced changes in fiber organization and myelin formation, glia-related and synaptic processes in the target region, and synchronization within targeted functional networks. These findings advance the mechanistic understanding of neural tDCS effects, thereby contributing to more targeted neural network modulation in future experimental and translation tDCS applications.
Article
Full-text available
Introduction Previous studies on the effects of electroconvulsive therapy (ECT) on cognition in schizophrenia have been inconclusive. This study aimed to identify factors that may predict cognitive improvement or deterioration in patients with schizophrenia after-ECT. Materials & methods Patients with schizophrenia or schizoaffective disorder with predominantly positive psychotic symptoms, who were treated with ECT at the Institute of Mental Health (IMH), Singapore, between January 2016 and January 2018, were assessed. Montreal Cognitive Assessment (MoCA), Brief Psychiatric Rating Scale (BPRS) and Global Assessment of Function (GAF) were performed before and after ECT. Patients with clinically significant improvement, deterioration or no change in MoCA scores were compared on demographics, concurrent clinical treatment and ECT parameters. Results Of the 125 patients analysed, 57 (45.6%), 36 (28.8%) and 32 (25.6%) showed improvements, deterioration and no change in cognition respectively. Age and voluntary admission predicted MoCA deterioration. Lower pre-ECT MoCA and female sex predicted MoCA improvement. Patients showed improvements in GAF, BPRS and BPRS subscale scores on average, except for the MoCA deterioration group, who did not show statistically significant improvement in negative symptom scores. Sensitivity analysis showed that nearly half the patients (48.3%) who were initially unable to complete MoCA pre-ECT were able to complete MoCA post-ECT. Conclusions The majority of patients with schizophrenia demonstrate improved cognition with ECT. Patients with poor cognition pre-ECT are more likely to see improvement post-ECT. Advanced age may be a risk factor for cognitive deterioration. Finally, improvements in cognition may be associated with improvements in negative symptoms.
Article
Full-text available
For many patients and their treating clinicians, the pharmacological management of psychotic symptoms centres on trying to find a regime that balances efficacy and quality of life, impairing side effects associated with dopamine antagonism. Recent reports of a positive Phase III study from Karuna Therapeutics indicate that the first primarily non-dopamine-based treatment for schizophrenia may come to market soon with the potential for substantially reduced or differentiated side effects. Against a background of repeated failures, Karuna's success promises a desperately needed new treatment option for patients. It also reflects some hard-won lessons about the methodology for schizophrenia drug development. Teaser A positive Phase II study and positive media report from a Phase III study with xanomeline/trospium may herald the first truly new treatment option for schizophrenia patients in decades. This drug's journey to this point reflects some hard-won lessons about the methodology for schizophrenia drug development.
Article
The aim of this review is to explore the clinical nursing application of cognitive behavioral therapy (CBT) in patients with schizophrenia. A literature search was conducted using the CINAHL and MEDLINE databases. The database search occurred during the month of December 2022. This article comprehensively summarizes the theoretical basis of CBT in improving schizophrenia in clinical nursing, its application in managing symptoms and improving social function, as well as research progress in this field. There are still inconsistencies in the research results on CBT, but overall, psychological intervention combined with drug treatment is more effective than conventional treatment alone. If social function training can be added at the same time, it is believed that it will have better effects on clinical treatment and can maintain long-lasting effectiveness. Only in this way can patients truly understand and recognize the disease, improve treatment compliance, and ultimately achieve the goal of improving prognosis and quality of life.