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ELife Jun 2024Downregulating emotional overreactions toward threats is fundamental for developing treatments for anxiety and post-traumatic disorders. The prefrontal cortex (PFC) is...
Downregulating emotional overreactions toward threats is fundamental for developing treatments for anxiety and post-traumatic disorders. The prefrontal cortex (PFC) is critical for top-down modulatory processes, and despite previous studies adopting repetitive transcranial magnetic stimulation (rTMS) over this region provided encouraging results in enhancing extinction, no studies have hitherto explored the effects of stimulating the medial anterior PFC (aPFC, encompassing the Brodmann area 10) on threat memory and generalization. Here we showed that rTMS over the aPFC applied before threat memory retrieval immediately decreases implicit reactions to learned and novel stimuli in humans. These effects enduringly persisted 1 week later in the absence of rTMS. No effects were detected on explicit recognition. Critically, rTMS over the aPFC resulted in a more pronounced reduction of defensive responses compared to rTMS targeting the dorsolateral PFC. These findings reveal a previously unexplored prefrontal region, the modulation of which can efficiently and durably inhibit implicit reactions to learned threats. This represents a significant advancement toward the long-term deactivation of exaggerated responses to threats.
Topics: Humans; Fear; Prefrontal Cortex; Transcranial Magnetic Stimulation; Male; Young Adult; Female; Adult; Extinction, Psychological
PubMed: 38913410
DOI: 10.7554/eLife.85951 -
The International Journal of... Jun 2024Transcranial direct current stimulation (tDCS) has been used with increasing frequency as a therapeutic tool to alleviate clinical symptoms of obsessive... (Review)
Review
Transcranial direct current stimulation (tDCS) has been used with increasing frequency as a therapeutic tool to alleviate clinical symptoms of obsessive compulsive-disorder (OCD). However, little is known about the effects of tDCS on neurocognitive functioning among OCD patients. The aim of this review was to provide a comprehensive overview of the literature examining the effects of tDCS on specific neurocognitive functions in OCD. A literature search following PRISMA guidelines was conducted on the following databases: PubMed, PsycINFO, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. The search yielded 4 results: one randomized, sham-controlled study (20 patients), one randomized, controlled, partial crossover trial (12 patients), one open-label study (5 patients), and one randomized, double-blind, sham-controlled, parallel-group trial (37 patients). A total of 51 patients received active tDCS with some diversity in electrode montages targeting the dorsolateral prefrontal cortex, the pre-supplementary motor area, or the orbitofrontal cortex. tDCS was associated with improved decision-making in study 1, enhanced attentional monitoring and response inhibition in study 2, improved executive and inhibitory control in study 3, and reduced attentional bias and improved response inhibition and working memory in study 4. Limitations of this review include its small sample, the absence of a sham group in half of the studies, and the heterogeneity in tDCS parameters. These preliminary results highlight the need for future testing in randomized, sham-controlled trials to examine whether and how tDCS induces relevant cognitive benefits in OCD.
PubMed: 38913323
DOI: 10.1080/00207454.2024.2371303 -
Ergonomics Jun 2024Based on multimodal measurement methods of NASA task load index (NASA-TLX), task performance, surface electromyography (sEMG), heart rate (HR), and functional...
Based on multimodal measurement methods of NASA task load index (NASA-TLX), task performance, surface electromyography (sEMG), heart rate (HR), and functional near-infrared spectroscopy (fNIRS), this study conducted experimental measurements and analyses under 16 different load levels of physical fatigue and mental fatigue combination conditions. This study observed the interaction between physical fatigue and mental fatigue at different levels, and at the subjective level, the effect of physical fatigue on mental fatigue was greater than that of mental fatigue on physical fatigue. Secondly, the results of fNIRS analysis showed that the premotor cortex is affected by physical fatigue, and the dorsolateral prefrontal cortex is affected by mental fatigue. Finally, this study constructed a fatigue classification model with an accuracy of 95.3%, which takes multimodal physiological data as input and 16 fatigue states as output. The research results will provide a basis for fatigue analysis, evaluation, and improvement in complex working situations.
PubMed: 38912844
DOI: 10.1080/00140139.2024.2364667 -
Frontiers in Aging Neuroscience 2024To explore the structural and functional changes in cognition-related brain regions in patients with chronic low back pain (CLBP) at earlier ages, and explore the impact...
OBJECTIVE
To explore the structural and functional changes in cognition-related brain regions in patients with chronic low back pain (CLBP) at earlier ages, and explore the impact of the interaction between CLBP and age on the brain.
METHODS
Seventy-six patients with CLBP were recruited and divided into "younger" age group (20-29 years, YA), "middle" age group (30-39 years, MA), and "older" age group (40-49 years, OA). All patients underwent functional magnetic resonance imaging (fMRI) as well as clinical psychological and pain-related symptoms assessments.
RESULTS
Structural analysis showed that patients in OA group had lower gray matter (GM) volumes in the orbitofrontal cortex (OFC) bilaterally and the right superior frontal gyrus (SFG) compared to YA group. The resting-state brain activity analysis showed that amplitude of low-frequency fluctuation (ALFF) values in the bilateral postcentral gyrus and left ventral medial prefrontal cortex (mPFC) were significantly different in the OA group. The functional connectivity (FC) in the right ventral dorsolateral prefrontal cortex (DLPFC) and the right insula was significantly decreased in the OA group compared to the YA and MA groups. Likewise, the FC in the left caudal parahippocampal gyrus (PHG) and left inferior parietal lobule (IPL) were significantly lower in the MA and OA groups compared to the YA group. In addition, both the structural properties and the FC values of these brain regions were significantly correlated with age.
CONCLUSION
This preliminary study concludes that CLBP affects the aging process. The synergistic effects of CLBP and aging accelerate the functional and structural decline of certain areas of the brain, which not only affects pain processing, but are also may be associated with cognitive declines.
PubMed: 38912520
DOI: 10.3389/fnagi.2024.1356507 -
The Journal of Pain Jun 2024Numerous genome-wide association studies have identified risk genes for chronic pain, yet the mechanisms by which genetic variants modify susceptibility have remained...
Numerous genome-wide association studies have identified risk genes for chronic pain, yet the mechanisms by which genetic variants modify susceptibility have remained elusive. We sought to identify key genes modulating chronic pain risk by regulating brain protein expression. We integrated brain proteomic data with the largest genome-wide dataset for multisite chronic pain (N=387,649) in a proteome-wide association study (PWAS) using discovery and confirmatory proteomic datasets (N=376 and 152) from the dorsolateral prefrontal cortex (dPFC). Leveraging summary data-based Mendelian randomization (SMR) and Bayesian colocalization analysis (COLOC), we pinpointed potential causal genes, while a transcriptome-wide association study (TWAS) integrating 452 human brain transcriptomes investigated whether cis-effects on protein abundance extended to the transcriptome. Single-cell RNA sequencing data and single-nucleus transcriptomic data revealed cell-type specific expression patterns for identified causal genes in the dPFC and dorsal root ganglia (DRG), complemented by RNA microarray analysis of expression profiles in other pain-related brain regions. Of the 22 genes cis-regulating protein abundance identified by the discovery PWAS, 18 (82%) were deemed causal by SMR or COLOC analyses, with 7 of these 18 genes (39%) replicating in the confirmatory PWAS, including GMPPB, which also associated at the transcriptome level. Several causal genes exhibited selective expression in excitatory neurons, inhibitory neurons, oligodendrocytes, and astrocytes, while most identified genes were expressed across additional pain-related brain regions. This integrative proteogenomic approach identified 18 high-confidence causal genes for chronic pain, regulated by cis-effects on brain protein levels, suggesting promising avenues for treatment research and indicating a contributory role for the DRG. PERSPECTIVE: The current post-GWAS analyses identified 18 high-confidence causal genes regulating chronic pain risk via cis-modulation of brain protein abundance, suggesting promising avenues for future chronic pain therapies. Additionally, the significant expression of these genes in the DRG indicated a potential contributory role, warranting further investigation.
PubMed: 38909833
DOI: 10.1016/j.jpain.2024.104610 -
Schizophrenia Research Jun 2024Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate...
Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30-60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40-70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR-). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR-. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR- = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11-12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR-, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response.
PubMed: 38909486
DOI: 10.1016/j.schres.2024.06.020 -
Journal of Affective Disorders Jun 2024We conducted a meta-analysis and qualitative review on the randomized controlled trials investigating the effects of transcranial direct current stimulation and... (Review)
Review
BACKGROUND
We conducted a meta-analysis and qualitative review on the randomized controlled trials investigating the effects of transcranial direct current stimulation and transcranial magnetic stimulation on fear extinction and the return of fear in non-primate animals and humans.
METHODS
The meta-analysis was conducted by searching PubMed, Web of science, PsycINFO, and Cochrane Library and extracting fear response in the active and sham groups in the randomized controlled trials. The pooled effect size was quantified by Hedges' g using a three-level meta-analytic model in R.
RESULTS
We identified 18 articles on the tDCS effect and 5 articles on the TMS effect, with 466 animal subjects and 621 human subjects. Our findings show that tDCS of the prefrontal cortex significantly inhibit fear retrieval in animal models (Hedges' g = -0.50). In human studies, TMS targeting the dorsolateral/ventromedial prefrontal cortex has an inhibiting effect on the return of fear (Hedges' g = -0.24).
LIMITATIONS
The limited number of studies and the heterogeneous designs of the selected studies made cross-study and cross-species comparison difficult.
CONCLUSIONS
Our findings shed light on the optimal non-invasive brain stimulation protocols for targeting the neural circuitry of threat extinction in humans.
PubMed: 38908557
DOI: 10.1016/j.jad.2024.06.060 -
Psychiatry Research. Neuroimaging Jun 2024Transcranial magnetic stimulation (TMS) is an FDA-approved neuromodulation treatment for major depressive disorder (MDD), thought to work by altering dysfunctional brain... (Review)
Review
Transcranial magnetic stimulation (TMS) is an FDA-approved neuromodulation treatment for major depressive disorder (MDD), thought to work by altering dysfunctional brain connectivity pathways, or by indirectly modulating the activity of subcortical brain regions. Clinical response to TMS remains highly variable, highlighting the need for baseline predictors of response and for understanding brain changes associated with response. This systematic review examined brain connectivity features, and changes in connectivity features, associated with clinical improvement following TMS in MDD. Forty-one studies met inclusion criteria, including 1097 people with MDD. Most studies delivered one of two types of TMS to left dorsolateral prefrontal cortex and measured connectivity using resting-state functional MRI. The subgenual anterior cingulate cortex was the most well-studied brain region, particularly its connectivity with the TMS target or with the "executive control network" of brain regions. There was marked heterogeneity in findings. There is a need for greater understanding of how cortical TMS modulates connectivity with, and the activity of, subcortical regions, and how these effects change within and across treatment sessions.
PubMed: 38908353
DOI: 10.1016/j.pscychresns.2024.111846 -
Cerebral Cortex (New York, N.Y. : 1991) Jun 2024Time-on-task effect is a common consequence of long-term cognitive demand work, which reflects reduced behavioral performance and increases the risk of accidents.... (Randomized Controlled Trial)
Randomized Controlled Trial
Time-on-task effect is a common consequence of long-term cognitive demand work, which reflects reduced behavioral performance and increases the risk of accidents. Neurofeedback is a neuromodulation method that can guide individuals to regulate their brain activity and manifest as changes in related symptoms and cognitive behaviors. This study aimed to examine the effects of functional near-infrared spectroscopy-based neurofeedback training on time-on-task effects and sustained cognitive performance. A randomized, single-blind, sham-controlled study was performed: 17 participants received feedback signals of their own dorsolateral prefrontal cortex activity (neurofeedback group), and 16 participants received feedback signals of dorsolateral prefrontal cortex activity from the neurofeedback group (sham-neurofeedback group). All participants received 5 neurofeedback training sessions and completed 2 sustained cognitive tasks, including a 2-back task and a psychomotor vigilance task, to evaluate behavioral performance changes following neurofeedback training. Results showed that neurofeedback relative to the sham-neurofeedback group exhibited increased dorsolateral prefrontal cortex activation, increased accuracy in the 2-back task, and decreased mean response time in the psychomotor vigilance task after neurofeedback training. In addition, the neurofeedback group showed slower decline performance during the sustained 2-back task after neurofeedback training compared with sham-neurofeedback group. These findings demonstrate that neurofeedback training could regulate time-on-task effects on difficult task and enhance performance on sustained cognitive tasks by increasing dorsolateral prefrontal cortex activity.
Topics: Humans; Neurofeedback; Spectroscopy, Near-Infrared; Male; Female; Young Adult; Single-Blind Method; Cognition; Adult; Psychomotor Performance; Dorsolateral Prefrontal Cortex; Reaction Time; Prefrontal Cortex
PubMed: 38904080
DOI: 10.1093/cercor/bhae259 -
MedRxiv : the Preprint Server For... May 2024Deep brain stimulation is a viable and efficacious treatment option for dystonia. While the internal pallidum serves as the primary target, more recently, stimulation of...
Deep brain stimulation is a viable and efficacious treatment option for dystonia. While the internal pallidum serves as the primary target, more recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its complex surroundings have not been studied in depth. Indeed, multiple historical targets that have been used for surgical treatment of dystonia are directly adjacent to the STN. Further, multiple types of dystonia exist, and outcomes are variable, suggesting that not all types would profit maximally from the exact same target. Therefore, a thorough investigation of the neural substrates underlying effects on dystonia symptoms is warranted. Here, we analyze a multi-center cohort of isolated dystonia patients with subthalamic implantations ( = 58) and relate their stimulation sites to improvement of appendicular and cervical symptoms as well as blepharospasm. Stimulation of the ventral oral posterior nucleus of thalamus and surrounding regions was associated with improvement in cervical dystonia, while stimulation of the dorsolateral STN was associated with improvement in limb dystonia and blepharospasm. This dissociation was also evident for structural connectivity, where the cerebellothalamic, corticospinal and pallidosubthalamic tracts were associated with improvement of cervical dystonia, while hyperdirect and subthalamopallidal pathways were associated with alleviation of limb dystonia and blepharospasm. Importantly, a single well-placed electrode may reach the three optimal target sites. On the level of functional networks, improvement of limb dystonia was correlated with connectivity to the corresponding somatotopic regions in primary motor cortex, while alleviation of cervical dystonia was correlated with connectivity to the recently described 'action-mode' network that involves supplementary motor and premotor cortex. Our findings suggest that different types of dystonia symptoms are modulated via distinct networks. Namely, appendicular dystonia and blepharospasm are improved with modulation of the basal ganglia, and, in particular, the subthalamic circuitry, including projections from the primary motor cortex. In contrast, cervical dystonia was more responsive when engaging the cerebello-thalamo-cortical circuit, including direct stimulation of ventral thalamic nuclei. These findings may inform DBS targeting and image-based programming strategies for patient-specific treatment of dystonia.
PubMed: 38903109
DOI: 10.1101/2024.05.24.24307896