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Background Traumatic brain injury (TBI) can precipitate new-onset psychiatric symptoms or worsen existing psychiatric conditions. To elucidate specific mechanisms for this interaction, neuroimaging is often used to study both psychiatric conditions and TBI. This systematic review aims to synthesize the existing literature of neuroimaging findings among patients with anxiety after TBI. Methods We conducted a Preferred Reporting Items for Systematic Review and Meta-Analyses–compliant literature search via PubMed (MEDLINE), PsychINFO, EMBASE, and Scopus databases before May, 2019. We included studies that clearly defined TBI, measured syndromic anxiety as a primary outcome, and statistically analyzed the relationship between neuroimaging findings and anxiety symptoms. Results A total of 5982 articles were retrieved from the systematic search, of which 65 studied anxiety and 13 met eligibility criteria. These studies were published between 2004 and 2017, collectively analyzing 764 participants comprised of 470 patients with TBI and 294 non-TBI controls. Imaging modalities used included magnetic resonance imaging, functional magnetic resonance imaging, diffusion tensor imaging, electroencephalogram, magnetic resonance spectrometry, and magnetoencephalography. Eight of 13 studies presented at least one significant finding and together reflect a complex set of changes that lead to anxiety in the setting of TBI. The left cingulate gyrus in particular was found to be significant in 2 studies using different imaging modalities. Two studies also revealed perturbances in functional connectivity within the default mode network. Conclusions This is the first systemic review of neuroimaging changes associated with anxiety after TBI, which implicated multiple brain structures and circuits, such as the default mode network. Future research with consistent, rigorous measurements of TBI and syndromic anxiety, as well as attention to control groups, previous TBIs, and time interval between TBI and neuroimaging, are warranted. By understanding neuroimaging correlates of psychiatric symptoms, this work could inform future post-TBI screening and surveillance, preventative efforts, and early interventions to improve neuropsychiatric outcomes.

Psychiatric conditions are common and often disabling. Although great strides have been made in alleviating symptoms with pharmacotherapy and psychotherapeutic approaches, many patients continue to have severe disease burden despite the best therapies available. One of the pervasive challenges to improving treatment is that present diagnostic and therapeutic strategies lag behind our modern conceptualization of the pathophysiology of these disorders. Psychiatric symptoms manifest through activity in specific neural circuits; thus, therapies capable of modulating these circuits are attractive. The investigators reviewed recent advances that facilitate treating medically refractory psychiatric disorders with intracranial neuromodulation in a way that intervenes more directly with the underlying pathophysiology. Specifically, they reviewed the prospects for using intracranial multielectrode arrays to record brain activity with high spatiotemporal resolution and identify circuit-level electrophysiological correlates of symptoms. A causal relationship of circuit electrophysiology to symptoms could then be established by modulating the circuits to disrupt the symptoms. Personalized therapeutic neuromodulation strategies can then proceed in a rational manner with stimulation protocols informed by the underlying circuit-based pathophysiology of the most bothersome symptoms. This strategy would enhance current methods in neurotherapeutics by identifying individualized anatomical targets with symptom-specific precision, circumventing many of the limitations inherent in modern psychiatric nosology and treatment.

Background At the group level, antidepressant efficacy of rTMS targets is inversely related to their normative connectivity with subgenual anterior cingulate cortex (sgACC). Individualized connectivity may yield better targets, particularly in patients with neuropsychiatric disorders who may have aberrant connectivity. However, sgACC connectivity shows poor test-retest reliability at the individual level. Individualized resting-state network mapping (RSNM) can reliably map inter-individual variability in brain network organization. Objective To identify individualized RSNM-based rTMS targets that reliably target the sgACC connectivity profile. Methods We used RSNM to identify network-based rTMS targets in 10 healthy controls and 13 individuals with traumatic brain injury-associated depression (TBI-D). These “RSNM targets” were compared with consensus structural targets and targets based on individualized anti-correlation with a group-mean-derived sgACC region (“anti-group-mean sgACC targets”). The TBI-D cohort was randomized to receive active (n=9) or sham (n=4) rTMS to RSNM targets. Results The group-mean sgACC connectivity profile was reliably estimated by individualized correlation with default mode network (DMN) and anti-correlation with dorsal attention network (DAN). Individualized RSNM targets were then identified based on DAN anti-correlation and DMN correlation. Counterintuitively, anti-correlation with the group-mean sgACC connectivity profile was stronger and more reliable for RSNM-derived targets than for “anti-group-mean sgACC targets”. Improvement in depression after RSNM-targeted rTMS was predicted by target anti-correlation with the portions of sgACC. Active treatment led to increased connectivity within and between several relevant regions. Conclusions RSNM may enable reliable individualized rTMS targeting, although further research is needed to determine whether this personalized approach can improve clinical outcomes.

The recent advent of individualized resting-state network mapping (RSNM) has revealed substantial interindividual variability in anatomical localization of brain networks identified by using resting-state functional MRI (rsfMRI). RSNM enables personalized targeting of focal neuromodulation techniques such as repetitive transcranial magnetic stimulation (rTMS). rTMS is believed to exert antidepressant efficacy by modulating connectivity between the stimulation site, the default mode network (DMN), and the subgenual anterior cingulate cortex (sgACC). Personalized rTMS may be particularly useful after repetitive traumatic brain injury (TBI), which is associated with neurodegenerative tauopathy in medial temporal limbic structures. These degenerative changes are believed to be related to treatment-resistant neurobehavioral disturbances observed in many retired athletes.The authors describe a case in which RSNM was successfully used to target rTMS to treat these neuropsychiatric disturbances in a retired NFL defensive lineman whose symptoms were not responsive to conventional treatments. RSNM was used to identify left-right dorsolateral prefrontal rTMS targets with maximal difference between dorsal attention network and DMN correlations. These targets were spatially distinct from those identified by prior methods. Twenty sessions of left-sided excitatory and right-sided inhibitory rTMS were administered at these targets.Treatment led to improvement in Montgomery-Åsberg Depression Rating Scale (72%), cognitive testing, and headache scales scores. Compared with healthy individuals and subjects with TBI-associated depression, baseline rsfMRI revealed substantially elevated DMN connectivity with the medial temporal lobe (MTL). Serial rsfMRI scans revealed gradual improvement in MTL-DMN connectivity and stimulation site connectivity with sgACC.These results highlight the possibility of individualized neuromodulation and biomarker-based monitoring for neuropsychiatric sequelae of repetitive TBI.

Cognitive dysfunction is a pervasive and disabling aspect of schizophrenia without adequate treatments. A recognized correlate to cognitive dysfunction in schizophrenia is attenuated frontal theta oscillations. Neuromodulation to normalize these frontal rhythms represents a potential novel therapeutic strategy. Here, we evaluate whether noninvasive neuromodulation of the cerebellum in patients with schizophrenia can enhance frontal theta oscillations, with the future goal of targeting the cerebellum as a possible therapy for cognitive dysfunction in schizophrenia. We stimulated the midline cerebellum using transcranial pulsed current stimulation (tPCS), a non-invasive transcranial direct current that can be delivered in a frequency specific manner. A single 20-minute session of theta frequency stimulation was delivered in 9 patients with schizophrenia (cathode on right shoulder). Delta frequency tPCS was also delivered as a control to evaluate for frequency specific effects. EEG signals from midfrontal electrode Cz were analyzed before and after cerebellar tPCS while patients estimated the passage of 3 and 12 second intervals. Theta oscillations were significantly larger following theta frequency cerebellar tPCS in the midfrontal region, which was not seen with delta frequency stimulation. As previously reported, patients with schizophrenia showed a baseline reduction in accuracy estimating 3 and 12 second intervals relative to control subjects, which did not significantly improve following a single session theta or delta frequency cerebellar tPCS. These preliminary results suggest that single session theta frequency cerebellar tPCS may modulate task-related oscillatory activity in the frontal cortex in a frequency-specific manner. These preliminary findings warrant further investigation to evaluate whether multiple sessions delivered daily may have an impact on cognitive performance and have therapeutic implications for schizophrenia.

Repetitive transcranial magnetic stimulation (rTMS) has demonstrated antidepressant efficacy but has limited evidence in depression associated with traumatic brain injury (TBI). Here, we investigate the use of rTMS targeted with individualized resting-state network mapping (RSNM) of dorsal attention network (DAN) and default mode network (DMN) in subjects with treatment-resistant depression associated with concussive or moderate TBI. The planned sample size was 50 with first interim analysis planned at 20, but only 15 were enrolled before the study was terminated for logistical reasons. Subjects were randomized to 20 sessions of bilateral rTMS (4000 left-sided excitatory pulses, 1000 right-sided inhibitory pulses) or sham. Treatment was targeted to the dorsolateral prefrontal cluster with maximal difference between DAN and DMN correlations based on resting-state functional magnetic resonance imaging with individualized RSNM. Mean improvement in the primary outcome, Montgomery-Asberg Depression Rating Scale (MADRS), was 56% ± 14% (n = 9) with active treatment and 27% ± 25% (n = 5) with sham (Cohen's d = 1.43). One subject randomized to sham withdrew before starting treatment. There were no seizures or other significant adverse events. MADRS improvement was inversely correlated with functional connectivity between the right-sided stimulation site and the subgenual anterior cingulate cortex (sgACC; r = -0.68, 95% confidence interval 0.03-0.925). Active treatment led to increased sgACC-DMN connectivity (d = 1.55) and increased sgACC anti-correlation with the left- and right-sided stimulation sites (d = -1.26 and -0.69, respectively). This pilot study provides evidence that RSNM-targeted rTMS is feasible in TBI patients with depression. Given the dearth of existing evidence-based treatments for depression in this patient population, these preliminarily encouraging results indicate that larger controlled trials are warranted.

The anatomical connections of the subthalamic nucleus (STN) have driven hypotheses about its functional anatomy, including the hypothesis that the precise anatomical location of STN deep brain stimulation (DBS) determines the variability of motor and non-motor responses across Parkinson disease (PD) patients. We previously tested that hypothesis using a three-dimensional (3D) statistical method to interpret the acute effects of unilateral DBS at each patient’s clinically optimized DBS settings and active contact. Here we report a similar analysis from a new study in which DBS parameters were standardized and DBS locations were chosen blind to clinical response. In 74 individuals with PD and STN DBS, STN contacts were selected near the dorsal and ventral border of the STN contralateral to the more affected side of the body. Participants were tested off PD medications in each of 3 conditions (ventral STN DBS, dorsal STN DBS and DBS off) for acute effects on mood, apathy, working memory, response inhibition and motor function. Voltage, frequency, and pulse width were standardized, and participants and raters were blind to condition. In a categorical analysis, both dorsal and ventral STN DBS improved mean motor function without affecting cognitive measures. Dorsal STN DBS induced greater improvement in rigidity than ventral STN DBS, whereas ventral STN DBS was more effective for improving anxiety and mood. In the 3D analysis, contact location was significant only for bradykinesia and resting tremor, with the greatest improvement occurring with DBS in dorsal STN and zona incerta. These results provide new, direct functional evidence for the anatomically-derived model of STN using the novel 3D analysis, in which motor function is most represented in dorsal STN. However, our data suggest that functional segregation between motor and non-motor areas of the STN is limited, since locations that induced improvements in motor function and mood overlapped substantially.

Brain damage induced by focal interruption of blood flow can be differentiated in two pathophysiologically different categories: a hemodynamic type of injury, resulting in primary necrotic brain damage, and a molecular type of injury which leads to delayed or secondary brain injury [15]. Primary necrotic brain injury occurs when blood flow declines - and remains - below the threshold of energy failure. In anaesthetized laboratory animals, this threshold gradually increases from about 15% of control shortly after the onset of ischemia to about 30% after several hours of vascular occlusion [29].

The effects of post-ischemic recirculation on regional cerebral metabolism and DNA fragmentation was examined in mice subjected to 30 min, 1 h or 2 h transient middle cerebral artery occlusion (MCAO) followed by 1 h to 3 days recirculation. At the end of ischemia, the regional extent of metabolic disturbances was roughly the same, irrespective of the length of ischemia (ATP depletion: 452–54%; cerebral protein synthesis (CPS) suppression: 59–65% of ipsilateral hemisphere). During recirculation, ATP initially recovered but then secondarily declined, the severity of deterioration depending on the duration of MCAO and the recovery of CPS. Areas of residual CPS suppression and secondary ATP depletion were 11±14% and 3±5% after 30 min MCAO, 37±7% and 35±9% after lh MCAO, and 60±8% and 61±10% after 2h MCAO, respectively. Single- and double-strand DNA breaks appeared after 3 h recirculation in those areas in which CPS did not return, covering 19±17% and 19±19% of contralateral hemisphere after 30 min MCAO, 27±9% and 32±9% after 60 min of MCAO, and 58±7% and 59±19% after 2 h MCAO. These data suggest that secondary energy failure after transient MCAO is heralded by persisting inhibition of CPS and accompanied by single- and double-strand DNA fragmentations.